---
_id: '14443'
abstract:
- lang: eng
text: "Importance Climate change, pollution, urbanization, socioeconomic inequality,
and psychosocial effects of the COVID-19 pandemic have caused massive changes
in environmental conditions that affect brain health during the life span, both
on a population level as well as on the level of the individual. How these environmental
factors influence the brain, behavior, and mental illness is not well known.\r\nObservations
\ A research strategy enabling population neuroscience to contribute to identify
brain mechanisms underlying environment-related mental illness by leveraging innovative
enrichment tools for data federation, geospatial observation, climate and pollution
measures, digital health, and novel data integration techniques is described.
This strategy can inform innovative treatments that target causal cognitive and
molecular mechanisms of mental illness related to the environment. An example
is presented of the environMENTAL Project that is leveraging federated cohort
data of over 1.5 million European citizens and patients enriched with deep phenotyping
data from large-scale behavioral neuroimaging cohorts to identify brain mechanisms
related to environmental adversity underlying symptoms of depression, anxiety,
stress, and substance misuse.\r\nConclusions and Relevance This research will
lead to the development of objective biomarkers and evidence-based interventions
that will significantly improve outcomes of environment-related mental illness."
article_processing_charge: No
article_type: review
author:
- first_name: Gunter
full_name: Schumann, Gunter
last_name: Schumann
- first_name: Ole A.
full_name: Andreassen, Ole A.
last_name: Andreassen
- first_name: Tobias
full_name: Banaschewski, Tobias
last_name: Banaschewski
- first_name: Vince D.
full_name: Calhoun, Vince D.
last_name: Calhoun
- first_name: Nicholas
full_name: Clinton, Nicholas
last_name: Clinton
- first_name: Sylvane
full_name: Desrivieres, Sylvane
last_name: Desrivieres
- first_name: Ragnhild Eek
full_name: Brandlistuen, Ragnhild Eek
last_name: Brandlistuen
- first_name: Jianfeng
full_name: Feng, Jianfeng
last_name: Feng
- first_name: Soeren
full_name: Hese, Soeren
last_name: Hese
- first_name: Esther
full_name: Hitchen, Esther
last_name: Hitchen
- first_name: Per
full_name: Hoffmann, Per
last_name: Hoffmann
- first_name: Tianye
full_name: Jia, Tianye
last_name: Jia
- first_name: Viktor
full_name: Jirsa, Viktor
last_name: Jirsa
- first_name: Andre F.
full_name: Marquand, Andre F.
last_name: Marquand
- first_name: Frauke
full_name: Nees, Frauke
last_name: Nees
- first_name: Markus M.
full_name: Nöthen, Markus M.
last_name: Nöthen
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Elli
full_name: Polemiti, Elli
last_name: Polemiti
- first_name: Markus
full_name: Ralser, Markus
last_name: Ralser
- first_name: Michael
full_name: Rapp, Michael
last_name: Rapp
- first_name: Kerstin
full_name: Schepanski, Kerstin
last_name: Schepanski
- first_name: Tamara
full_name: Schikowski, Tamara
last_name: Schikowski
- first_name: Mel
full_name: Slater, Mel
last_name: Slater
- first_name: Peter
full_name: Sommer, Peter
last_name: Sommer
- first_name: Bernd Carsten
full_name: Stahl, Bernd Carsten
last_name: Stahl
- first_name: Paul M.
full_name: Thompson, Paul M.
last_name: Thompson
- first_name: Sven
full_name: Twardziok, Sven
last_name: Twardziok
- first_name: Dennis
full_name: Van Der Meer, Dennis
last_name: Van Der Meer
- first_name: Henrik
full_name: Walter, Henrik
last_name: Walter
- first_name: Lars
full_name: Westlye, Lars
last_name: Westlye
citation:
ama: 'Schumann G, Andreassen OA, Banaschewski T, et al. Addressing global environmental
challenges to mental health using population neuroscience: A review. JAMA Psychiatry.
2023;80(10):1066-1074. doi:10.1001/jamapsychiatry.2023.2996'
apa: 'Schumann, G., Andreassen, O. A., Banaschewski, T., Calhoun, V. D., Clinton,
N., Desrivieres, S., … Westlye, L. (2023). Addressing global environmental challenges
to mental health using population neuroscience: A review. JAMA Psychiatry.
American Medical Association. https://doi.org/10.1001/jamapsychiatry.2023.2996'
chicago: 'Schumann, Gunter, Ole A. Andreassen, Tobias Banaschewski, Vince D. Calhoun,
Nicholas Clinton, Sylvane Desrivieres, Ragnhild Eek Brandlistuen, et al. “Addressing
Global Environmental Challenges to Mental Health Using Population Neuroscience:
A Review.” JAMA Psychiatry. American Medical Association, 2023. https://doi.org/10.1001/jamapsychiatry.2023.2996.'
ieee: 'G. Schumann et al., “Addressing global environmental challenges to
mental health using population neuroscience: A review,” JAMA Psychiatry,
vol. 80, no. 10. American Medical Association, pp. 1066–1074, 2023.'
ista: 'Schumann G, Andreassen OA, Banaschewski T, Calhoun VD, Clinton N, Desrivieres
S, Brandlistuen RE, Feng J, Hese S, Hitchen E, Hoffmann P, Jia T, Jirsa V, Marquand
AF, Nees F, Nöthen MM, Novarino G, Polemiti E, Ralser M, Rapp M, Schepanski K,
Schikowski T, Slater M, Sommer P, Stahl BC, Thompson PM, Twardziok S, Van Der
Meer D, Walter H, Westlye L. 2023. Addressing global environmental challenges
to mental health using population neuroscience: A review. JAMA Psychiatry. 80(10),
1066–1074.'
mla: 'Schumann, Gunter, et al. “Addressing Global Environmental Challenges to Mental
Health Using Population Neuroscience: A Review.” JAMA Psychiatry, vol.
80, no. 10, American Medical Association, 2023, pp. 1066–74, doi:10.1001/jamapsychiatry.2023.2996.'
short: G. Schumann, O.A. Andreassen, T. Banaschewski, V.D. Calhoun, N. Clinton,
S. Desrivieres, R.E. Brandlistuen, J. Feng, S. Hese, E. Hitchen, P. Hoffmann,
T. Jia, V. Jirsa, A.F. Marquand, F. Nees, M.M. Nöthen, G. Novarino, E. Polemiti,
M. Ralser, M. Rapp, K. Schepanski, T. Schikowski, M. Slater, P. Sommer, B.C. Stahl,
P.M. Thompson, S. Twardziok, D. Van Der Meer, H. Walter, L. Westlye, JAMA Psychiatry
80 (2023) 1066–1074.
date_created: 2023-10-22T22:01:14Z
date_published: 2023-10-01T00:00:00Z
date_updated: 2023-10-31T12:17:20Z
day: '01'
department:
- _id: GaNo
doi: 10.1001/jamapsychiatry.2023.2996
external_id:
pmid:
- '37610741'
intvolume: ' 80'
issue: '10'
language:
- iso: eng
month: '10'
oa_version: None
page: 1066-1074
pmid: 1
publication: JAMA Psychiatry
publication_identifier:
eissn:
- 2168-6238
publication_status: published
publisher: American Medical Association
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Addressing global environmental challenges to mental health using population
neuroscience: A review'
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 80
year: '2023'
...
---
_id: '13168'
abstract:
- lang: eng
text: Urban-living individuals are exposed to many environmental factors that may
combine and interact to influence mental health. While individual factors of an
urban environment have been investigated in isolation, no attempt has been made
to model how complex, real-life exposure to living in the city relates to brain
and mental health, and how this is moderated by genetic factors. Using the data
of 156,075 participants from the UK Biobank, we carried out sparse canonical correlation
analyses to investigate the relationships between urban environments and psychiatric
symptoms. We found an environmental profile of social deprivation, air pollution,
street network and urban land-use density that was positively correlated with
an affective symptom group (r = 0.22, Pperm < 0.001), mediated by brain volume
differences consistent with reward processing, and moderated by genes enriched
for stress response, including CRHR1, explaining 2.01% of the variance in brain
volume differences. Protective factors such as greenness and generous destination
accessibility were negatively correlated with an anxiety symptom group (r = 0.10,
Pperm < 0.001), mediated by brain regions necessary for emotion regulation and
moderated by EXD3, explaining 1.65% of the variance. The third urban environmental
profile was correlated with an emotional instability symptom group (r = 0.03,
Pperm < 0.001). Our findings suggest that different environmental profiles of
urban living may influence specific psychiatric symptom groups through distinct
neurobiological pathways.
acknowledgement: This work received support from the European Union-funded Horizon
Europe project ‘environMENTAL’ (no. 101057429 to G.S., A.M. and M.M.N.) and cofunding
by UK Research and Innovation under the UK Government’s Horizon Europe funding guarantee
(nos. 10041392 and 10038599) for study design and data analysis; the Horizon 2020-funded
European Research Council Advanced Grant ‘STRATIFY’ (no. 695313 to G.S. for study
design and data analysis); the Human Brain Project (HBP SGA3, no. 945539 to G.S.
for study design and data analysis); the National Institutes of Health (grant no.
R01DA049238 to G.S. for study design and data analysis); the German Research Foundation
(COPE; grant no. 675346 to G.S. for study design and data analysis); the National
Natural Science Foundation of China (grant no. 82001797 to J.X., grant no. 82030053
to C.Y., grant no. 82202093 to J.T. and grant no. 82150710554 to G.S. for study
design, data analysis and preparation of the manuscript); National Key Research
and Development Program of China (grant no. 2018YFC1314301 to C.Y. for study design
and data analysis); Tianjin Applied Basic Research Diversified Investment Foundation
(grant no. 21JCYBJC01360 to J.X. for study design and data analysis); Tianjin Health
Technology Project (grant no. TJWJ2021QN002 to J.X. for preparation of the manuscript);
Science & Technology Development Fund of the Tianjin Education Commission for Higher
Education (grant no. 2019KJ195 to J.X. for preparation of the manuscript); the Tianjin
Medical University ‘Clinical Talent Training 123 Climbing Plan’ to J.X. for the
preparation of the manuscript; Tianjin Key Medical Discipline (Specialty) Construction
Project (grant no. TJYXZDXK-001A to C.Y. for preparation of the manuscript); the
National Key R&D Program of China (grant no. 2022YFE0209400 to L.Y. for study design
and data analysis); the Tsinghua University Initiative Scientific Research Program
(grant no. 2021Z11GHX002 to L.Y. for study design and data analysis); the National
Key Scientific and Technological Infrastructure Project ‘Earth System Science Numerical
Simulator Facility’ (EarthLab to L.Y. for study design and data analysis); the Chinese
National High-end Foreign Expert Recruitment Plan to G.S.; and the Alexander von
Humboldt Foundation to G.S. for study design and data analysis.
article_processing_charge: No
article_type: original
author:
- first_name: Jiayuan
full_name: Xu, Jiayuan
last_name: Xu
- first_name: Nana
full_name: Liu, Nana
last_name: Liu
- first_name: Elli
full_name: Polemiti, Elli
last_name: Polemiti
- first_name: Liliana
full_name: Garcia-Mondragon, Liliana
last_name: Garcia-Mondragon
- first_name: Jie
full_name: Tang, Jie
last_name: Tang
- first_name: Xiaoxuan
full_name: Liu, Xiaoxuan
last_name: Liu
- first_name: Tristram
full_name: Lett, Tristram
last_name: Lett
- first_name: Le
full_name: Yu, Le
last_name: Yu
- first_name: Markus M.
full_name: Nöthen, Markus M.
last_name: Nöthen
- first_name: Jianfeng
full_name: Feng, Jianfeng
last_name: Feng
- first_name: Chunshui
full_name: Yu, Chunshui
last_name: Yu
- first_name: Andre
full_name: Marquand, Andre
last_name: Marquand
- first_name: Gunter
full_name: Schumann, Gunter
last_name: Schumann
- first_name: Henrik
full_name: Walter, Henrik
last_name: Walter
- first_name: Andreas
full_name: Heinz, Andreas
last_name: Heinz
- first_name: Markus
full_name: Ralser, Markus
last_name: Ralser
- first_name: Sven
full_name: Twardziok, Sven
last_name: Twardziok
- first_name: Nilakshi
full_name: Vaidya, Nilakshi
last_name: Vaidya
- first_name: Emin
full_name: Serin, Emin
last_name: Serin
- first_name: Marcel
full_name: Jentsch, Marcel
last_name: Jentsch
- first_name: Esther
full_name: Hitchen, Esther
last_name: Hitchen
- first_name: Roland
full_name: Eils, Roland
last_name: Eils
- first_name: Ulrike Helene
full_name: Taron, Ulrike Helene
last_name: Taron
- first_name: Tatjana
full_name: Schütz, Tatjana
last_name: Schütz
- first_name: Kerstin
full_name: Schepanski, Kerstin
last_name: Schepanski
- first_name: Jamie
full_name: Banks, Jamie
last_name: Banks
- first_name: Tobias
full_name: Banaschewski, Tobias
last_name: Banaschewski
- first_name: Karina
full_name: Jansone, Karina
last_name: Jansone
- first_name: Nina
full_name: Christmann, Nina
last_name: Christmann
- first_name: Andreas
full_name: Meyer-Lindenberg, Andreas
last_name: Meyer-Lindenberg
- first_name: Heike
full_name: Tost, Heike
last_name: Tost
- first_name: Nathalie
full_name: Holz, Nathalie
last_name: Holz
- first_name: Emanuel
full_name: Schwarz, Emanuel
last_name: Schwarz
- first_name: Argyris
full_name: Stringaris, Argyris
last_name: Stringaris
- first_name: Maja
full_name: Neidhart, Maja
last_name: Neidhart
- first_name: Frauke
full_name: Nees, Frauke
last_name: Nees
- first_name: Sebastian
full_name: Siehl, Sebastian
last_name: Siehl
- first_name: Ole
full_name: A. Andreassen, Ole
last_name: A. Andreassen
- first_name: Lars
full_name: T. Westlye, Lars
last_name: T. Westlye
- first_name: Dennis
full_name: Van Der Meer, Dennis
last_name: Van Der Meer
- first_name: Sara
full_name: Fernandez, Sara
last_name: Fernandez
- first_name: Rikka
full_name: Kjelkenes, Rikka
last_name: Kjelkenes
- first_name: Helga
full_name: Ask, Helga
last_name: Ask
- first_name: Michael
full_name: Rapp, Michael
last_name: Rapp
- first_name: Mira
full_name: Tschorn, Mira
last_name: Tschorn
- first_name: Sarah Jane
full_name: Böttger, Sarah Jane
last_name: Böttger
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Lena
full_name: Marr, Lena
id: 4406F586-F248-11E8-B48F-1D18A9856A87
last_name: Marr
- first_name: Mel
full_name: Slater, Mel
last_name: Slater
- first_name: Guillem Feixas
full_name: Viapiana, Guillem Feixas
last_name: Viapiana
- first_name: Francisco Eiroa
full_name: Orosa, Francisco Eiroa
last_name: Orosa
- first_name: Jaime
full_name: Gallego, Jaime
last_name: Gallego
- first_name: Alvaro
full_name: Pastor, Alvaro
last_name: Pastor
- first_name: Andreas
full_name: Forstner, Andreas
last_name: Forstner
- first_name: Per
full_name: Hoffmann, Per
last_name: Hoffmann
- first_name: Markus
full_name: M. Nöthen, Markus
last_name: M. Nöthen
- first_name: Andreas
full_name: J. Forstner, Andreas
last_name: J. Forstner
- first_name: Isabelle
full_name: Claus, Isabelle
last_name: Claus
- first_name: Abbi
full_name: Miller, Abbi
last_name: Miller
- first_name: Stefanie
full_name: Heilmann-Heimbach, Stefanie
last_name: Heilmann-Heimbach
- first_name: Peter
full_name: Sommer, Peter
last_name: Sommer
- first_name: Mona
full_name: Boye, Mona
last_name: Boye
- first_name: Johannes
full_name: Wilbertz, Johannes
last_name: Wilbertz
- first_name: Karen
full_name: Schmitt, Karen
last_name: Schmitt
- first_name: Viktor
full_name: Jirsa, Viktor
last_name: Jirsa
- first_name: Spase
full_name: Petkoski, Spase
last_name: Petkoski
- first_name: Séverine
full_name: Pitel, Séverine
last_name: Pitel
- first_name: Lisa
full_name: Otten, Lisa
last_name: Otten
- first_name: Anastasios Polykarpos
full_name: Athanasiadis, Anastasios Polykarpos
last_name: Athanasiadis
- first_name: Charlie
full_name: Pearmund, Charlie
last_name: Pearmund
- first_name: Bernhard
full_name: Spanlang, Bernhard
last_name: Spanlang
- first_name: Elena
full_name: Alvarez, Elena
last_name: Alvarez
- first_name: Mavi
full_name: Sanchez, Mavi
last_name: Sanchez
- first_name: Arantxa
full_name: Giner, Arantxa
last_name: Giner
- first_name: Sören
full_name: Hese, Sören
last_name: Hese
- first_name: Paul
full_name: Renner, Paul
last_name: Renner
- first_name: Tianye
full_name: Jia, Tianye
last_name: Jia
- first_name: Yanting
full_name: Gong, Yanting
last_name: Gong
- first_name: Yunman
full_name: Xia, Yunman
last_name: Xia
- first_name: Xiao
full_name: Chang, Xiao
last_name: Chang
- first_name: Vince
full_name: Calhoun, Vince
last_name: Calhoun
- first_name: Jingyu
full_name: Liu, Jingyu
last_name: Liu
- first_name: Paul
full_name: Thompson, Paul
last_name: Thompson
- first_name: Nicholas
full_name: Clinton, Nicholas
last_name: Clinton
- first_name: Sylvane
full_name: Desrivieres, Sylvane
last_name: Desrivieres
- first_name: Allan
full_name: H. Young, Allan
last_name: H. Young
- first_name: Bernd
full_name: Stahl, Bernd
last_name: Stahl
- first_name: George
full_name: Ogoh, George
last_name: Ogoh
citation:
ama: Xu J, Liu N, Polemiti E, et al. Effects of urban living environments on mental
health in adults. Nature Medicine. 2023;29:1456-1467. doi:10.1038/s41591-023-02365-w
apa: Xu, J., Liu, N., Polemiti, E., Garcia-Mondragon, L., Tang, J., Liu, X., … Ogoh,
G. (2023). Effects of urban living environments on mental health in adults. Nature
Medicine. Springer Nature. https://doi.org/10.1038/s41591-023-02365-w
chicago: Xu, Jiayuan, Nana Liu, Elli Polemiti, Liliana Garcia-Mondragon, Jie Tang,
Xiaoxuan Liu, Tristram Lett, et al. “Effects of Urban Living Environments on Mental
Health in Adults.” Nature Medicine. Springer Nature, 2023. https://doi.org/10.1038/s41591-023-02365-w.
