[{"file_date_updated":"2023-11-07T08:53:21Z","article_number":"107780","volume":26,"date_created":"2023-09-24T22:01:11Z","date_updated":"2023-12-13T12:27:30Z","author":[{"full_name":"Maes, Margaret E","first_name":"Margaret E","last_name":"Maes","id":"3838F452-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9642-1085"},{"id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9434-8902","first_name":"Gloria","last_name":"Colombo","full_name":"Colombo, Gloria"},{"full_name":"Schoot Uiterkamp, Florianne E","first_name":"Florianne E","last_name":"Schoot Uiterkamp","id":"3526230C-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Sternberg, Felix","first_name":"Felix","last_name":"Sternberg"},{"first_name":"Alessandro","last_name":"Venturino","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2356-9403","full_name":"Venturino, Alessandro"},{"first_name":"Elena E.","last_name":"Pohl","full_name":"Pohl, Elena E."},{"full_name":"Siegert, Sandra","orcid":"0000-0001-8635-0877","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","last_name":"Siegert","first_name":"Sandra"}],"department":[{"_id":"SaSi"}],"publisher":"Elsevier","publication_status":"published","pmid":1,"acknowledgement":"We thank the Scientific Service Units (SSU) of ISTA through resources provided by the Imaging and Optics Facility (IOF), the Lab Support Facility (LSF), and the Pre-Clinical Facility (PCF) team, specifically Sonja Haslinger and Michael Schunn for excellent mouse colony management and support. This research was supported by the FWF Sonderforschungsbereich F83 (to E.E.P). We thank Bálint Nagy, Ryan John A. Cubero, Marco Benevento and all members of the Siegert group for constant feedback on the project and article.","year":"2023","publication_identifier":{"eissn":["2589-0042"]},"month":"10","language":[{"iso":"eng"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"doi":"10.1016/j.isci.2023.107780","isi":1,"quality_controlled":"1","oa":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"external_id":{"isi":["001080403500001"],"pmid":["37731609"]},"issue":"10","abstract":[{"text":"Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.","lang":"eng"}],"type":"journal_article","oa_version":"Published Version","file":[{"access_level":"open_access","file_name":"2023_iScience_Maes.pdf","content_type":"application/pdf","file_size":8197935,"creator":"dernst","relation":"main_file","file_id":"14497","checksum":"be1a560efdd96d20712311f4fc54aac2","success":1,"date_updated":"2023-11-07T08:53:21Z","date_created":"2023-11-07T08:53:21Z"}],"intvolume":" 26","title":"Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout","ddc":["570"],"status":"public","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","_id":"14363","article_processing_charge":"Yes","has_accepted_license":"1","day":"20","scopus_import":"1","date_published":"2023-10-20T00:00:00Z","article_type":"original","citation":{"ista":"Maes ME, Colombo G, Schoot Uiterkamp FE, Sternberg F, Venturino A, Pohl EE, Siegert S. 2023. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. iScience. 26(10), 107780.","apa":"Maes, M. E., Colombo, G., Schoot Uiterkamp, F. E., Sternberg, F., Venturino, A., Pohl, E. E., & Siegert, S. (2023). Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. IScience. Elsevier. https://doi.org/10.1016/j.isci.2023.107780","ieee":"M. E. Maes et al., “Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout,” iScience, vol. 26, no. 10. Elsevier, 2023.","ama":"Maes ME, Colombo G, Schoot Uiterkamp FE, et al. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. iScience. 2023;26(10). doi:10.1016/j.isci.2023.107780","chicago":"Maes, Margaret E, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg, Alessandro Venturino, Elena E. Pohl, and Sandra Siegert. “Mitochondrial Network Adaptations of Microglia Reveal Sex-Specific Stress Response after Injury and UCP2 Knockout.” IScience. Elsevier, 2023. https://doi.org/10.1016/j.isci.2023.107780.","mla":"Maes, Margaret E., et al. “Mitochondrial Network Adaptations of Microglia Reveal Sex-Specific Stress Response after Injury and UCP2 Knockout.” IScience, vol. 26, no. 10, 107780, Elsevier, 2023, doi:10.1016/j.isci.2023.107780.","short":"M.E. Maes, G. Colombo, F.E. Schoot Uiterkamp, F. Sternberg, A. Venturino, E.E. Pohl, S. Siegert, IScience 26 (2023)."},"publication":"iScience"},{"abstract":[{"text":"Background: \r\nPro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. BAX activation occurs in two stages including translocation of latent BAX to the mitochondrial outer membrane (MOM) and then permeabilization of the MOM to facilitate the release of apoptotic signaling molecules. As a critical component of RGC death, BAX is an attractive target for neuroprotective therapies and an understanding of the kinetics of BAX activation and the mechanisms controlling the two stages of this process in RGCs is potentially valuable in informing the development of a neuroprotective strategy.