ieee: J. Xu et al., “Effects of urban living environments on mental health
in adults,” Nature Medicine, vol. 29. Springer Nature, pp. 1456–1467, 2023.
ista: Xu J, Liu N, Polemiti E, Garcia-Mondragon L, Tang J, Liu X, Lett T, Yu L,
Nöthen MM, Feng J, Yu C, Marquand A, Schumann G, Walter H, Heinz A, Ralser M,
Twardziok S, Vaidya N, Serin E, Jentsch M, Hitchen E, Eils R, Taron UH, Schütz
T, Schepanski K, Banks J, Banaschewski T, Jansone K, Christmann N, Meyer-Lindenberg
A, Tost H, Holz N, Schwarz E, Stringaris A, Neidhart M, Nees F, Siehl S, A. Andreassen
O, T. Westlye L, Van Der Meer D, Fernandez S, Kjelkenes R, Ask H, Rapp M, Tschorn
M, Böttger SJ, Novarino G, Marr L, Slater M, Viapiana GF, Orosa FE, Gallego J,
Pastor A, Forstner A, Hoffmann P, M. Nöthen M, J. Forstner A, Claus I, Miller
A, Heilmann-Heimbach S, Sommer P, Boye M, Wilbertz J, Schmitt K, Jirsa V, Petkoski
S, Pitel S, Otten L, Athanasiadis AP, Pearmund C, Spanlang B, Alvarez E, Sanchez
M, Giner A, Hese S, Renner P, Jia T, Gong Y, Xia Y, Chang X, Calhoun V, Liu J,
Thompson P, Clinton N, Desrivieres S, H. Young A, Stahl B, Ogoh G. 2023. Effects
of urban living environments on mental health in adults. Nature Medicine. 29,
1456–1467.
mla: Xu, Jiayuan, et al. “Effects of Urban Living Environments on Mental Health
in Adults.” Nature Medicine, vol. 29, Springer Nature, 2023, pp. 1456–67,
doi:10.1038/s41591-023-02365-w.
short: J. Xu, N. Liu, E. Polemiti, L. Garcia-Mondragon, J. Tang, X. Liu, T. Lett,
L. Yu, M.M. Nöthen, J. Feng, C. Yu, A. Marquand, G. Schumann, H. Walter, A. Heinz,
M. Ralser, S. Twardziok, N. Vaidya, E. Serin, M. Jentsch, E. Hitchen, R. Eils,
U.H. Taron, T. Schütz, K. Schepanski, J. Banks, T. Banaschewski, K. Jansone, N.
Christmann, A. Meyer-Lindenberg, H. Tost, N. Holz, E. Schwarz, A. Stringaris,
M. Neidhart, F. Nees, S. Siehl, O. A. Andreassen, L. T. Westlye, D. Van Der Meer,
S. Fernandez, R. Kjelkenes, H. Ask, M. Rapp, M. Tschorn, S.J. Böttger, G. Novarino,
L. Marr, M. Slater, G.F. Viapiana, F.E. Orosa, J. Gallego, A. Pastor, A. Forstner,
P. Hoffmann, M. M. Nöthen, A. J. Forstner, I. Claus, A. Miller, S. Heilmann-Heimbach,
P. Sommer, M. Boye, J. Wilbertz, K. Schmitt, V. Jirsa, S. Petkoski, S. Pitel,
L. Otten, A.P. Athanasiadis, C. Pearmund, B. Spanlang, E. Alvarez, M. Sanchez,
A. Giner, S. Hese, P. Renner, T. Jia, Y. Gong, Y. Xia, X. Chang, V. Calhoun, J.
Liu, P. Thompson, N. Clinton, S. Desrivieres, A. H. Young, B. Stahl, G. Ogoh,
Nature Medicine 29 (2023) 1456–1467.
date_created: 2023-06-25T22:00:46Z
date_published: 2023-06-15T00:00:00Z
date_updated: 2023-12-13T11:25:55Z
day: '15'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.1038/s41591-023-02365-w
external_id:
isi:
- '001013172700001'
file:
- access_level: open_access
checksum: bcd3225b2731c3442fa98987fd3bd46d
content_type: application/pdf
creator: dernst
date_created: 2023-06-26T10:15:44Z
date_updated: 2023-06-26T10:15:44Z
file_id: '13171'
file_name: 2023_NatureMedicine_Xu.pdf
file_size: 7365360
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language:
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month: '06'
oa: 1
oa_version: Published Version
page: 1456-1467
publication: Nature Medicine
publication_identifier:
eissn:
- 1546-170X
issn:
- 1078-8956
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Effects of urban living environments on mental health in adults
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 29
year: '2023'
...
---
_id: '14455'
acknowledgement: The author(s) declare that financial support was received for the
research, authorship, and/or publication of this article. This work has been partially
supported by Italian Ministry of Health Grant RC2023 (and the 5 × 1,000 voluntary
contributions). The authors thank the children and their families with whom they
work daily.
article_number: '1287879'
article_processing_charge: Yes
article_type: letter_note
author:
- first_name: Antonio
full_name: Narzisi, Antonio
last_name: Narzisi
- first_name: Alycia
full_name: Halladay, Alycia
last_name: Halladay
- first_name: Gabriele
full_name: Masi, Gabriele
last_name: Masi
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Catherine
full_name: Lord, Catherine
last_name: Lord
citation:
ama: 'Narzisi A, Halladay A, Masi G, Novarino G, Lord C. Tempering expectations:
Considerations on the current state of stem cells therapy for autism treatment.
Frontiers in Psychiatry. 2023;14. doi:10.3389/fpsyt.2023.1287879'
apa: 'Narzisi, A., Halladay, A., Masi, G., Novarino, G., & Lord, C. (2023).
Tempering expectations: Considerations on the current state of stem cells therapy
for autism treatment. Frontiers in Psychiatry. Frontiers. https://doi.org/10.3389/fpsyt.2023.1287879'
chicago: 'Narzisi, Antonio, Alycia Halladay, Gabriele Masi, Gaia Novarino, and Catherine
Lord. “Tempering Expectations: Considerations on the Current State of Stem Cells
Therapy for Autism Treatment.” Frontiers in Psychiatry. Frontiers, 2023.
https://doi.org/10.3389/fpsyt.2023.1287879.'
ieee: 'A. Narzisi, A. Halladay, G. Masi, G. Novarino, and C. Lord, “Tempering expectations:
Considerations on the current state of stem cells therapy for autism treatment,”
Frontiers in Psychiatry, vol. 14. Frontiers, 2023.'
ista: 'Narzisi A, Halladay A, Masi G, Novarino G, Lord C. 2023. Tempering expectations:
Considerations on the current state of stem cells therapy for autism treatment.
Frontiers in Psychiatry. 14, 1287879.'
mla: 'Narzisi, Antonio, et al. “Tempering Expectations: Considerations on the Current
State of Stem Cells Therapy for Autism Treatment.” Frontiers in Psychiatry,
vol. 14, 1287879, Frontiers, 2023, doi:10.3389/fpsyt.2023.1287879.'
short: A. Narzisi, A. Halladay, G. Masi, G. Novarino, C. Lord, Frontiers in Psychiatry
14 (2023).
date_created: 2023-10-29T23:01:16Z
date_published: 2023-10-03T00:00:00Z
date_updated: 2023-12-13T13:06:07Z
day: '03'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.3389/fpsyt.2023.1287879
external_id:
isi:
- '001084841700001'
pmid:
- '37854442'
file:
- access_level: open_access
checksum: 0a76373e9a4c0fc199f80380de257e86
content_type: application/pdf
creator: dernst
date_created: 2023-10-30T12:48:40Z
date_updated: 2023-10-30T12:48:40Z
file_id: '14468'
file_name: 2023_FrontiersPsychiatry_Narzisi.pdf
file_size: 147878
relation: main_file
success: 1
file_date_updated: 2023-10-30T12:48:40Z
has_accepted_license: '1'
intvolume: ' 14'
isi: 1
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
pmid: 1
publication: Frontiers in Psychiatry
publication_identifier:
eissn:
- 1664-0640
publication_status: published
publisher: Frontiers
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Tempering expectations: Considerations on the current state of stem cells
therapy for autism treatment'
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 14
year: '2023'
...
---
_id: '13267'
abstract:
- lang: eng
text: Three-dimensional (3D) reconstruction of living brain tissue down to an individual
synapse level would create opportunities for decoding the dynamics and structure–function
relationships of the brain’s complex and dense information processing network;
however, this has been hindered by insufficient 3D resolution, inadequate signal-to-noise
ratio and prohibitive light burden in optical imaging, whereas electron microscopy
is inherently static. Here we solved these challenges by developing an integrated
optical/machine-learning technology, LIONESS (live information-optimized nanoscopy
enabling saturated segmentation). This leverages optical modifications to stimulated
emission depletion microscopy in comprehensively, extracellularly labeled tissue
and previous information on sample structure via machine learning to simultaneously
achieve isotropic super-resolution, high signal-to-noise ratio and compatibility
with living tissue. This allows dense deep-learning-based instance segmentation
and 3D reconstruction at a synapse level, incorporating molecular, activity and
morphodynamic information. LIONESS opens up avenues for studying the dynamic functional
(nano-)architecture of living brain tissue.
acknowledged_ssus:
- _id: ScienComp
- _id: Bio
- _id: PreCl
- _id: E-Lib
- _id: LifeSc
- _id: M-Shop
acknowledgement: "We thank J. Vorlaufer, N. Agudelo and A. Wartak for microscope maintenance
and troubleshooting, C. Kreuzinger and A. Freeman for technical assistance, M. Šuplata
for hardware control support and M. Cunha dos Santos for initial exploration of
software. We\r\nthank P. Henderson for advice on deep-learning training and M. Sixt,
S. Boyd and T. Weiss for discussions and critical reading of the manuscript. L.
Lavis (Janelia Research Campus) generously provided the JF585-HaloTag ligand. We
acknowledge expert support by IST\r\nAustria’s scientific computing, imaging and
optics, preclinical, library and laboratory support facilities and by the Miba machine
shop. We gratefully acknowledge funding by the following sources: Austrian Science
Fund (F.W.F.) grant no. I3600-B27 (J.G.D.), grant no. DK W1232\r\n(J.G.D. and J.M.M.)
and grant no. Z 312-B27, Wittgenstein award (P.J.); the Gesellschaft für Forschungsförderung
NÖ grant no. LSC18-022 (J.G.D.); an ISTA Interdisciplinary project grant (J.G.D.
and B.B.); the European Union’s Horizon 2020 research and innovation programme,\r\nMarie-Skłodowska
Curie grant 665385 (J.M.M. and J.L.); the European Union’s Horizon 2020 research
and innovation programme, European Research Council grant no. 715767, MATERIALIZABLE
(B.B.); grant no. 715508, REVERSEAUTISM (G.N.); grant no. 695568, SYNNOVATE (S.G.N.G.);
and grant no. 692692, GIANTSYN (P.J.); the Simons\r\nFoundation Autism Research
Initiative grant no. 529085 (S.G.N.G.); the Wellcome Trust Technology Development
grant no. 202932 (S.G.N.G.); the Marie Skłodowska-Curie Actions Individual Fellowship
no. 101026635 under the EU Horizon 2020 program (J.F.W.);\r\nthe Human Frontier
Science Program postdoctoral fellowship LT000557/2018 (W.J.); and the National Science
Foundation grant no. IIS-1835231 (H.P.) and NCS-FO-2124179 (H.P.)."
article_processing_charge: Yes
article_type: original
author:
- first_name: Philipp
full_name: Velicky, Philipp
id: 39BDC62C-F248-11E8-B48F-1D18A9856A87
last_name: Velicky
orcid: 0000-0002-2340-7431
- first_name: Eder
full_name: Miguel Villalba, Eder
id: 3FB91342-F248-11E8-B48F-1D18A9856A87
last_name: Miguel Villalba
orcid: 0000-0001-5665-0430
- first_name: Julia M
full_name: Michalska, Julia M
id: 443DB6DE-F248-11E8-B48F-1D18A9856A87
last_name: Michalska
orcid: 0000-0003-3862-1235
- first_name: Julia
full_name: Lyudchik, Julia
id: 46E28B80-F248-11E8-B48F-1D18A9856A87
last_name: Lyudchik
- first_name: Donglai
full_name: Wei, Donglai
last_name: Wei
- first_name: Zudi
full_name: Lin, Zudi
last_name: Lin
- first_name: Jake
full_name: Watson, Jake
id: 63836096-4690-11EA-BD4E-32803DDC885E
last_name: Watson
orcid: 0000-0002-8698-3823
- first_name: Jakob
full_name: Troidl, Jakob
last_name: Troidl
- first_name: Johanna
full_name: Beyer, Johanna
last_name: Beyer
- first_name: Yoav
full_name: Ben Simon, Yoav
id: 43DF3136-F248-11E8-B48F-1D18A9856A87
last_name: Ben Simon
- first_name: Christoph M
full_name: Sommer, Christoph M
id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
last_name: Sommer
orcid: 0000-0003-1216-9105
- first_name: Wiebke
full_name: Jahr, Wiebke
id: 425C1CE8-F248-11E8-B48F-1D18A9856A87
last_name: Jahr
- first_name: Alban
full_name: Cenameri, Alban
id: 9ac8f577-2357-11eb-997a-e566c5550886
last_name: Cenameri
- first_name: Johannes
full_name: Broichhagen, Johannes
last_name: Broichhagen
- first_name: Seth G.N.
full_name: Grant, Seth G.N.
last_name: Grant
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Hanspeter
full_name: Pfister, Hanspeter
last_name: Pfister
- first_name: Bernd
full_name: Bickel, Bernd
id: 49876194-F248-11E8-B48F-1D18A9856A87
last_name: Bickel
orcid: 0000-0001-6511-9385
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
citation:
ama: Velicky P, Miguel Villalba E, Michalska JM, et al. Dense 4D nanoscale reconstruction
of living brain tissue. Nature Methods. 2023;20:1256-1265. doi:10.1038/s41592-023-01936-6
apa: Velicky, P., Miguel Villalba, E., Michalska, J. M., Lyudchik, J., Wei, D.,
Lin, Z., … Danzl, J. G. (2023). Dense 4D nanoscale reconstruction of living brain
tissue. Nature Methods. Springer Nature. https://doi.org/10.1038/s41592-023-01936-6
chicago: Velicky, Philipp, Eder Miguel Villalba, Julia M Michalska, Julia Lyudchik,
Donglai Wei, Zudi Lin, Jake Watson, et al. “Dense 4D Nanoscale Reconstruction
of Living Brain Tissue.” Nature Methods. Springer Nature, 2023. https://doi.org/10.1038/s41592-023-01936-6.
ieee: P. Velicky et al., “Dense 4D nanoscale reconstruction of living brain
tissue,” Nature Methods, vol. 20. Springer Nature, pp. 1256–1265, 2023.
ista: Velicky P, Miguel Villalba E, Michalska JM, Lyudchik J, Wei D, Lin Z, Watson
J, Troidl J, Beyer J, Ben Simon Y, Sommer CM, Jahr W, Cenameri A, Broichhagen
J, Grant SGN, Jonas PM, Novarino G, Pfister H, Bickel B, Danzl JG. 2023. Dense
4D nanoscale reconstruction of living brain tissue. Nature Methods. 20, 1256–1265.
mla: Velicky, Philipp, et al. “Dense 4D Nanoscale Reconstruction of Living Brain
Tissue.” Nature Methods, vol. 20, Springer Nature, 2023, pp. 1256–65, doi:10.1038/s41592-023-01936-6.
short: P. Velicky, E. Miguel Villalba, J.M. Michalska, J. Lyudchik, D. Wei, Z. Lin,
J. Watson, J. Troidl, J. Beyer, Y. Ben Simon, C.M. Sommer, W. Jahr, A. Cenameri,
J. Broichhagen, S.G.N. Grant, P.M. Jonas, G. Novarino, H. Pfister, B. Bickel,
J.G. Danzl, Nature Methods 20 (2023) 1256–1265.
date_created: 2023-07-23T22:01:13Z
date_published: 2023-08-01T00:00:00Z
date_updated: 2024-01-10T08:37:48Z
day: '01'
department:
- _id: PeJo
- _id: GaNo
- _id: BeBi
- _id: JoDa
- _id: Bio
doi: 10.1038/s41592-023-01936-6
ec_funded: 1
external_id:
isi:
- '001025621500001'
pmid:
- '37429995'
intvolume: ' 20'
isi: 1
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1038/s41592-023-01936-6
month: '08'
oa: 1
oa_version: Published Version
page: 1256-1265
pmid: 1
project:
- _id: 265CB4D0-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: I03600
name: Optical control of synaptic function via adhesion molecules
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
- _id: 25C5A090-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: Z00312
name: The Wittgenstein Prize
- _id: 23889792-32DE-11EA-91FC-C7463DDC885E
name: High content imaging to decode human immune cell interactions in health and
allergic disease
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '665385'
name: International IST Doctoral Program
- _id: 24F9549A-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715767'
name: 'MATERIALIZABLE: Intelligent fabrication-oriented Computational Design and
Modeling'
- _id: 25444568-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715508'
name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
and in vitro Models
- _id: 25B7EB9E-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '692692'
name: Biophysics and circuit function of a giant cortical glumatergic synapse
- _id: fc2be41b-9c52-11eb-aca3-faa90aa144e9
call_identifier: H2020
grant_number: '101026635'
name: Synaptic computations of the hippocampal CA3 circuitry
- _id: 2668BFA0-B435-11E9-9278-68D0E5697425
grant_number: LT00057
name: High-speed 3D-nanoscopy to study the role of adhesion during 3D cell migration
publication: Nature Methods
publication_identifier:
eissn:
- 1548-7105
issn:
- 1548-7091
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
link:
- relation: software
url: https://github.com/danzllab/LIONESS
record:
- id: '12817'
relation: research_data
status: public
- id: '14770'
relation: shorter_version
status: public
scopus_import: '1'
status: public
title: Dense 4D nanoscale reconstruction of living brain tissue
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 20
year: '2023'
...
---
_id: '12802'
abstract:
- lang: eng
text: Little is known about the critical metabolic changes that neural cells have
to undergo during development and how temporary shifts in this program can influence
brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5,
a transporter of metabolically essential large neutral amino acids (LNAAs), lead
to autism, we employed metabolomic profiling to study the metabolic states of
the cerebral cortex across different developmental stages. We found that the forebrain
undergoes significant metabolic remodeling throughout development, with certain
groups of metabolites showing stage-specific changes, but what are the consequences
of perturbing this metabolic program? By manipulating Slc7a5 expression in neural
cells, we found that the metabolism of LNAAs and lipids are interconnected in
the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state,
leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific
alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.
acknowledged_ssus:
- _id: PreCl
- _id: EM-Fac
- _id: Bio
- _id: LifeSc
acknowledgement: We thank A. Freeman and V. Voronin for technical assistance, S. Deixler,
A. Stichelberger, M. Schunn, and the Preclinical Facility for managing our animal
colony. We thank L. Andersen and J. Sonntag, who were involved in generating the
MADM lines. We thank the ISTA LSF Mass Spectrometry Core Facility for assistance
with the proteomic analysis, as well as the ISTA electron microscopy and Imaging
and Optics facility for technical support. Metabolomics LC-MS/MS analysis was performed
by the Metabolomics Facility at Vienna BioCenter Core Facilities (VBCF). We acknowledge
the support of the EMBL Metabolomics Core Facility (MCF) for lipidomics and intracellular
metabolomics mass spectrometry data acquisition and analysis. RNA sequencing was
performed by the Next Generation Sequencing Facility at VBCF. Schematics were generated
using Biorender.com. This work was supported by the Austrian Science Fund (FWF,
DK W1232-B24) and by the European Union’s Horizon 2020 research and innovation program
(ERC) grant 725780 (LinPro) to S.H. and 715508 (REVERSEAUTISM) to G.N.
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Bernadette
full_name: Basilico, Bernadette
id: 36035796-5ACA-11E9-A75E-7AF2E5697425
last_name: Basilico
orcid: 0000-0003-1843-3173
- first_name: Daniel
full_name: Malzl, Daniel
last_name: Malzl
- first_name: Maria
full_name: Gerykova Bujalkova, Maria
last_name: Gerykova Bujalkova
- first_name: Mateja
full_name: Smogavec, Mateja
last_name: Smogavec
- first_name: Lena A.
full_name: Schwarz, Lena A.
last_name: Schwarz
- first_name: Sarah
full_name: Gorkiewicz, Sarah
id: f141a35d-15a9-11ec-9fb2-fef6becc7b6f
last_name: Gorkiewicz
- first_name: Nicole
full_name: Amberg, Nicole
id: 4CD6AAC6-F248-11E8-B48F-1D18A9856A87
last_name: Amberg
orcid: 0000-0002-3183-8207
- first_name: Florian
full_name: Pauler, Florian
id: 48EA0138-F248-11E8-B48F-1D18A9856A87
last_name: Pauler
orcid: 0000-0002-7462-0048
- first_name: Christian
full_name: Knittl-Frank, Christian
last_name: Knittl-Frank
- first_name: Marianna
full_name: Tassinari, Marianna
id: 7af593f1-d44a-11ed-bf94-a3646a6bb35e
last_name: Tassinari
- first_name: Nuno
full_name: Maulide, Nuno
last_name: Maulide
- first_name: Thomas
full_name: Rülicke, Thomas
last_name: Rülicke
- first_name: Jörg
full_name: Menche, Jörg
last_name: Menche
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Knaus L, Basilico B, Malzl D, et al. Large neutral amino acid levels tune perinatal
neuronal excitability and survival. Cell. 2023;186(9):1950-1967.e25. doi:10.1016/j.cell.2023.02.037
apa: Knaus, L., Basilico, B., Malzl, D., Gerykova Bujalkova, M., Smogavec, M., Schwarz,
L. A., … Novarino, G. (2023). Large neutral amino acid levels tune perinatal neuronal
excitability and survival. Cell. Elsevier. https://doi.org/10.1016/j.cell.2023.02.037
chicago: Knaus, Lisa, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova,
Mateja Smogavec, Lena A. Schwarz, Sarah Gorkiewicz, et al. “Large Neutral Amino
Acid Levels Tune Perinatal Neuronal Excitability and Survival.” Cell. Elsevier,
2023. https://doi.org/10.1016/j.cell.2023.02.037.
ieee: L. Knaus et al., “Large neutral amino acid levels tune perinatal neuronal
excitability and survival,” Cell, vol. 186, no. 9. Elsevier, p. 1950–1967.e25,
2023.
ista: Knaus L, Basilico B, Malzl D, Gerykova Bujalkova M, Smogavec M, Schwarz LA,
Gorkiewicz S, Amberg N, Pauler F, Knittl-Frank C, Tassinari M, Maulide N, Rülicke
T, Menche J, Hippenmeyer S, Novarino G. 2023. Large neutral amino acid levels
tune perinatal neuronal excitability and survival. Cell. 186(9), 1950–1967.e25.
mla: Knaus, Lisa, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal
Excitability and Survival.” Cell, vol. 186, no. 9, Elsevier, 2023, p. 1950–1967.e25,
doi:10.1016/j.cell.2023.02.037.
short: L. Knaus, B. Basilico, D. Malzl, M. Gerykova Bujalkova, M. Smogavec, L.A.
Schwarz, S. Gorkiewicz, N. Amberg, F. Pauler, C. Knittl-Frank, M. Tassinari, N.
Maulide, T. Rülicke, J. Menche, S. Hippenmeyer, G. Novarino, Cell 186 (2023) 1950–1967.e25.
date_created: 2023-04-05T08:15:40Z
date_published: 2023-04-27T00:00:00Z
date_updated: 2024-02-07T08:03:32Z
day: '27'
ddc:
- '570'
department:
- _id: SiHi
- _id: GaNo
doi: 10.1016/j.cell.2023.02.037
ec_funded: 1
external_id:
isi:
- '000991468700001'
file:
- access_level: open_access
checksum: 47e94fbe19e86505b429cb7a5b503ce6
content_type: application/pdf
creator: dernst
date_created: 2023-05-02T09:26:21Z
date_updated: 2023-05-02T09:26:21Z
file_id: '12889'
file_name: 2023_Cell_Knaus.pdf
file_size: 15712841
relation: main_file
success: 1
file_date_updated: 2023-05-02T09:26:21Z
has_accepted_license: '1'
intvolume: ' 186'
isi: 1
issue: '9'
keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
page: 1950-1967.e25
project:
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
- _id: 260018B0-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '725780'
name: Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development
- _id: 25444568-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715508'
name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
and in vitro Models
publication: Cell
publication_identifier:
issn:
- 0092-8674
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
link:
- description: News on ISTA Website
relation: press_release
url: https://ista.ac.at/en/news/feed-them-or-lose-them/
record:
- id: '13107'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: Large neutral amino acid levels tune perinatal neuronal excitability and survival
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 186
year: '2023'
...
---
_id: '14257'
abstract:
- lang: eng
text: Mapping the complex and dense arrangement of cells and their connectivity
in brain tissue demands nanoscale spatial resolution imaging. Super-resolution
optical microscopy excels at visualizing specific molecules and individual cells
but fails to provide tissue context. Here we developed Comprehensive Analysis
of Tissues across Scales (CATS), a technology to densely map brain tissue architecture
from millimeter regional to nanometer synaptic scales in diverse chemically fixed
brain preparations, including rodent and human. CATS uses fixation-compatible
extracellular labeling and optical imaging, including stimulated emission depletion
or expansion microscopy, to comprehensively delineate cellular structures. It
enables three-dimensional reconstruction of single synapses and mapping of synaptic
connectivity by identification and analysis of putative synaptic cleft regions.
Applying CATS to the mouse hippocampal mossy fiber circuitry, we reconstructed
and quantified the synaptic input and output structure of identified neurons.
We furthermore demonstrate applicability to clinically derived human tissue samples,
including formalin-fixed paraffin-embedded routine diagnostic specimens, for visualizing
the cellular architecture of brain tissue in health and disease.
acknowledged_ssus:
- _id: ScienComp
- _id: Bio
- _id: PreCl
- _id: LifeSc
- _id: M-Shop
- _id: E-Lib
acknowledgement: 'We thank J. Vorlaufer, N. Agudelo-Dueñas, W. Jahr and A. Wartak
for microscope maintenance and troubleshooting; C. Kreuzinger, A. Freeman and I.
Erber for technical assistance; and M. Tomschik for support with obtaining human
samples. We gratefully acknowledge E. Miguel for setting up webKnossos and M. Šuplata
for computational support and hardware control. We are grateful to R. Shigemoto
and B. Bickel for generous support and M. Sixt and S. Boyd (Stanford University)
for discussions and critical reading of the paper. PSD95-HaloTag mice were kindly
provided by S. Grant (University of Edinburgh). We acknowledge expert support by
Institute of Science and Technology Austria’s scientific computing, imaging and
optics, preclinical and lab support facilities and by the Miba machine shop and
library. We gratefully acknowledge funding by the following sources: Austrian Science
Fund (FWF) grant I3600-B27 (J.G.D.); Austrian Science Fund (FWF) grant DK W1232
(J.G.D. and J.M.M.); Austrian Science Fund (FWF) grant Z 312-B27, Wittgenstein award
(P.J.); Austrian Science Fund (FWF) projects I4685-B, I6565-B (SYNABS) and DOC 33-B27
(R.H.); Gesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022 (J.G.D.);
European Union’s Horizon 2020 research and innovation programme, European Research
Council (ERC) grant 715508 – REVERSEAUTISM (G.N.); European Union’s Horizon 2020
research and innovation programme, European Research Council (ERC) grant 692692
– GIANTSYN (P.J.); Marie Skłodowska-Curie Actions Fellowship GA no. 665385 under
the EU Horizon 2020 program (J.M.M. and J.L.); and Marie Skłodowska-Curie Actions
Individual Fellowship no. 101026635 under the EU Horizon 2020 program (J.F.W.).'
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Julia M
full_name: Michalska, Julia M
id: 443DB6DE-F248-11E8-B48F-1D18A9856A87
last_name: Michalska
orcid: 0000-0003-3862-1235
- first_name: Julia
full_name: Lyudchik, Julia
id: 46E28B80-F248-11E8-B48F-1D18A9856A87
last_name: Lyudchik
- first_name: Philipp
full_name: Velicky, Philipp
id: 39BDC62C-F248-11E8-B48F-1D18A9856A87
last_name: Velicky
orcid: 0000-0002-2340-7431
- first_name: Hana
full_name: Korinkova, Hana
id: ee3cb6ca-ec98-11ea-ae11-ff703e2254ed
last_name: Korinkova
- first_name: Jake
full_name: Watson, Jake
id: 63836096-4690-11EA-BD4E-32803DDC885E
last_name: Watson
orcid: 0000-0002-8698-3823
- first_name: Alban
full_name: Cenameri, Alban
id: 9ac8f577-2357-11eb-997a-e566c5550886
last_name: Cenameri
- first_name: Christoph M
full_name: Sommer, Christoph M
id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
last_name: Sommer
orcid: 0000-0003-1216-9105
- first_name: Nicole
full_name: Amberg, Nicole
id: 4CD6AAC6-F248-11E8-B48F-1D18A9856A87
last_name: Amberg
orcid: 0000-0002-3183-8207
- first_name: Alessandro
full_name: Venturino, Alessandro
id: 41CB84B2-F248-11E8-B48F-1D18A9856A87
last_name: Venturino
orcid: 0000-0003-2356-9403
- first_name: Karl
full_name: Roessler, Karl
last_name: Roessler
- first_name: Thomas
full_name: Czech, Thomas
last_name: Czech
- first_name: Romana
full_name: Höftberger, Romana
last_name: Höftberger
- first_name: Sandra
full_name: Siegert, Sandra
id: 36ACD32E-F248-11E8-B48F-1D18A9856A87
last_name: Siegert
orcid: 0000-0001-8635-0877
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
citation:
ama: Michalska JM, Lyudchik J, Velicky P, et al. Imaging brain tissue architecture
across millimeter to nanometer scales. Nature Biotechnology. 2023. doi:10.1038/s41587-023-01911-8
apa: Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J., Cenameri,
A., … Danzl, J. G. (2023). Imaging brain tissue architecture across millimeter
to nanometer scales. Nature Biotechnology. Springer Nature. https://doi.org/10.1038/s41587-023-01911-8
chicago: Michalska, Julia M, Julia Lyudchik, Philipp Velicky, Hana Korinkova, Jake
Watson, Alban Cenameri, Christoph M Sommer, et al. “Imaging Brain Tissue Architecture
across Millimeter to Nanometer Scales.” Nature Biotechnology. Springer
Nature, 2023. https://doi.org/10.1038/s41587-023-01911-8.
ieee: J. M. Michalska et al., “Imaging brain tissue architecture across millimeter
to nanometer scales,” Nature Biotechnology. Springer Nature, 2023.
ista: Michalska JM, Lyudchik J, Velicky P, Korinkova H, Watson J, Cenameri A, Sommer
CM, Amberg N, Venturino A, Roessler K, Czech T, Höftberger R, Siegert S, Novarino
G, Jonas PM, Danzl JG. 2023. Imaging brain tissue architecture across millimeter
to nanometer scales. Nature Biotechnology.
mla: Michalska, Julia M., et al. “Imaging Brain Tissue Architecture across Millimeter
to Nanometer Scales.” Nature Biotechnology, Springer Nature, 2023, doi:10.1038/s41587-023-01911-8.
short: J.M. Michalska, J. Lyudchik, P. Velicky, H. Korinkova, J. Watson, A. Cenameri,
C.M. Sommer, N. Amberg, A. Venturino, K. Roessler, T. Czech, R. Höftberger, S.