\r\nMethods:\r\nThe kinetics of BAX translocation were assessed by both static and live-cell imaging of a GFP-BAX fusion protein introduced into RGCs using AAV2-mediated gene transfer in mice. Activation of BAX was achieved using an acute optic nerve crush (ONC) protocol. Live-cell imaging of GFP-BAX was achieved using explants of mouse retina harvested 7 days after ONC. Kinetics of translocation in RGCs were compared to GFP-BAX translocation in 661W tissue culture cells. Permeabilization of GFP-BAX was assessed by staining with the 6A7 monoclonal antibody, which recognizes a conformational change in this protein after MOM insertion. Assessment of individual kinases associated with both stages of activation was made using small molecule inhibitors injected into the vitreous either independently or in concert with ONC surgery. The contribution of the Dual Leucine Zipper-JUN-N-Terminal Kinase cascade was evaluated using mice with a double conditional knock-out of both Mkk4 and Mkk7.\r\nResults:\r\nONC induces the translocation of GFP-BAX in RGCs at a slower rate and with less intracellular synchronicity than 661W cells, but exhibits less variability among mitochondrial foci within a single cell. GFP-BAX was also found to translocate in all compartments of an RGC including the dendritic arbor and axon. Approximately 6% of translocating RGCs exhibited retrotranslocation of BAX immediately following translocation. Unlike tissue culture cells, which exhibit simultaneous translocation and permeabilization, RGCs exhibited a significant delay between these two stages, similar to detached cells undergoing anoikis. Translocation, with minimal permeabilization could be induced in a subset of RGCs using an inhibitor of Focal Adhesion Kinase (PF573228). Permeabilization after ONC, in a majority of RGCs, could be inhibited with a broad spectrum kinase inhibitor (sunitinib) or a selective inhibitor for p38/MAPK14 (SB203580). Intervention of DLK-JNK axis signaling abrogated GFP-BAX translocation after ONC.\r\nConclusions:\r\nA comparison between BAX activation kinetics in tissue culture cells and in cells of a complex tissue environment shows distinct differences indicating that caution should be used when translating findings from one condition to the other. RGCs exhibit both a delay between translocation and permeabilization and the ability for translocated BAX to be retrotranslocated, suggesting several stages at which intervention of the activation process could be exploited in the design of a therapeutic strategy.","lang":"eng"}],"type":"journal_article","oa_version":"Published Version","file":[{"content_type":"application/pdf","file_size":11568350,"creator":"dernst","file_name":"2023_MolecularNeurodegeneration_Maes.pdf","access_level":"open_access","date_updated":"2024-01-30T14:33:31Z","date_created":"2024-01-30T14:33:31Z","checksum":"3aa218ddea4a082d8fd5e196ae55ca06","success":1,"relation":"main_file","file_id":"14917"}],"intvolume":" 18","ddc":["570"],"status":"public","title":"BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","_id":"14401","article_processing_charge":"Yes","has_accepted_license":"1","day":"26","scopus_import":"1","date_published":"2023-09-26T00:00:00Z","article_type":"original","citation":{"chicago":"Maes, Margaret E, Ryan J. Donahue, Cassandra L. Schlamp, Olivia J. Marola, Richard T. Libby, and Robert W. Nickells. “BAX Activation in Mouse Retinal Ganglion Cells Occurs in Two Temporally and Mechanistically Distinct Steps.” Molecular Neurodegeneration. Springer Nature, 2023. https://doi.org/10.1186/s13024-023-00659-8.","mla":"Maes, Margaret E., et al. “BAX Activation in Mouse Retinal Ganglion Cells Occurs in Two Temporally and Mechanistically Distinct Steps.” Molecular Neurodegeneration, vol. 18, 67, Springer Nature, 2023, doi:10.1186/s13024-023-00659-8.","short":"M.E. Maes, R.J. Donahue, C.L. Schlamp, O.J. Marola, R.T. Libby, R.W. Nickells, Molecular Neurodegeneration 18 (2023).","ista":"Maes ME, Donahue RJ, Schlamp CL, Marola OJ, Libby RT, Nickells RW. 2023. BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps. Molecular Neurodegeneration. 18, 67.","ieee":"M. E. Maes, R. J. Donahue, C. L. Schlamp, O. J. Marola, R. T. Libby, and R. W. Nickells, “BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps,” Molecular Neurodegeneration, vol. 18. Springer Nature, 2023.","apa":"Maes, M. E., Donahue, R. J., Schlamp, C. L., Marola, O. J., Libby, R. T., & Nickells, R. W. (2023). BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps. Molecular Neurodegeneration. Springer Nature. https://doi.org/10.1186/s13024-023-00659-8","ama":"Maes ME, Donahue RJ, Schlamp CL, Marola OJ, Libby RT, Nickells RW. BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps. Molecular Neurodegeneration. 