Siegert, G. Novarino, P.M. Jonas, J.G. Danzl, Nature Biotechnology (2023).
date_created: 2023-09-03T22:01:15Z
date_published: 2023-08-31T00:00:00Z
date_updated: 2024-02-21T12:18:18Z
day: '31'
department:
- _id: SaSi
- _id: GaNo
- _id: PeJo
- _id: JoDa
- _id: Bio
- _id: RySh
doi: 10.1038/s41587-023-01911-8
ec_funded: 1
external_id:
isi:
- '001065254200001'
isi: 1
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1038/s41587-023-01911-8
month: '08'
oa: 1
oa_version: Published Version
project:
- _id: 265CB4D0-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: I03600
name: Optical control of synaptic function via adhesion molecules
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
- _id: 25C5A090-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: Z00312
name: The Wittgenstein Prize
- _id: 23889792-32DE-11EA-91FC-C7463DDC885E
name: High content imaging to decode human immune cell interactions in health and
allergic disease
- _id: 25444568-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715508'
name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
and in vitro Models
- _id: 25B7EB9E-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '692692'
name: Biophysics and circuit function of a giant cortical glumatergic synapse
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '665385'
name: International IST Doctoral Program
- _id: fc2be41b-9c52-11eb-aca3-faa90aa144e9
call_identifier: H2020
grant_number: '101026635'
name: Synaptic computations of the hippocampal CA3 circuitry
publication: Nature Biotechnology
publication_identifier:
eissn:
- 1546-1696
issn:
- 1087-0156
publication_status: epub_ahead
publisher: Springer Nature
quality_controlled: '1'
related_material:
link:
- relation: software
url: https://github.com/danzllab/CATS
record:
- id: '13126'
relation: research_data
status: public
scopus_import: '1'
status: public
title: Imaging brain tissue architecture across millimeter to nanometer scales
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2023'
...
---
_id: '12174'
abstract:
- lang: eng
text: "Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety
of cellular membranes that acts as an ATP-dependent proton pump and plays a key
role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal
genes encode for a redundant set of subunits allowing the composition of diverse
V-ATPase complexes with specific properties and expression. Sixteen subunits have
been linked to human disease.\r\nHere we describe 26 patients harbouring 20 distinct
pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP
synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes:
6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures
included early lethal encephalopathies with rapidly progressive massive brain
atrophy, severe developmental epileptic encephalopathies and static intellectual
disability with epilepsy. The first clinical manifestation was early hypotonia,
in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies
in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic
encephalopathies failed to achieve any developmental, communicative or motor skills.
Less severe outcomes were observed in 23% of patients who, at a mean age of 10
years and 6 months, exhibited moderate intellectual disability, with independent
walking and variable epilepsy. None of the patients developed communicative language.
Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional
clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy
in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs.\r\n
\ Fibroblasts of two patients with developmental epileptic
encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased
organelle pH, consistent with lysosomal impairment and loss of V-ATPase function.
Fibroblasts of two patients with milder disease, exhibited a different phenotype
with increased Lysotracker staining, decreased organelle pH and no significant
modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes
in cellular extracts from four patients revealed discrete accumulation. Transmission
electron microscopy of fibroblasts of four patients with variable severity and
of induced pluripotent stem cell-derived neurons from two patients with developmental
epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic
material and lamellated membrane structures resembling phospholipids. Quantitative
assessment in induced pluripotent stem cell-derived neurons identified significantly
smaller lysosomes.\r\nATP6V1A-related encephalopathy represents a new paradigm
among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane
protein causing altered pH homeostasis. Its pathophysiology implies intracellular
accumulation of substrates whose composition remains unclear, and a combination
of developmental brain abnormalities and neurodegenerative changes established
during prenatal and early postanal development, whose severity is variably determined
by specific pathogenic variants."
acknowledged_ssus:
- _id: EM-Fac
- _id: LifeSc
acknowledgement: "We thank all patients and family members for their participation
in this study. We thank Melanie Pieraks and Eva Reinthaler (Neurolentech, Austria)
for generating the human iPSC lines and\r\nfor performing quality checks. We thank
Vanessa Zheden and Daniel Gütl for their excellent technical support in the specimen
preparation for transmission electron microscopy and Flavia Leite for preparing
the lentiviruses. The support from Electron Microscopy Facility and Molecular Biology
Services at IST Austria is greatly acknowledged. We would like to thank Doctors
Jane Hurst and Richard Scott for their help in retrieving the detailed clinical
information of Patient 17. The research team acknowledges the support of the National
Institute for Health Research, through the Comprehensive Clinical Research Network.
See Supplementary Material for Undiagnosed Disease Network consortium details. Genetic
information on Patient 23 was made available through access to the data and findings
generated by the 100 000 Genomes\r\nProject; www.genomicsengland.co.uk (to K.L.).
\r\nThis work was supported by the EU 7th Framework Programme (FP7) under the project
DESIRE grant N602531 (to R.G.); the Regione Toscana under the Call for Health 2018
(grant\r\nDECODE-EE) (to R.G.); the ‘Brain Project’ by Fondazione Cassa di Risparmio
di Firenze (to R.G.); IRCCS Ospedale Policlinico San Martino 5×1000 and Ricerca
Corrente (to A.F. and F.B.). The European Reference Network (ERN) for rare and complex
epilepsies (EpiCARE) provided financial support for meetings organization. The DDD
study presents independent research commissioned by the Health Innovation Challenge
Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome
and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051).
The views expressed in this publication\r\nare those of the author(s) and not necessarily
those of Wellcome or the Department of Health. The study has UK Research Ethics
Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12
granted by the Republic of Ireland REC). This study makes use of DECIPHER (https://www.deciphergenomics.org),
which is funded by Wellcome. K.K.-S. was supported by the ISTplus fellowship. "
article_processing_charge: No
article_type: original
author:
- first_name: Renzo
full_name: Guerrini, Renzo
last_name: Guerrini
- first_name: Davide
full_name: Mei, Davide
last_name: Mei
- first_name: Margit Katalin
full_name: Szigeti, Margit Katalin
id: 44F4BDC0-F248-11E8-B48F-1D18A9856A87
last_name: Szigeti
orcid: 0000-0001-9500-8758
- first_name: Sara
full_name: Pepe, Sara
last_name: Pepe
- first_name: Mary Kay
full_name: Koenig, Mary Kay
last_name: Koenig
- first_name: Gretchen
full_name: Von Allmen, Gretchen
last_name: Von Allmen
- first_name: Megan T
full_name: Cho, Megan T
last_name: Cho
- first_name: Kimberly
full_name: McDonald, Kimberly
last_name: McDonald
- first_name: Janice
full_name: Baker, Janice
last_name: Baker
- first_name: Vikas
full_name: Bhambhani, Vikas
last_name: Bhambhani
- first_name: Zöe
full_name: Powis, Zöe
last_name: Powis
- first_name: Lance
full_name: Rodan, Lance
last_name: Rodan
- first_name: Rima
full_name: Nabbout, Rima
last_name: Nabbout
- first_name: Giulia
full_name: Barcia, Giulia
last_name: Barcia
- first_name: Jill A
full_name: Rosenfeld, Jill A
last_name: Rosenfeld
- first_name: Carlos A
full_name: Bacino, Carlos A
last_name: Bacino
- first_name: Cyril
full_name: Mignot, Cyril
last_name: Mignot
- first_name: Lillian H
full_name: Power, Lillian H
last_name: Power
- first_name: Catharine J
full_name: Harris, Catharine J
last_name: Harris
- first_name: Dragan
full_name: Marjanovic, Dragan
last_name: Marjanovic
- first_name: Rikke S
full_name: Møller, Rikke S
last_name: Møller
- first_name: Trine B
full_name: Hammer, Trine B
last_name: Hammer
- first_name: Riikka
full_name: Keski Filppula, Riikka
last_name: Keski Filppula
- first_name: Päivi
full_name: Vieira, Päivi
last_name: Vieira
- first_name: Clara
full_name: Hildebrandt, Clara
last_name: Hildebrandt
- first_name: Stephanie
full_name: Sacharow, Stephanie
last_name: Sacharow
- first_name: Luca
full_name: Maragliano, Luca
last_name: Maragliano
- first_name: Fabio
full_name: Benfenati, Fabio
last_name: Benfenati
- first_name: Katherine
full_name: Lachlan, Katherine
last_name: Lachlan
- first_name: Andreas
full_name: Benneche, Andreas
last_name: Benneche
- first_name: Florence
full_name: Petit, Florence
last_name: Petit
- first_name: Jean Madeleine
full_name: de Sainte Agathe, Jean Madeleine
last_name: de Sainte Agathe
- first_name: Barbara
full_name: Hallinan, Barbara
last_name: Hallinan
- first_name: Yue
full_name: Si, Yue
last_name: Si
- first_name: Ingrid M
full_name: Wentzensen, Ingrid M
last_name: Wentzensen
- first_name: Fanggeng
full_name: Zou, Fanggeng
last_name: Zou
- first_name: Vinodh
full_name: Narayanan, Vinodh
last_name: Narayanan
- first_name: Naomichi
full_name: Matsumoto, Naomichi
last_name: Matsumoto
- first_name: Alessandra
full_name: Boncristiano, Alessandra
last_name: Boncristiano
- first_name: Giancarlo
full_name: la Marca, Giancarlo
last_name: la Marca
- first_name: Mitsuhiro
full_name: Kato, Mitsuhiro
last_name: Kato
- first_name: Kristin
full_name: Anderson, Kristin
last_name: Anderson
- first_name: Carmen
full_name: Barba, Carmen
last_name: Barba
- first_name: Luisa
full_name: Sturiale, Luisa
last_name: Sturiale
- first_name: Domenico
full_name: Garozzo, Domenico
last_name: Garozzo
- first_name: Roberto
full_name: Bei, Roberto
last_name: Bei
- first_name: Laura
full_name: Masuelli, Laura
last_name: Masuelli
- first_name: Valerio
full_name: Conti, Valerio
last_name: Conti
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Anna
full_name: Fassio, Anna
last_name: Fassio
citation:
ama: 'Guerrini R, Mei D, Szigeti MK, et al. Phenotypic and genetic spectrum of ATP6V1A
encephalopathy: A disorder of lysosomal homeostasis. Brain. 2022;145(8):2687-2703.
doi:10.1093/brain/awac145'
apa: 'Guerrini, R., Mei, D., Szigeti, M. K., Pepe, S., Koenig, M. K., Von Allmen,
G., … Fassio, A. (2022). Phenotypic and genetic spectrum of ATP6V1A encephalopathy:
A disorder of lysosomal homeostasis. Brain. Oxford University Press. https://doi.org/10.1093/brain/awac145'
chicago: 'Guerrini, Renzo, Davide Mei, Margit Katalin Szigeti, Sara Pepe, Mary Kay
Koenig, Gretchen Von Allmen, Megan T Cho, et al. “Phenotypic and Genetic Spectrum
of ATP6V1A Encephalopathy: A Disorder of Lysosomal Homeostasis.” Brain.
Oxford University Press, 2022. https://doi.org/10.1093/brain/awac145.'
ieee: 'R. Guerrini et al., “Phenotypic and genetic spectrum of ATP6V1A encephalopathy:
A disorder of lysosomal homeostasis,” Brain, vol. 145, no. 8. Oxford University
Press, pp. 2687–2703, 2022.'
ista: 'Guerrini R, Mei D, Szigeti MK, Pepe S, Koenig MK, Von Allmen G, Cho MT, McDonald
K, Baker J, Bhambhani V, Powis Z, Rodan L, Nabbout R, Barcia G, Rosenfeld JA,
Bacino CA, Mignot C, Power LH, Harris CJ, Marjanovic D, Møller RS, Hammer TB,
Keski Filppula R, Vieira P, Hildebrandt C, Sacharow S, Maragliano L, Benfenati
F, Lachlan K, Benneche A, Petit F, de Sainte Agathe JM, Hallinan B, Si Y, Wentzensen
IM, Zou F, Narayanan V, Matsumoto N, Boncristiano A, la Marca G, Kato M, Anderson
K, Barba C, Sturiale L, Garozzo D, Bei R, Masuelli L, Conti V, Novarino G, Fassio
A. 2022. Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder
of lysosomal homeostasis. Brain. 145(8), 2687–2703.'
mla: 'Guerrini, Renzo, et al. “Phenotypic and Genetic Spectrum of ATP6V1A Encephalopathy:
A Disorder of Lysosomal Homeostasis.” Brain, vol. 145, no. 8, Oxford University
Press, 2022, pp. 2687–703, doi:10.1093/brain/awac145.'
short: R. Guerrini, D. Mei, M.K. Szigeti, S. Pepe, M.K. Koenig, G. Von Allmen, M.T.
Cho, K. McDonald, J. Baker, V. Bhambhani, Z. Powis, L. Rodan, R. Nabbout, G. Barcia,
J.A. Rosenfeld, C.A. Bacino, C. Mignot, L.H. Power, C.J. Harris, D. Marjanovic,
R.S. Møller, T.B. Hammer, R. Keski Filppula, P. Vieira, C. Hildebrandt, S. Sacharow,
L. Maragliano, F. Benfenati, K. Lachlan, A. Benneche, F. Petit, J.M. de Sainte
Agathe, B. Hallinan, Y. Si, I.M. Wentzensen, F. Zou, V. Narayanan, N. Matsumoto,
A. Boncristiano, G. la Marca, M. Kato, K. Anderson, C. Barba, L. Sturiale, D.
Garozzo, R. Bei, L. Masuelli, V. Conti, G. Novarino, A. Fassio, Brain 145 (2022)
2687–2703.
date_created: 2023-01-12T12:11:45Z
date_published: 2022-08-01T00:00:00Z
date_updated: 2023-08-04T09:13:08Z
day: '01'
department:
- _id: GaNo
doi: 10.1093/brain/awac145
ec_funded: 1
external_id:
isi:
- '000807770000001'
intvolume: ' 145'
isi: 1
issue: '8'
keyword:
- Neurology (clinical)
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1093/brain/awac145
month: '08'
oa: 1
oa_version: Published Version
page: 2687-2703
project:
- _id: 260C2330-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '754411'
name: ISTplus - Postdoctoral Fellowships
publication: Brain
publication_identifier:
eissn:
- 1460-2156
issn:
- 0006-8950
publication_status: published
publisher: Oxford University Press
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal
homeostasis'
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 145
year: '2022'
...
---
_id: '11943'
abstract:
- lang: eng
text: Complex wiring between neurons underlies the information-processing network
enabling all brain functions, including cognition and memory. For understanding
how the network is structured, processes information, and changes over time, comprehensive
visualization of the architecture of living brain tissue with its cellular and
molecular components would open up major opportunities. However, electron microscopy
(EM) provides nanometre-scale resolution required for full in-silico
reconstruction1–5, yet is limited to fixed specimens and
static representations. Light microscopy allows live observation, with super-resolution
approaches6–12 facilitating nanoscale visualization, but
comprehensive 3D-reconstruction of living brain tissue has been hindered by tissue
photo-burden, photobleaching, insufficient 3D-resolution, and inadequate signal-to-noise
ratio (SNR). Here we demonstrate saturated reconstruction of living brain tissue.
We developed an integrated imaging and analysis technology, adapting stimulated
emission depletion (STED) microscopy6,13 in extracellularly
labelled tissue14 for high SNR and near-isotropic resolution.
Centrally, a two-stage deep-learning approach leveraged previously obtained information
on sample structure to drastically reduce photo-burden and enable automated volumetric
reconstruction down to single synapse level. Live reconstruction provides unbiased
analysis of tissue architecture across time in relation to functional activity
and targeted activation, and contextual understanding of molecular labelling.
This adoptable technology will facilitate novel insights into the dynamic functional
architecture of living brain tissue.
article_processing_charge: No
author:
- first_name: Philipp
full_name: Velicky, Philipp
id: 39BDC62C-F248-11E8-B48F-1D18A9856A87
last_name: Velicky
orcid: 0000-0002-2340-7431
- first_name: Eder
full_name: Miguel Villalba, Eder
id: 3FB91342-F248-11E8-B48F-1D18A9856A87
last_name: Miguel Villalba
orcid: 0000-0001-5665-0430
- first_name: Julia M
full_name: Michalska, Julia M
id: 443DB6DE-F248-11E8-B48F-1D18A9856A87
last_name: Michalska
orcid: 0000-0003-3862-1235
- first_name: Donglai
full_name: Wei, Donglai
last_name: Wei
- first_name: Zudi
full_name: Lin, Zudi
last_name: Lin
- first_name: Jake
full_name: Watson, Jake
id: 63836096-4690-11EA-BD4E-32803DDC885E
last_name: Watson
orcid: 0000-0002-8698-3823
- first_name: Jakob
full_name: Troidl, Jakob
last_name: Troidl
- first_name: Johanna
full_name: Beyer, Johanna
last_name: Beyer
- first_name: Yoav
full_name: Ben Simon, Yoav
id: 43DF3136-F248-11E8-B48F-1D18A9856A87
last_name: Ben Simon
- first_name: Christoph M
full_name: Sommer, Christoph M
id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
last_name: Sommer
orcid: 0000-0003-1216-9105
- first_name: Wiebke
full_name: Jahr, Wiebke
id: 425C1CE8-F248-11E8-B48F-1D18A9856A87
last_name: Jahr
- first_name: Alban
full_name: Cenameri, Alban
id: 9ac8f577-2357-11eb-997a-e566c5550886
last_name: Cenameri
- first_name: Johannes
full_name: Broichhagen, Johannes
last_name: Broichhagen
- first_name: Seth G. N.
full_name: Grant, Seth G. N.
last_name: Grant
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Hanspeter
full_name: Pfister, Hanspeter
last_name: Pfister
- first_name: Bernd
full_name: Bickel, Bernd
id: 49876194-F248-11E8-B48F-1D18A9856A87
last_name: Bickel
orcid: 0000-0001-6511-9385
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
citation:
ama: Velicky P, Miguel Villalba E, Michalska JM, et al. Saturated reconstruction
of living brain tissue. bioRxiv. doi:10.1101/2022.03.16.484431
apa: Velicky, P., Miguel Villalba, E., Michalska, J. M., Wei, D., Lin, Z., Watson,
J., … Danzl, J. G. (n.d.). Saturated reconstruction of living brain tissue. bioRxiv.
Cold Spring Harbor Laboratory. https://doi.org/10.1101/2022.03.16.484431
chicago: Velicky, Philipp, Eder Miguel Villalba, Julia M Michalska, Donglai Wei,
Zudi Lin, Jake Watson, Jakob Troidl, et al. “Saturated Reconstruction of Living
Brain Tissue.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2022.03.16.484431.
ieee: P. Velicky et al., “Saturated reconstruction of living brain tissue,”
bioRxiv. Cold Spring Harbor Laboratory.
ista: Velicky P, Miguel Villalba E, Michalska JM, Wei D, Lin Z, Watson J, Troidl
J, Beyer J, Ben Simon Y, Sommer CM, Jahr W, Cenameri A, Broichhagen J, Grant SGN,
Jonas PM, Novarino G, Pfister H, Bickel B, Danzl JG. Saturated reconstruction
of living brain tissue. bioRxiv, 10.1101/2022.03.16.484431.
mla: Velicky, Philipp, et al. “Saturated Reconstruction of Living Brain Tissue.”
BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2022.03.16.484431.
short: P. Velicky, E. Miguel Villalba, J.M. Michalska, D. Wei, Z. Lin, J. Watson,
J. Troidl, J. Beyer, Y. Ben Simon, C.M. Sommer, W. Jahr, A. Cenameri, J. Broichhagen,
S.G.N. Grant, P.M. Jonas, G. Novarino, H. Pfister, B. Bickel, J.G. Danzl, BioRxiv
(n.d.).
date_created: 2022-08-23T11:07:59Z
date_published: 2022-05-09T00:00:00Z
date_updated: 2024-03-28T23:30:20Z
day: '09'
department:
- _id: PeJo
- _id: GaNo
- _id: BeBi
- _id: JoDa
doi: 10.1101/2022.03.16.484431
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1101/2022.03.16.484431
month: '05'
oa: 1
oa_version: Preprint
publication: bioRxiv
publication_status: submitted
publisher: Cold Spring Harbor Laboratory
related_material:
record:
- id: '12470'
relation: dissertation_contains
status: public
status: public
title: Saturated reconstruction of living brain tissue
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2022'
...
---
_id: '11950'
abstract:
- lang: eng
text: Mapping the complex and dense arrangement of cells and their connectivity
in brain tissue demands nanoscale spatial resolution imaging. Super-resolution
optical microscopy excels at visualizing specific molecules and individual cells
but fails to provide tissue context. Here we developed Comprehensive Analysis
of Tissues across Scales (CATS), a technology to densely map brain tissue architecture
from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed
brain preparations, including rodent and human. CATS leverages fixation-compatible
extracellular labeling and advanced optical readout, in particular stimulated-emission
depletion and expansion microscopy, to comprehensively delineate cellular structures.
It enables 3D-reconstructing single synapses and mapping synaptic connectivity
by identification and tailored analysis of putative synaptic cleft regions. Applying
CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal
the system’s molecularly informed ultrastructure across spatial scales and assess
local connectivity by reconstructing and quantifying the synaptic input and output
structure of identified neurons.
article_processing_charge: No
author:
- first_name: Julia M
full_name: Michalska, Julia M
id: 443DB6DE-F248-11E8-B48F-1D18A9856A87
last_name: Michalska
orcid: 0000-0003-3862-1235
- first_name: Julia
full_name: Lyudchik, Julia
id: 46E28B80-F248-11E8-B48F-1D18A9856A87
last_name: Lyudchik
- first_name: Philipp
full_name: Velicky, Philipp
id: 39BDC62C-F248-11E8-B48F-1D18A9856A87
last_name: Velicky
orcid: 0000-0002-2340-7431
- first_name: Hana
full_name: Korinkova, Hana
id: ee3cb6ca-ec98-11ea-ae11-ff703e2254ed
last_name: Korinkova
- first_name: Jake
full_name: Watson, Jake
id: 63836096-4690-11EA-BD4E-32803DDC885E
last_name: Watson
orcid: 0000-0002-8698-3823
- first_name: Alban
full_name: Cenameri, Alban
id: 9ac8f577-2357-11eb-997a-e566c5550886
last_name: Cenameri
- first_name: Christoph M
full_name: Sommer, Christoph M
id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
last_name: Sommer
orcid: 0000-0003-1216-9105
- first_name: Alessandro
full_name: Venturino, Alessandro
id: 41CB84B2-F248-11E8-B48F-1D18A9856A87
last_name: Venturino
orcid: 0000-0003-2356-9403
- first_name: Karl
full_name: Roessler, Karl
last_name: Roessler
- first_name: Thomas
full_name: Czech, Thomas
last_name: Czech
- first_name: Sandra
full_name: Siegert, Sandra
id: 36ACD32E-F248-11E8-B48F-1D18A9856A87
last_name: Siegert
orcid: 0000-0001-8635-0877
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
citation:
ama: Michalska JM, Lyudchik J, Velicky P, et al. Uncovering brain tissue architecture
across scales with super-resolution light microscopy. bioRxiv. doi:10.1101/2022.08.17.504272
apa: Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J., Cenameri,
A., … Danzl, J. G. (n.d.). Uncovering brain tissue architecture across scales
with super-resolution light microscopy. bioRxiv. Cold Spring Harbor Laboratory.
https://doi.org/10.1101/2022.08.17.504272
chicago: Michalska, Julia M, Julia Lyudchik, Philipp Velicky, Hana Korinkova, Jake
Watson, Alban Cenameri, Christoph M Sommer, et al. “Uncovering Brain Tissue Architecture
across Scales with Super-Resolution Light Microscopy.” BioRxiv. Cold Spring
Harbor Laboratory, n.d. https://doi.org/10.1101/2022.08.17.504272.
ieee: J. M. Michalska et al., “Uncovering brain tissue architecture across
scales with super-resolution light microscopy,” bioRxiv. Cold Spring Harbor
Laboratory.
ista: Michalska JM, Lyudchik J, Velicky P, Korinkova H, Watson J, Cenameri A, Sommer
CM, Venturino A, Roessler K, Czech T, Siegert S, Novarino G, Jonas PM, Danzl JG.
Uncovering brain tissue architecture across scales with super-resolution light
microscopy. bioRxiv, 10.1101/2022.08.17.504272.
mla: Michalska, Julia M., et al. “Uncovering Brain Tissue Architecture across Scales
with Super-Resolution Light Microscopy.” BioRxiv, Cold Spring Harbor Laboratory,
doi:10.1101/2022.08.17.504272.
short: J.M. Michalska, J. Lyudchik, P. Velicky, H. Korinkova, J. Watson, A. Cenameri,
C.M. Sommer, A. Venturino, K. Roessler, T. Czech, S. Siegert, G. Novarino, P.M.
Jonas, J.G. Danzl, BioRxiv (n.d.).
date_created: 2022-08-24T08:24:52Z
date_published: 2022-08-18T00:00:00Z
date_updated: 2024-03-28T23:30:20Z
day: '18'
department:
- _id: SaSi
- _id: GaNo
- _id: PeJo
- _id: JoDa
doi: 10.1101/2022.08.17.504272
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1101/2022.08.17.504272
month: '08'
oa: 1
oa_version: Preprint
publication: bioRxiv
publication_status: submitted
publisher: Cold Spring Harbor Laboratory
related_material:
record:
- id: '12470'
relation: dissertation_contains
status: public
status: public
title: Uncovering brain tissue architecture across scales with super-resolution light
microscopy
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2022'
...
---
_id: '11160'
abstract:
- lang: eng
text: Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent
cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses
macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency
affects neurodevelopmental is unclear. Here, employing human cerebral organoids,
we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories
with an accelerated and delayed generation of, respectively, inhibitory and excitatory
neurons that yields, at days 60 and 120, symmetrically opposite expansions in
their proportions. This imbalance is consistent with an enlargement of cerebral
organoids as an in vitro correlate of patients’ macrocephaly. Through an isogenic
design of patient-specific mutations and mosaic organoids, we define genotype-phenotype
relationships and uncover their cell-autonomous nature. Our results define cell-type-specific
CHD8-dependent molecular defects related to an abnormal program of proliferation
and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations,
our study uncovers reproducible developmental alterations that may be employed
for neurodevelopmental disease modeling.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
acknowledgement: We thank Farnaz Freeman for technical assistance. This research was
supported by the Scientific Service Units (SSU) of IST Austria through resources
provided by the Bioimaging Facility (BIF) and the Life Science Facility (LSF). This
work supported by the European Union’s Horizon 2020 research and innovation program
(ERC) grant 715508 to G.N. (REVERSEAUTISM) and grant 825759 to G.T. (ENDpoiNTs);
the Fondazione Cariplo 2017-0886 to A.L.T.; E-Rare-3 JTC 2018 IMPACT to M. Gabriele;
and the Austrian Science Fund FWF I 4205-B to G.N. Graphical abstract and figures
were created using BioRender.com.
article_number: '110615'
article_processing_charge: Yes
article_type: original
author:
- first_name: Carlo Emanuele
full_name: Villa, Carlo Emanuele
last_name: Villa
- first_name: Cristina
full_name: Cheroni, Cristina
last_name: Cheroni
- first_name: Christoph
full_name: Dotter, Christoph
id: 4C66542E-F248-11E8-B48F-1D18A9856A87
last_name: Dotter
orcid: 0000-0002-9033-9096
- first_name: Alejandro
full_name: López-Tóbon, Alejandro
last_name: López-Tóbon
- first_name: Bárbara
full_name: Oliveira, Bárbara
id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
last_name: Oliveira
- first_name: Roberto
full_name: Sacco, Roberto
id: 42C9F57E-F248-11E8-B48F-1D18A9856A87
last_name: Sacco
- first_name: Aysan Çerağ
full_name: Yahya, Aysan Çerağ
id: 365A65F8-F248-11E8-B48F-1D18A9856A87
last_name: Yahya
- first_name: Jasmin
full_name: Morandell, Jasmin
id: 4739D480-F248-11E8-B48F-1D18A9856A87
last_name: Morandell
- first_name: Michele
full_name: Gabriele, Michele
last_name: Gabriele
- first_name: Mojtaba
full_name: Tavakoli, Mojtaba
id: 3A0A06F4-F248-11E8-B48F-1D18A9856A87
last_name: Tavakoli
orcid: 0000-0002-7667-6854
- first_name: Julia
full_name: Lyudchik, Julia
id: 46E28B80-F248-11E8-B48F-1D18A9856A87
last_name: Lyudchik
- first_name: Christoph M
full_name: Sommer, Christoph M
id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
last_name: Sommer
orcid: 0000-0003-1216-9105
- first_name: Mariano
full_name: Gabitto, Mariano
last_name: Gabitto
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
- first_name: Giuseppe
full_name: Testa, Giuseppe
last_name: Testa
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Villa CE, Cheroni C, Dotter C, et al. CHD8 haploinsufficiency links autism
to transient alterations in excitatory and inhibitory trajectories. Cell Reports.
2022;39(1). doi:10.1016/j.celrep.2022.110615
apa: Villa, C. E., Cheroni, C., Dotter, C., López-Tóbon, A., Oliveira, B., Sacco,
R., … Novarino, G. (2022). CHD8 haploinsufficiency links autism to transient alterations
in excitatory and inhibitory trajectories. Cell Reports. Elsevier. https://doi.org/10.1016/j.celrep.2022.110615
chicago: Villa, Carlo Emanuele, Cristina Cheroni, Christoph Dotter, Alejandro López-Tóbon,
Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, et al. “CHD8 Haploinsufficiency
Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.”
Cell Reports. Elsevier, 2022. https://doi.org/10.1016/j.celrep.2022.110615.
ieee: C. E. Villa et al., “CHD8 haploinsufficiency links autism to transient
alterations in excitatory and inhibitory trajectories,” Cell Reports, vol.
39, no. 1. Elsevier, 2022.
ista: Villa CE, Cheroni C, Dotter C, López-Tóbon A, Oliveira B, Sacco R, Yahya AÇ,
Morandell J, Gabriele M, Tavakoli M, Lyudchik J, Sommer CM, Gabitto M, Danzl JG,
Testa G, Novarino G. 2022. CHD8 haploinsufficiency links autism to transient alterations
in excitatory and inhibitory trajectories. Cell Reports. 39(1), 110615.
mla: Villa, Carlo Emanuele, et al. “CHD8 Haploinsufficiency Links Autism to Transient
Alterations in Excitatory and Inhibitory Trajectories.” Cell Reports, vol.
39, no. 1, 110615, Elsevier, 2022, doi:10.1016/j.celrep.2022.110615.
short: C.E. Villa, C. Cheroni, C. Dotter, A. López-Tóbon, B. Oliveira, R. Sacco,
A.Ç. Yahya, J. Morandell, M. Gabriele, M. Tavakoli, J. Lyudchik, C.M. Sommer,
M. Gabitto, J.G. Danzl, G. Testa, G. Novarino, Cell Reports 39 (2022).
date_created: 2022-04-15T09:03:10Z
date_published: 2022-04-05T00:00:00Z
date_updated: 2024-03-28T23:30:45Z
day: '05'
ddc:
- '570'
department:
- _id: JoDa
- _id: GaNo
doi: 10.1016/j.celrep.2022.110615
ec_funded: 1
external_id:
isi:
- '000785983900003'
pmid:
- '35385734'
file:
- access_level: open_access
checksum: b4e8d68f0268dec499af333e6fd5d8e1
content_type: application/pdf
creator: dernst
date_created: 2022-04-15T09:06:25Z
date_updated: 2022-04-15T09:06:25Z
file_id: '11164'
file_name: 2022_CellReports_Villa.pdf
file_size: '7808644'
relation: main_file
success: 1
file_date_updated: 2022-04-15T09:06:25Z
has_accepted_license: '1'
intvolume: ' 39'
isi: 1
issue: '1'
keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 25444568-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715508'
name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
and in vitro Models
- _id: 2690FEAC-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: I04205
name: Identification of converging Molecular Pathways Across Chromatinopathies as
Targets for Therapy
publication: Cell Reports
publication_identifier:
issn:
- 2211-1247
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
record:
- id: '12364'
relation: dissertation_contains
status: public
status: public
title: CHD8 haploinsufficiency links autism to transient alterations in excitatory
and inhibitory trajectories
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
volume: 39
year: '2022'
...
---
_id: '10281'
abstract:
- lang: eng
text: Mutations affecting mTOR or RAS signaling underlie defined syndromes (the
so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder
(ASD). These syndromes show a broad variety of somatic phenotypes including cancers,
skin abnormalities, heart disease and facial dysmorphisms. Less well studied are
the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these
signalopathies in ASD reviewing genetic, human cell model, rodent studies and
clinical trials. We conclude that signalopathies have an increased liability for
ASD and that, in particular, ASD individuals with dysmorphic features and intellectual
disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related
genes. Studies on rodent and human cell models confirm aberrant neuronal development
as the underlying pathology. Human studies further suggest that multiple hits
are necessary to induce the respective phenotypes. Recent clinical trials do only
report improvements for comorbid conditions such as epilepsy or cancer but not
for behavioral aspects. Animal models show that treatment during early development
can rescue behavioral phenotypes. Taken together, we suggest investigating the
differential roles of mTOR and RAS signaling in both human and rodent models,
and to test drug treatment both during and after neuronal development in the available
model systems
acknowledgement: 'This review was funded by the IMI2 Initiative under the grant AIMS-2-TRIALS
No 777394, by the Hessian Ministry for Science and Arts; State of Hesse Ministry
for Science and Arts: LOEWE-Grant to the CePTER-Consortium (www.uni-frankfurt.de/67689811);
Research (BMBF) under the grant RAISE-genic No 779282 all to AGC. This work was
also supported by the European Union’s Horizon 2020 research and innovation program
(ERC) grant 715508 (REVERSEAUTISM) and by the Austrian Science Fund (FWF) (DK W1232-B24)
both to G.N. and both BMBF GeNeRARe 01GM1519A and CRC 1080, project B10, of the
German Research Foundation (DFG) to M.J.S, respectively. We want to thank R. Waltes
for her support in preparing this manuscript.'
alternative_title:
- Special Issue "From Genes to Therapy in Autism Spectrum Disorder"
article_number: '1746'
article_processing_charge: No
article_type: original
author:
- first_name: Verica
full_name: Vasic, Verica
last_name: Vasic
- first_name: Mattson S.O.
full_name: Jones, Mattson S.O.
last_name: Jones
- first_name: Denise
full_name: Haslinger, Denise
id: 76922BDA-3D3B-11EA-90BD-A44F3DDC885E
last_name: Haslinger
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Michael J.
full_name: Schmeisser, Michael J.
last_name: Schmeisser
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Andreas G.
full_name: Chiocchetti, Andreas G.
last_name: Chiocchetti
citation:
ama: 'Vasic V, Jones MSO, Haslinger D, et al. Translating the role of mtor-and ras-associated
signalopathies in autism spectrum disorder: Models, mechanisms and treatment.
Genes. 2021;12(11). doi:10.3390/genes12111746'
apa: 'Vasic, V., Jones, M. S. O., Haslinger, D., Knaus, L., Schmeisser, M. J., Novarino,
G., & Chiocchetti, A. G. (2021). Translating the role of mtor-and ras-associated
signalopathies in autism spectrum disorder: Models, mechanisms and treatment.
Genes. MDPI. https://doi.org/10.3390/genes12111746'
chicago: 'Vasic, Verica, Mattson S.O. Jones, Denise Haslinger, Lisa Knaus, Michael
J. Schmeisser, Gaia Novarino, and Andreas G. Chiocchetti. “Translating the Role
of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models,
Mechanisms and Treatment.” Genes. MDPI, 2021. https://doi.org/10.3390/genes12111746.'
ieee: 'V. Vasic et al., “Translating the role of mtor-and ras-associated
signalopathies in autism spectrum disorder: Models, mechanisms and treatment,”
Genes, vol. 12, no. 11. MDPI, 2021.'
ista: 'Vasic V, Jones MSO, Haslinger D, Knaus L, Schmeisser MJ, Novarino G, Chiocchetti
AG. 2021. Translating the role of mtor-and ras-associated signalopathies in autism
spectrum disorder: Models, mechanisms and treatment. Genes. 12(11), 1746.'
mla: 'Vasic, Verica, et al. “Translating the Role of Mtor-and Ras-Associated Signalopathies
in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” Genes,
vol. 12, no. 11, 1746, MDPI, 2021, doi:10.3390/genes12111746.'
short: V. Vasic, M.S.O. Jones, D. Haslinger, L. Knaus, M.J. Schmeisser, G. Novarino,
A.G. Chiocchetti, Genes 12 (2021).
date_created: 2021-11-14T23:01:24Z
date_published: 2021-10-30T00:00:00Z
date_updated: 2023-08-14T11:46:12Z
day: '30'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.3390/genes12111746
ec_funded: 1
external_id:
isi:
- '000834044200002'
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checksum: 256cb832a9c3051c7dc741f6423b8cbd
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date_updated: 2022-05-16T07:02:27Z
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file_name: 2021_Genes_Vasic.pdf
file_size: 1335308
relation: main_file
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file_date_updated: 2022-05-16T07:02:27Z
has_accepted_license: '1'
intvolume: ' 12'
isi: 1
issue: '11'
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
project:
- _id: 25444568-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715508'
name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
and in vitro Models
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
publication: Genes
publication_identifier:
eissn:
- 2073-4425
publication_status: published
publisher: MDPI
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Translating the role of mtor-and ras-associated signalopathies in autism spectrum
disorder: Models, mechanisms and treatment'
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 12
year: '2021'
...
---
_id: '8730'
abstract:
- lang: eng
text: P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict
at the blood–brain barrier (BBB) the brain distribution of the majority of currently
known molecularly targeted anticancer drugs. To improve brain delivery of dual
ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously
at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition
with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution
of the model ABCB1/ABCG2 substrate [11C]erlotinib in mice and rhesus macaques
with PET. Tolerability of the erlotinib/tariquidar combination was assessed in
human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline
brain distribution of [11C]erlotinib was low (brain distribution volume, VT,brain < 0.3 mL/cm3).
Co-infusion of erlotinib and tariquidar increased VT,brain in mice by 3.0-fold
and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar
alone led to less pronounced VT,brain increases in both species. Treatment of
cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent
apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete
ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted
EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly
targeted anticancer drugs for a more effective treatment of brain tumors.
article_processing_charge: No
article_type: original
author:
- first_name: N
full_name: Tournier, N
last_name: Tournier
- first_name: S
full_name: Goutal, S
last_name: Goutal
- first_name: S
full_name: Mairinger, S
last_name: Mairinger
- first_name: IH
full_name: Lozano, IH
last_name: Lozano
- first_name: T
full_name: Filip, T
last_name: Filip
- first_name: M
full_name: Sauberer, M
last_name: Sauberer
- first_name: F
full_name: Caillé, F
last_name: Caillé
- first_name: L
full_name: Breuil, L
last_name: Breuil
- first_name: J
full_name: Stanek, J
last_name: Stanek
- first_name: AF
full_name: Freeman, AF
last_name: Freeman
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: C
full_name: Truillet, C
last_name: Truillet
- first_name: T
full_name: Wanek, T
last_name: Wanek
- first_name: O
full_name: Langer, O
last_name: Langer
citation:
ama: Tournier N, Goutal S, Mairinger S, et al. Complete inhibition of ABCB1 and
ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to
improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal
of Cerebral Blood Flow and Metabolism. 2021;41(7):1634-1646. doi:10.1177/0271678X20965500
apa: Tournier, N., Goutal, S., Mairinger, S., Lozano, I., Filip, T., Sauberer, M.,
… Langer, O. (2021). Complete inhibition of ABCB1 and ABCG2 at the blood-brain
barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of
the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal of Cerebral Blood Flow
and Metabolism. SAGE Publications. https://doi.org/10.1177/0271678X20965500
chicago: Tournier, N, S Goutal, S Mairinger, IH Lozano, T Filip, M Sauberer, F Caillé,
et al. “Complete Inhibition of ABCB1 and ABCG2 at the Blood-Brain Barrier by Co-Infusion
of Erlotinib and Tariquidar to Improve Brain Delivery of the Model ABCB1/ABCG2
Substrate [11C]Erlotinib.” Journal of Cerebral Blood Flow and Metabolism.
SAGE Publications, 2021. https://doi.org/10.1177/0271678X20965500.
ieee: N. Tournier et al., “Complete inhibition of ABCB1 and ABCG2 at the
blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain
delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib,” Journal of Cerebral
Blood Flow and Metabolism, vol. 41, no. 7. SAGE Publications, pp. 1634–1646,
2021.
ista: Tournier N, Goutal S, Mairinger S, Lozano I, Filip T, Sauberer M, Caillé F,
Breuil L, Stanek J, Freeman A, Novarino G, Truillet C, Wanek T, Langer O. 2021.
Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion
of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2
substrate [11C]erlotinib. Journal of Cerebral Blood Flow and Metabolism. 41(7),
1634–1646.
mla: Tournier, N., et al. “Complete Inhibition of ABCB1 and ABCG2 at the Blood-Brain
Barrier by Co-Infusion of Erlotinib and Tariquidar to Improve Brain Delivery of
the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Journal of Cerebral Blood
Flow and Metabolism, vol. 41, no. 7, SAGE Publications, 2021, pp. 1634–46,
doi:10.1177/0271678X20965500.
short: N. Tournier, S. Goutal, S. Mairinger, I. Lozano, T. Filip, M. Sauberer, F.
Caillé, L. Breuil, J. Stanek, A. Freeman, G. Novarino, C. Truillet, T. Wanek,
O. Langer, Journal of Cerebral Blood Flow and Metabolism 41 (2021) 1634–1646.
date_created: 2020-11-06T08:39:01Z
date_published: 2021-07-01T00:00:00Z
date_updated: 2023-10-18T06:45:30Z
day: '01'
department:
- _id: GaNo
doi: 10.1177/0271678X20965500
external_id:
isi:
- '000664214100012'
pmid:
- '33081568'
intvolume: ' 41'
isi: 1
issue: '7'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221757/
month: '07'
oa: 1
oa_version: Published Version
page: 1634-1646
pmid: 1
publication: Journal of Cerebral Blood Flow and Metabolism
publication_identifier:
eissn:
- 1559-7016
issn:
- 0271-678x
publication_status: published
publisher: SAGE Publications
quality_controlled: '1'
scopus_import: '1'
status: public
title: Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion
of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate
[11C]erlotinib
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 41
year: '2021'
...
---
_id: '9429'
abstract:
- lang: eng
text: De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3
lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency
leads to motor coordination deficits as well as ASD-relevant social and cognitive
impairments. However, induction of Cul3 haploinsufficiency later in life does
not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during
a critical developmental window. Here we show that Cul3 is essential to regulate
neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice
display cortical lamination abnormalities. At the molecular level, we found that
Cul3 controls neuronal migration by tightly regulating the amount of Plastin3
(Pls3), a previously unrecognized player of neural migration. Furthermore, we
found that Pls3 cell-autonomously regulates cell migration by regulating actin
cytoskeleton organization, and its levels are inversely proportional to neural
migration speed. Finally, we provide evidence that cellular phenotypes associated
with autism-linked gene haploinsufficiency can be rescued by transcriptional activation
of the intact allele in vitro, offering a proof of concept for a potential therapeutic
approach for ASDs.
acknowledged_ssus:
- _id: PreCl
acknowledgement: We thank A. Coll Manzano, F. Freeman, M. Ladron de Guevara, and A.
Ç. Yahya for technical assistance, S. Deixler, A. Lepold, and A. Schlerka for the
management of our animal colony, as well as M. Schunn and the Preclinical Facility
team for technical assistance. We thank K. Heesom and her team at the University
of Bristol Proteomics Facility for the proteomics sample preparation, data generation,
and analysis support. We thank Y. B. Simon for kindly providing the plasmid for
lentiviral labeling. Further, we thank M. Sixt for his advice regarding cell migration
and the fruitful discussions. This work was supported by the ISTPlus postdoctoral
fellowship (Grant Agreement No. 754411) to B.B., by the European Union’s Horizon
2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM), and by
the Austrian Science Fund (FWF) to G.N. (DK W1232-B24 and SFB F7807-B) and to J.G.D
(I3600-B27).
article_number: '3058'
article_processing_charge: No
article_type: original
author:
- first_name: Jasmin
full_name: Morandell, Jasmin
id: 4739D480-F248-11E8-B48F-1D18A9856A87
last_name: Morandell
- first_name: Lena A
full_name: Schwarz, Lena A
id: 29A8453C-F248-11E8-B48F-1D18A9856A87
last_name: Schwarz
- first_name: Bernadette
full_name: Basilico, Bernadette
id: 36035796-5ACA-11E9-A75E-7AF2E5697425
last_name: Basilico
orcid: 0000-0003-1843-3173
- first_name: Saren
full_name: Tasciyan, Saren
id: 4323B49C-F248-11E8-B48F-1D18A9856A87
last_name: Tasciyan
orcid: 0000-0003-1671-393X
- first_name: Georgi A
full_name: Dimchev, Georgi A
id: 38C393BE-F248-11E8-B48F-1D18A9856A87
last_name: Dimchev
orcid: 0000-0001-8370-6161
- first_name: Armel
full_name: Nicolas, Armel
id: 2A103192-F248-11E8-B48F-1D18A9856A87
last_name: Nicolas
- first_name: Christoph M
full_name: Sommer, Christoph M
id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
last_name: Sommer
orcid: 0000-0003-1216-9105
- first_name: Caroline
full_name: Kreuzinger, Caroline
id: 382077BA-F248-11E8-B48F-1D18A9856A87
last_name: Kreuzinger
- first_name: Christoph
full_name: Dotter, Christoph
id: 4C66542E-F248-11E8-B48F-1D18A9856A87
last_name: Dotter
orcid: 0000-0002-9033-9096
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Zoe
full_name: Dobler, Zoe
id: D23090A2-9057-11EA-883A-A8396FC7A38F
last_name: Dobler
- first_name: Emanuele
full_name: Cacci, Emanuele
last_name: Cacci
- first_name: Florian KM
full_name: Schur, Florian KM
id: 48AD8942-F248-11E8-B48F-1D18A9856A87
last_name: Schur
orcid: 0000-0003-4790-8078
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein
homeostasis and cell migration during a critical window of brain development.
Nature Communications. 2021;12(1). doi:10.1038/s41467-021-23123-x
apa: Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Dimchev, G. A.,
Nicolas, A., … Novarino, G. (2021). Cul3 regulates cytoskeleton protein homeostasis
and cell migration during a critical window of brain development. Nature Communications.
Springer Nature. https://doi.org/10.1038/s41467-021-23123-x
chicago: Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan,
Georgi A Dimchev, Armel Nicolas, Christoph M Sommer, et al. “Cul3 Regulates Cytoskeleton
Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.”
Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-23123-x.
ieee: J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis
and cell migration during a critical window of brain development,” Nature Communications,
vol. 12, no. 1. Springer Nature, 2021.
ista: Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev GA, Nicolas A, Sommer
CM, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur FK, Danzl JG, Novarino
G. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during
a critical window of brain development. Nature Communications. 12(1), 3058.
mla: Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis
and Cell Migration during a Critical Window of Brain Development.” Nature Communications,
vol. 12, no. 1, 3058, Springer Nature, 2021, doi:10.1038/s41467-021-23123-x.
short: J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, G.A. Dimchev, A. Nicolas,
C.M. Sommer, C. Kreuzinger, C. Dotter, L. Knaus, Z. Dobler, E. Cacci, F.K. Schur,
J.G. Danzl, G. Novarino, Nature Communications 12 (2021).
date_created: 2021-05-28T11:49:46Z
date_published: 2021-05-24T00:00:00Z
date_updated: 2024-03-28T23:30:23Z
day: '24'
ddc:
- '572'
department:
- _id: GaNo
- _id: JoDa
- _id: FlSc
- _id: MiSi
- _id: LifeSc
- _id: Bio
doi: 10.1038/s41467-021-23123-x
ec_funded: 1
external_id:
isi:
- '000658769900010'
file:
- access_level: open_access
checksum: 337e0f7959c35ec959984cacdcb472ba
content_type: application/pdf
creator: kschuh
date_created: 2021-05-28T12:39:43Z
date_updated: 2021-05-28T12:39:43Z
file_id: '9430'
file_name: 2021_NatureCommunications_Morandell.pdf
file_size: 9358599
relation: main_file
success: 1
file_date_updated: 2021-05-28T12:39:43Z
has_accepted_license: '1'
intvolume: ' 12'
isi: 1
issue: '1'
keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
month: '05'
oa: 1
oa_version: Published Version
project:
- _id: 260C2330-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '754411'
name: ISTplus - Postdoctoral Fellowships
- _id: 25444568-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715508'
name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
and in vitro Models
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
- _id: 05A0D778-7A3F-11EA-A408-12923DDC885E
grant_number: F07807
name: Neural stem cells in autism and epilepsy
- _id: 265CB4D0-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: I03600
name: Optical control of synaptic function via adhesion molecules
publication: Nature Communications
publication_identifier:
eissn:
- 2041-1723
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
link:
- relation: press_release
url: https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/
record:
- id: '7800'
relation: earlier_version
status: public
- id: '12401'
relation: dissertation_contains
status: public
status: public
title: Cul3 regulates cytoskeleton protein homeostasis and cell migration during a
critical window of brain development
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 12
year: '2021'
...
---
_id: '7586'
abstract:
- lang: eng
text: CLC chloride/proton exchangers may support acidification of endolysosomes
and raise their luminal Cl− concentration. Disruption of endosomal ClC‐3 causes
severe neurodegeneration. To assess the importance of ClC‐3 Cl−/H+ exchange, we
now generate Clcn3unc/unc mice in which ClC‐3 is converted into a Cl− channel.
Unlike Clcn3−/− mice, Clcn3unc/unc mice appear normal owing to compensation by
ClC‐4 with which ClC‐3 forms heteromers. ClC‐4 protein levels are strongly reduced
in Clcn3−/−, but not in Clcn3unc/unc mice because ClC‐3unc binds and stabilizes
ClC‐4 like wild‐type ClC‐3. Although mice lacking ClC‐4 appear healthy, its absence
in Clcn3unc/unc/Clcn4−/− mice entails even stronger neurodegeneration than observed
in Clcn3−/− mice. A fraction of ClC‐3 is found on synaptic vesicles, but miniature
postsynaptic currents and synaptic vesicle acidification are not affected in Clcn3unc/unc
or Clcn3−/− mice before neurodegeneration sets in. Both, Cl−/H+‐exchange activity
and the stabilizing effect on ClC‐4, are central to the biological function of
ClC‐3.
acknowledgement: "We thank T. Stauber and T. Breiderhoff for cloning expression constructs;
K. Räbel, S. Hohensee, and C. Backhaus for technical assistance; R. Jahn (MPIbpc,
Göttingen) for providing the equipment required for SV purification; and A\r\nWoehler
(MDC, Berlin) for assistance with SV imaging. Supported, in part, by grants from
the Deutsche Forschungsgemeinschaft (JE164/9-2, SFB740 TP C5, FOR 2625 (JE164/14-1),
NeuroCure Cluster of Excellence), the European Research Council Advanced Grant CYTOVOLION
(ERC 294435) and the Prix Louis-Jeantet de Médecine to TJJ, and Peter and Traudl
Engelhorn fellowship to ZF."
article_number: e103358
article_processing_charge: No
article_type: original
author:
- first_name: Stefanie
full_name: Weinert, Stefanie
last_name: Weinert
- first_name: Niclas
full_name: Gimber, Niclas
last_name: Gimber
- first_name: Dorothea
full_name: Deuschel, Dorothea
last_name: Deuschel
- first_name: Till
full_name: Stuhlmann, Till
last_name: Stuhlmann
- first_name: Dmytro
full_name: Puchkov, Dmytro
last_name: Puchkov
- first_name: Zohreh
full_name: Farsi, Zohreh
last_name: Farsi
- first_name: Carmen F.
full_name: Ludwig, Carmen F.
last_name: Ludwig
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Karen I.
full_name: López-Cayuqueo, Karen I.
last_name: López-Cayuqueo
- first_name: Rosa
full_name: Planells-Cases, Rosa
last_name: Planells-Cases
- first_name: Thomas J.
full_name: Jentsch, Thomas J.
last_name: Jentsch
citation:
ama: Weinert S, Gimber N, Deuschel D, et al. Uncoupling endosomal CLC chloride/proton
exchange causes severe neurodegeneration. EMBO Journal. 2020;39. doi:10.15252/embj.2019103358
apa: Weinert, S., Gimber, N., Deuschel, D., Stuhlmann, T., Puchkov, D., Farsi, Z.,
… Jentsch, T. J. (2020). Uncoupling endosomal CLC chloride/proton exchange causes
severe neurodegeneration. EMBO Journal. EMBO Press. https://doi.org/10.15252/embj.2019103358
chicago: Weinert, Stefanie, Niclas Gimber, Dorothea Deuschel, Till Stuhlmann, Dmytro
Puchkov, Zohreh Farsi, Carmen F. Ludwig, et al. “Uncoupling Endosomal CLC Chloride/Proton
Exchange Causes Severe Neurodegeneration.” EMBO Journal. EMBO Press, 2020.
https://doi.org/10.15252/embj.2019103358.
ieee: S. Weinert et al., “Uncoupling endosomal CLC chloride/proton exchange
causes severe neurodegeneration,” EMBO Journal, vol. 39. EMBO Press, 2020.
ista: Weinert S, Gimber N, Deuschel D, Stuhlmann T, Puchkov D, Farsi Z, Ludwig CF,
Novarino G, López-Cayuqueo KI, Planells-Cases R, Jentsch TJ. 2020. Uncoupling
endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal.
39, e103358.
mla: Weinert, Stefanie, et al. “Uncoupling Endosomal CLC Chloride/Proton Exchange
Causes Severe Neurodegeneration.” EMBO Journal, vol. 39, e103358, EMBO
Press, 2020, doi:10.15252/embj.2019103358.
short: S. Weinert, N. Gimber, D. Deuschel, T. Stuhlmann, D. Puchkov, Z. Farsi, C.F.
Ludwig, G. Novarino, K.I. López-Cayuqueo, R. Planells-Cases, T.J. Jentsch, EMBO
Journal 39 (2020).
date_created: 2020-03-15T23:00:55Z
date_published: 2020-03-02T00:00:00Z
date_updated: 2023-08-18T07:07:36Z
day: '02'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.15252/embj.2019103358
external_id:
isi:
- '000517335000001'
pmid:
- '32118314'
file:
- access_level: open_access
checksum: 82750a7a93e3740decbce8474004111a
content_type: application/pdf
creator: dernst
date_created: 2020-03-23T13:51:11Z
date_updated: 2020-07-14T12:48:00Z
file_id: '7615'
file_name: 2020_EMBO_Weinert.pdf
file_size: 12243278
relation: main_file
file_date_updated: 2020-07-14T12:48:00Z
has_accepted_license: '1'
intvolume: ' 39'
isi: 1
language:
- iso: eng
month: '03'
oa: 1
oa_version: Published Version
pmid: 1
publication: EMBO Journal
publication_identifier:
eissn:
- '14602075'
issn:
- '02614189'
publication_status: published
publisher: EMBO Press
quality_controlled: '1'
scopus_import: '1'
status: public
title: Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 39
year: '2020'
...
---
_id: '7957'
abstract:
- lang: eng
text: "Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain
development and function and are characterized by wide genetic and clinical variability.
In this review, we discuss the multiple factors that influence the clinical presentation
of NDDs, with particular attention to gene vulnerability, mutational load, and
the two-hit model. Despite the complex architecture of\r\nmutational events associated
with NDDs, the various proteins involved appear to converge on common pathways,
such as synaptic plasticity/function, chromatin remodelers and the mammalian target
of rapamycin (mTOR) pathway. A thorough understanding of the mechanisms behind
these pathways will hopefully lead to the identification of candidates that could
be targeted for treatment approaches."
acknowledgement: We wish to thank Jasmin Morandell for generously sharing Figure 2.
This work was supported by the European Research Council Starting Grant (grant 715508
) to G.N.
article_processing_charge: No
article_type: original
author:
- first_name: Ilaria
full_name: Parenti, Ilaria
id: D93538B0-5B71-11E9-AC62-02EBE5697425
last_name: Parenti
- first_name: Luis E
full_name: Garcia Rabaneda, Luis E
id: 33D1B084-F248-11E8-B48F-1D18A9856A87
last_name: Garcia Rabaneda
- first_name: Hanna
full_name: Schön, Hanna
id: C8E17EDC-D7AA-11E9-B7B7-45ECE5697425
last_name: Schön
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: 'Parenti I, Garcia Rabaneda LE, Schön H, Novarino G. Neurodevelopmental disorders:
From genetics to functional pathways. Trends in Neurosciences. 2020;43(8):608-621.
doi:10.1016/j.tins.2020.05.004'
apa: 'Parenti, I., Garcia Rabaneda, L. E., Schön, H., & Novarino, G. (2020).
Neurodevelopmental disorders: From genetics to functional pathways. Trends
in Neurosciences. Elsevier. https://doi.org/10.1016/j.tins.2020.05.004'
chicago: 'Parenti, Ilaria, Luis E Garcia Rabaneda, Hanna Schön, and Gaia Novarino.
“Neurodevelopmental Disorders: From Genetics to Functional Pathways.” Trends
in Neurosciences. Elsevier, 2020. https://doi.org/10.1016/j.tins.2020.05.004.'
ieee: 'I. Parenti, L. E. Garcia Rabaneda, H. Schön, and G. Novarino, “Neurodevelopmental
disorders: From genetics to functional pathways,” Trends in Neurosciences,
vol. 43, no. 8. Elsevier, pp. 608–621, 2020.'
ista: 'Parenti I, Garcia Rabaneda LE, Schön H, Novarino G. 2020. Neurodevelopmental
disorders: From genetics to functional pathways. Trends in Neurosciences. 43(8),
608–621.'
mla: 'Parenti, Ilaria, et al. “Neurodevelopmental Disorders: From Genetics to Functional
Pathways.” Trends in Neurosciences, vol. 43, no. 8, Elsevier, 2020, pp.
608–21, doi:10.1016/j.tins.2020.05.004.'
short: I. Parenti, L.E. Garcia Rabaneda, H. Schön, G. Novarino, Trends in Neurosciences
43 (2020) 608–621.
date_created: 2020-06-14T22:00:49Z
date_published: 2020-08-01T00:00:00Z
date_updated: 2023-08-21T08:25:31Z
day: '01'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.1016/j.tins.2020.05.004
ec_funded: 1
external_id:
isi:
- '000553090600008'
pmid:
- '32507511'
file:
- access_level: open_access
checksum: 67db0251b1d415ae59005f876fcf9e34
content_type: application/pdf
creator: dernst
date_created: 2020-11-25T09:43:40Z
date_updated: 2020-11-25T09:43:40Z
file_id: '8805'
file_name: 2020_TrendsNeuroscience_Parenti.pdf
file_size: 1439550
relation: main_file
success: 1
file_date_updated: 2020-11-25T09:43:40Z
has_accepted_license: '1'
intvolume: ' 43'
isi: 1
issue: '8'
language:
- iso: eng
month: '08'
oa: 1
oa_version: Published Version
page: 608-621
pmid: 1
project:
- _id: 25444568-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '715508'
name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
and in vitro Models
publication: Trends in Neurosciences
publication_identifier:
eissn:
- 1878108X
issn:
- '01662236'
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Neurodevelopmental disorders: From genetics to functional pathways'
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 43
year: '2020'
...
---
_id: '7800'
abstract:
- lang: eng
text: De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3
(CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models
to evaluate the consequences of Cul3 mutations in vivo. Our results show that
Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as
ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical
lamination abnormalities due to defective neuronal migration and reduced numbers
of excitatory and inhibitory neurons. In line with the observed abnormal columnar
organization, Cul3 haploinsufficiency is associated with decreased spontaneous
excitatory and inhibitory activity in the cortex. At the molecular level, employing
a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and
adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal
proteins in Cul3 mutant neuronal cells results in atypical organization of the
actin mesh at the cell leading edge, likely causing the observed migration deficits.
In contrast to these important functions early in development, Cul3 deficiency
appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency
in adult mice does not result in the behavioral defects observed in constitutive
Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has
a critical role in the regulation of cytoskeletal proteins and neuronal migration
and that ASD-associated defects and behavioral abnormalities are primarily due
to Cul3 functions at early developmental stages.
acknowledged_ssus:
- _id: PreCl
article_processing_charge: No
author:
- first_name: Jasmin
full_name: Morandell, Jasmin
id: 4739D480-F248-11E8-B48F-1D18A9856A87
last_name: Morandell
- first_name: Lena A
full_name: Schwarz, Lena A
id: 29A8453C-F248-11E8-B48F-1D18A9856A87
last_name: Schwarz
- first_name: Bernadette
full_name: Basilico, Bernadette
id: 36035796-5ACA-11E9-A75E-7AF2E5697425
last_name: Basilico
orcid: 0000-0003-1843-3173
- first_name: Saren
full_name: Tasciyan, Saren
id: 4323B49C-F248-11E8-B48F-1D18A9856A87
last_name: Tasciyan
orcid: 0000-0003-1671-393X
- first_name: Armel
full_name: Nicolas, Armel
id: 2A103192-F248-11E8-B48F-1D18A9856A87
last_name: Nicolas
- first_name: Christoph M
full_name: Sommer, Christoph M
id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
last_name: Sommer
orcid: 0000-0003-1216-9105
- first_name: Caroline
full_name: Kreuzinger, Caroline
id: 382077BA-F248-11E8-B48F-1D18A9856A87
last_name: Kreuzinger
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Zoe
full_name: Dobler, Zoe
id: D23090A2-9057-11EA-883A-A8396FC7A38F
last_name: Dobler
- first_name: Emanuele
full_name: Cacci, Emanuele
last_name: Cacci
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein
homeostasis and cell migration during a critical window of brain development.
bioRxiv. doi:10.1101/2020.01.10.902064
apa: Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer,
C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis
and cell migration during a critical window of brain development. bioRxiv.
Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.01.10.902064
chicago: Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan,
Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates
Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of
Brain Development.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2020.01.10.902064 .
ieee: J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis
and cell migration during a critical window of brain development,” bioRxiv.
Cold Spring Harbor Laboratory.
ista: Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger
C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton
protein homeostasis and cell migration during a critical window of brain development.
bioRxiv, 10.1101/2020.01.10.902064
.
mla: Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis
and Cell Migration during a Critical Window of Brain Development.” BioRxiv,
Cold Spring Harbor Laboratory, doi:10.1101/2020.01.10.902064 .
short: J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer,
C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv
(n.d.).
date_created: 2020-05-05T14:31:33Z
date_published: 2020-01-11T00:00:00Z
date_updated: 2024-03-28T23:30:14Z
day: '11'
ddc:
- '570'
department:
- _id: JoDa
- _id: GaNo
- _id: LifeSc
doi: '10.1101/2020.01.10.902064 '
file:
- access_level: open_access
checksum: c6799ab5daba80efe8e2ed63c15f8c81
content_type: application/pdf
creator: rsix
date_created: 2020-05-05T14:31:19Z
date_updated: 2020-07-14T12:48:03Z
file_id: '7801'
file_name: 2020.01.10.902064v1.full.pdf
file_size: 2931370
relation: main_file
file_date_updated: 2020-07-14T12:48:03Z
has_accepted_license: '1'
language:
- iso: eng
month: '01'
oa: 1
oa_version: Preprint
project:
- _id: 265CB4D0-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: I03600
name: Optical control of synaptic function via adhesion molecules
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
publication: bioRxiv
publication_status: submitted
publisher: Cold Spring Harbor Laboratory
related_material:
record:
- id: '9429'
relation: later_version
status: public
- id: '8620'
relation: dissertation_contains
status: public
status: public
title: Cul3 regulates cytoskeleton protein homeostasis and cell migration during a
critical window of brain development
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2020'
...
---
_id: '8131'
abstract:
- lang: eng
text: The possibility to generate construct valid animal models enabled the development
and testing of therapeutic strategies targeting the core features of autism spectrum
disorders (ASDs). At the same time, these studies highlighted the necessity of
identifying sensitive developmental time windows for successful therapeutic interventions.
Animal and human studies also uncovered the possibility to stratify the variety
of ASDs in molecularly distinct subgroups, potentially facilitating effective
treatment design. Here, we focus on the molecular pathways emerging as commonly
affected by mutations in diverse ASD-risk genes, on their role during critical
windows of brain development and the potential treatments targeting these biological
processes.
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Bernadette
full_name: Basilico, Bernadette
id: 36035796-5ACA-11E9-A75E-7AF2E5697425
last_name: Basilico
orcid: 0000-0003-1843-3173
- first_name: Jasmin
full_name: Morandell, Jasmin
id: 4739D480-F248-11E8-B48F-1D18A9856A87
last_name: Morandell
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Basilico B, Morandell J, Novarino G. Molecular mechanisms for targeted ASD
treatments. Current Opinion in Genetics and Development. 2020;65(12):126-137.
doi:10.1016/j.gde.2020.06.004
apa: Basilico, B., Morandell, J., & Novarino, G. (2020). Molecular mechanisms
for targeted ASD treatments. Current Opinion in Genetics and Development.
Elsevier. https://doi.org/10.1016/j.gde.2020.06.004
chicago: Basilico, Bernadette, Jasmin Morandell, and Gaia Novarino. “Molecular Mechanisms
for Targeted ASD Treatments.” Current Opinion in Genetics and Development.
Elsevier, 2020. https://doi.org/10.1016/j.gde.2020.06.004.
ieee: B. Basilico, J. Morandell, and G. Novarino, “Molecular mechanisms for targeted
ASD treatments,” Current Opinion in Genetics and Development, vol. 65,
no. 12. Elsevier, pp. 126–137, 2020.
ista: Basilico B, Morandell J, Novarino G. 2020. Molecular mechanisms for targeted
ASD treatments. Current Opinion in Genetics and Development. 65(12), 126–137.
mla: Basilico, Bernadette, et al. “Molecular Mechanisms for Targeted ASD Treatments.”
Current Opinion in Genetics and Development, vol. 65, no. 12, Elsevier,
2020, pp. 126–37, doi:10.1016/j.gde.2020.06.004.
short: B. Basilico, J. Morandell, G. Novarino, Current Opinion in Genetics and Development
65 (2020) 126–137.
date_created: 2020-07-19T22:00:58Z
date_published: 2020-12-01T00:00:00Z
date_updated: 2024-03-28T23:30:14Z
day: '01'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.1016/j.gde.2020.06.004
ec_funded: 1
external_id:
isi:
- '000598918900019'
pmid:
- '32659636'
file:
- access_level: open_access
content_type: application/pdf
creator: dernst
date_created: 2020-07-22T06:47:45Z
date_updated: 2020-07-22T06:47:45Z
file_id: '8146'
file_name: 2020_CurrentOpGenetics_Basilico.pdf
file_size: 1381545
relation: main_file
success: 1
file_date_updated: 2020-07-22T06:47:45Z
has_accepted_license: '1'
intvolume: ' 65'
isi: 1
issue: '12'
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
page: 126-137
pmid: 1
project:
- _id: 260C2330-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '754411'
name: ISTplus - Postdoctoral Fellowships
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
- _id: 05A0D778-7A3F-11EA-A408-12923DDC885E
grant_number: F07807
name: Neural stem cells in autism and epilepsy
publication: Current Opinion in Genetics and Development
publication_identifier:
eissn:
- '18790380'
issn:
- 0959437X
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
record:
- id: '8620'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: Molecular mechanisms for targeted ASD treatments
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 65
year: '2020'
...
---
_id: '105'
abstract:
- lang: eng
text: 'Clinical Utility Gene Card. 1. Name of Disease (Synonyms): Pontocerebellar
hypoplasia type 9 (PCH9) and spastic paraplegia-63 (SPG63). 2. OMIM# of the Disease:
615809 and 615686. 3. Name of the Analysed Genes or DNA/Chromosome Segments: AMPD2
at 1p13.3. 4. OMIM# of the Gene(s): 102771.'
acknowledgement: 'This work was supported by EuroGentest2 (Unit 2: “Genetic testing
as part of health care”), a Coordination Action under FP7 (Grant Agreement Number
261469) and the European Society of Human Genetics. We acknowledge the participation
of the patients and their families in these studies, as well as the generous financial
support of the Lefroy and Handbury families. APLM was supported by an Australian
Postgraduate Award. PJL is supported by an NHMRC Career Development Fellowship (GNT1032364).
RJL is supported by a Melbourne Children’s Clinician Scientist Fellowship.'
article_processing_charge: No
article_type: original
author:
- first_name: Ashley
full_name: Marsh, Ashley
last_name: Marsh
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Paul
full_name: Lockhart, Paul
last_name: Lockhart
- first_name: Richard
full_name: Leventer, Richard
last_name: Leventer
citation:
ama: Marsh A, Novarino G, Lockhart P, Leventer R. CUGC for pontocerebellar hypoplasia
type 9 and spastic paraplegia-63. European Journal of Human Genetics. 2019;27:161-166.
doi:10.1038/s41431-018-0231-2
apa: Marsh, A., Novarino, G., Lockhart, P., & Leventer, R. (2019). CUGC for
pontocerebellar hypoplasia type 9 and spastic paraplegia-63. European Journal
of Human Genetics. Springer Nature. https://doi.org/10.1038/s41431-018-0231-2
chicago: Marsh, Ashley, Gaia Novarino, Paul Lockhart, and Richard Leventer. “CUGC
for Pontocerebellar Hypoplasia Type 9 and Spastic Paraplegia-63.” European
Journal of Human Genetics. Springer Nature, 2019. https://doi.org/10.1038/s41431-018-0231-2.
ieee: A. Marsh, G. Novarino, P. Lockhart, and R. Leventer, “CUGC for pontocerebellar
hypoplasia type 9 and spastic paraplegia-63,” European Journal of Human Genetics,
vol. 27. Springer Nature, pp. 161–166, 2019.
ista: Marsh A, Novarino G, Lockhart P, Leventer R. 2019. CUGC for pontocerebellar
hypoplasia type 9 and spastic paraplegia-63. European Journal of Human Genetics.
27, 161–166.
mla: Marsh, Ashley, et al. “CUGC for Pontocerebellar Hypoplasia Type 9 and Spastic
Paraplegia-63.” European Journal of Human Genetics, vol. 27, Springer Nature,
2019, pp. 161–66, doi:10.1038/s41431-018-0231-2.
short: A. Marsh, G. Novarino, P. Lockhart, R. Leventer, European Journal of Human
Genetics 27 (2019) 161–166.
date_created: 2018-12-11T11:44:39Z
date_published: 2019-01-01T00:00:00Z
date_updated: 2023-08-24T14:28:24Z
day: '01'
department:
- _id: GaNo
doi: 10.1038/s41431-018-0231-2
external_id:
isi:
- '000454111500019'
pmid:
- '30089829'
intvolume: ' 27'
isi: 1
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1038/s41431-018-0231-2
month: '01'
oa: 1
oa_version: Published Version
page: 161-166
pmid: 1
publication: European Journal of Human Genetics
publication_status: published
publisher: Springer Nature
publist_id: '7949'
quality_controlled: '1'
scopus_import: '1'
status: public
title: CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 27
year: '2019'
...
---
_id: '6088'
abstract:
- lang: eng
text: P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two
efflux transporters at the blood–brain barrier (BBB), which effectively restrict
brain distribution of diverse drugs, such as tyrosine kinase inhibitors. There
is a crucial need for pharmacological ABCB1 and ABCG2 inhibition protocols for
a more effective treatment of brain diseases. In the present study, seven marketed
drugs (osimertinib, erlotinib, nilotinib, imatinib, lapatinib, pazopanib, and
cyclosporine A) and one nonmarketed drug (tariquidar), with known in vitro ABCB1/ABCG2
inhibitory properties, were screened for their inhibitory potency at the BBB in
vivo. Positron emission tomography (PET) using the model ABCB1/ABCG2 substrate
[11C]erlotinib was performed in mice. Tested inhibitors were administered as i.v.
bolus injections at 30 min before the start of the PET scan, followed by a continuous
i.v. infusion for the duration of the PET scan. Five of the tested drugs increased
total distribution volume of [11C]erlotinib in the brain (VT,brain) compared to
vehicle-treated animals (tariquidar, + 69%; erlotinib, + 19% and +23% for the
21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 22%; lapatinib, +
25%; and cyclosporine A, + 49%). For all drugs, increases in [11C]erlotinib brain
distribution were lower than in Abcb1a/b(−/−)Abcg2(−/−) mice (+149%), which suggested
that only partial ABCB1/ABCG2 inhibition was reached at the mouse BBB. The plasma
concentrations of the tested drugs at the time of the PET scan were higher than
clinically achievable plasma concentrations. Some of the tested drugs led to significant
increases in blood radioactivity concentrations measured at the end of the PET
scan (erlotinib, + 103% and +113% for the 21.5 mg/kg and the 43 mg/kg dose, respectively;
imatinib, + 125%; and cyclosporine A, + 101%), which was most likely caused by
decreased hepatobiliary excretion of radioactivity. Taken together, our data suggest
that some marketed tyrosine kinase inhibitors may be repurposed to inhibit ABCB1
and ABCG2 at the BBB. From a clinical perspective, moderate increases in brain
delivery despite the administration of high i.v. doses as well as peripheral drug–drug
interactions due to transporter inhibition in clearance organs question the translatability
of this concept.
article_processing_charge: No
author:
- first_name: Alexander
full_name: Traxl, Alexander
last_name: Traxl
- first_name: Severin
full_name: Mairinger, Severin
last_name: Mairinger
- first_name: Thomas
full_name: Filip, Thomas
last_name: Filip
- first_name: Michael
full_name: Sauberer, Michael
last_name: Sauberer
- first_name: Johann
full_name: Stanek, Johann
last_name: Stanek
- first_name: Stefan
full_name: Poschner, Stefan
last_name: Poschner
- first_name: Walter
full_name: Jäger, Walter
last_name: Jäger
- first_name: Viktoria
full_name: Zoufal, Viktoria
last_name: Zoufal
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Nicolas
full_name: Tournier, Nicolas
last_name: Tournier
- first_name: Martin
full_name: Bauer, Martin
last_name: Bauer
- first_name: Thomas
full_name: Wanek, Thomas
last_name: Wanek
- first_name: Oliver
full_name: Langer, Oliver
last_name: Langer
citation:
ama: Traxl A, Mairinger S, Filip T, et al. Inhibition of ABCB1 and ABCG2 at the
mouse blood-brain barrier with marketed drugs to improve brain delivery of the
model ABCB1/ABCG2 substrate [11C]erlotinib. Molecular Pharmaceutics. 2019;16(3):1282-1293.
doi:10.1021/acs.molpharmaceut.8b01217
apa: Traxl, A., Mairinger, S., Filip, T., Sauberer, M., Stanek, J., Poschner, S.,
… Langer, O. (2019). Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier
with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate
[11C]erlotinib. Molecular Pharmaceutics. American Chemical Society. https://doi.org/10.1021/acs.molpharmaceut.8b01217
chicago: Traxl, Alexander, Severin Mairinger, Thomas Filip, Michael Sauberer, Johann
Stanek, Stefan Poschner, Walter Jäger, et al. “Inhibition of ABCB1 and ABCG2 at
the Mouse Blood-Brain Barrier with Marketed Drugs to Improve Brain Delivery of
the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Molecular Pharmaceutics.
American Chemical Society, 2019. https://doi.org/10.1021/acs.molpharmaceut.8b01217.
ieee: A. Traxl et al., “Inhibition of ABCB1 and ABCG2 at the mouse blood-brain
barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2
substrate [11C]erlotinib,” Molecular Pharmaceutics, vol. 16, no. 3. American
Chemical Society, pp. 1282–1293, 2019.
ista: Traxl A, Mairinger S, Filip T, Sauberer M, Stanek J, Poschner S, Jäger W,
Zoufal V, Novarino G, Tournier N, Bauer M, Wanek T, Langer O. 2019. Inhibition
of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve
brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Molecular Pharmaceutics.
16(3), 1282–1293.
mla: Traxl, Alexander, et al. “Inhibition of ABCB1 and ABCG2 at the Mouse Blood-Brain
Barrier with Marketed Drugs to Improve Brain Delivery of the Model ABCB1/ABCG2
Substrate [11C]Erlotinib.” Molecular Pharmaceutics, vol. 16, no. 3, American
Chemical Society, 2019, pp. 1282–93, doi:10.1021/acs.molpharmaceut.8b01217.
short: A. Traxl, S. Mairinger, T. Filip, M. Sauberer, J. Stanek, S. Poschner, W.
Jäger, V. Zoufal, G. Novarino, N. Tournier, M. Bauer, T. Wanek, O. Langer, Molecular
Pharmaceutics 16 (2019) 1282–1293.
date_created: 2019-03-10T22:59:19Z
date_published: 2019-03-04T00:00:00Z
date_updated: 2023-08-25T08:02:51Z
day: '04'
department:
- _id: GaNo
doi: 10.1021/acs.molpharmaceut.8b01217
external_id:
isi:
- '000460600400031'
pmid:
- '30694684'
intvolume: ' 16'
isi: 1
issue: '3'
language:
- iso: eng
month: '03'
oa_version: None
page: 1282-1293
pmid: 1
publication: Molecular Pharmaceutics
publication_status: published
publisher: American Chemical Society
quality_controlled: '1'
scopus_import: '1'
status: public
title: Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed
drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 16
year: '2019'
...
---
_id: '6896'
abstract:
- lang: eng
text: "Until recently, a great amount of brain studies have been conducted in human
post mortem tissues, cell lines and model organisms. These researches provided
useful insights regarding cell-cell interactions occurring in the brain. However,
such approaches suffer from technical limitations and inaccurate modeling of the
tissue 3D cytoarchitecture. Importantly, they might lack a human genetic background
essential for disease modeling. With the development of protocols to generate
human cerebral organoids, we are now closer to reproducing the early stages of
human brain development in vitro. As a result, more relevant cell-cell interaction
studies can be conducted.\r\n\r\nIn this review, we discuss the advantages of
3D cultures over 2D in modulating brain cell-cell interactions during physiological
and pathological development, as well as the progress made in developing organoids
in which neurons, macroglia, microglia and vascularization are present. Finally,
we debate the limitations of those models and possible future directions."
article_number: '146458'
article_processing_charge: No
article_type: original
author:
- first_name: Bárbara
full_name: Oliveira, Bárbara
id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
last_name: Oliveira
- first_name: Aysan Çerağ
full_name: Yahya, Aysan Çerağ
id: 365A65F8-F248-11E8-B48F-1D18A9856A87
last_name: Yahya
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Oliveira B, Yahya AÇ, Novarino G. Modeling cell-cell interactions in the brain
using cerebral organoids. Brain Research. 2019;1724. doi:10.1016/j.brainres.2019.146458
apa: Oliveira, B., Yahya, A. Ç., & Novarino, G. (2019). Modeling cell-cell interactions
in the brain using cerebral organoids. Brain Research. Elsevier. https://doi.org/10.1016/j.brainres.2019.146458
chicago: Oliveira, Bárbara, Aysan Çerağ Yahya, and Gaia Novarino. “Modeling Cell-Cell
Interactions in the Brain Using Cerebral Organoids.” Brain Research. Elsevier,
2019. https://doi.org/10.1016/j.brainres.2019.146458.
ieee: B. Oliveira, A. Ç. Yahya, and G. Novarino, “Modeling cell-cell interactions
in the brain using cerebral organoids,” Brain Research, vol. 1724. Elsevier,
2019.
ista: Oliveira B, Yahya AÇ, Novarino G. 2019. Modeling cell-cell interactions in
the brain using cerebral organoids. Brain Research. 1724, 146458.
mla: Oliveira, Bárbara, et al. “Modeling Cell-Cell Interactions in the Brain Using
Cerebral Organoids.” Brain Research, vol. 1724, 146458, Elsevier, 2019,
doi:10.1016/j.brainres.2019.146458.
short: B. Oliveira, A.Ç. Yahya, G. Novarino, Brain Research 1724 (2019).
date_created: 2019-09-22T22:00:35Z
date_published: 2019-12-01T00:00:00Z
date_updated: 2023-08-30T06:19:49Z
day: '01'
department:
- _id: GaNo
doi: 10.1016/j.brainres.2019.146458
external_id:
isi:
- '000491646600033'
pmid:
- '31521639'
intvolume: ' 1724'
isi: 1
language:
- iso: eng
month: '12'
oa_version: None
pmid: 1
publication: Brain Research
publication_identifier:
eissn:
- '18726240'
issn:
- '00068993'
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Modeling cell-cell interactions in the brain using cerebral organoids
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 1724
year: '2019'
...