2023;18. doi:10.1186/s13024-023-00659-8"},"publication":"Molecular Neurodegeneration","file_date_updated":"2024-01-30T14:33:31Z","article_number":"67","volume":18,"date_updated":"2024-01-30T14:34:21Z","date_created":"2023-10-08T22:01:15Z","author":[{"full_name":"Maes, Margaret E","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","last_name":"Maes","first_name":"Margaret E"},{"full_name":"Donahue, Ryan J.","last_name":"Donahue","first_name":"Ryan J."},{"full_name":"Schlamp, Cassandra L.","first_name":"Cassandra L.","last_name":"Schlamp"},{"last_name":"Marola","first_name":"Olivia J.","full_name":"Marola, Olivia J."},{"last_name":"Libby","first_name":"Richard T.","full_name":"Libby, Richard T."},{"last_name":"Nickells","first_name":"Robert W.","full_name":"Nickells, Robert W."}],"publisher":"Springer Nature","department":[{"_id":"SaSi"}],"publication_status":"published","pmid":1,"acknowledgement":"The authors would like to thank Mr. Joel Dietz for management of the mouse colony and helpful advice for conducting quantitative PCR studies and Mr. Santoshi Kinoshita at the Translational Research Initiative in Pathology laboratory at the University of Wisconsin-Madison for cutting sections analyzed in this study.\r\nThis work was supported by National Eye Institute grants R01 EY030123 (RWN), R01 EY018606 (RTL), P30 EY016665 (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), T32 EY027721 (RJD) and F31 EY030739 (OJM). Additional funding was provided by the BrightFocus Foundation (RWN) and unrestricted grants from Research to Prevent Blindness, Inc to the Department of Ophthalmology and Visual Sciences (University of Wisconsin-Madison) and to the Department of Ophthalmology (University of Rochester).","year":"2023","publication_identifier":{"eissn":["1750-1326"]},"month":"09","language":[{"iso":"eng"}],"doi":"10.1186/s13024-023-00659-8","isi":1,"quality_controlled":"1","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"external_id":{"isi":["001071403800001"],"pmid":["37292963"]}},{"oa_version":"Submitted Version","intvolume":" 26","title":"Characteristics of intracellular propagation of mitochondrial BAX recruitment during apoptosis","status":"public","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","_id":"9009","issue":"2","abstract":[{"text":"Recent advancements in live cell imaging technologies have identified the phenomenon of intracellular propagation of late apoptotic events, such as cytochrome c release and caspase activation. The mechanism, prevalence, and speed of apoptosis propagation remain unclear. Additionally, no studies have demonstrated propagation of the pro-apoptotic protein, BAX. To evaluate the role of BAX in intracellular apoptotic propagation, we used high speed live-cell imaging to visualize fluorescently tagged-BAX recruitment to mitochondria in four immortalized cell lines. We show that propagation of mitochondrial BAX recruitment occurs in parallel to cytochrome c and SMAC/Diablo release and is affected by cellular morphology, such that cells with processes are more likely to exhibit propagation. The initiation of propagation events is most prevalent in the distal tips of processes, while the rate of propagation is influenced by the 2-dimensional width of the process. Propagation was rarely observed in the cell soma, which exhibited near synchronous recruitment of BAX. Propagation velocity is not affected by mitochondrial volume in segments of processes, but is negatively affected by mitochondrial density. There was no evidence of a propagating wave of increased levels of intracellular calcium ions. Alternatively, we did observe a uniform increase in superoxide build-up in cellular mitochondria, which was released as a propagating wave simultaneously with the propagating recruitment of BAX to the mitochondrial outer membrane.","lang":"eng"}],"type":"journal_article","date_published":"2021-02-01T00:00:00Z","page":"132-145","article_type":"original","citation":{"mla":"Grosser, Joshua A., et al. “Characteristics of Intracellular Propagation of Mitochondrial BAX Recruitment during Apoptosis.” Apoptosis, vol. 26, no. 2, Springer Nature, 2021, pp. 132–45, doi:10.1007/s10495-020-01654-w.","short":"J.A. Grosser, M.E. Maes, R.W. Nickells, Apoptosis 26 (2021) 132–145.","chicago":"Grosser, Joshua A., Margaret E Maes, and Robert W. Nickells. “Characteristics of Intracellular Propagation of Mitochondrial BAX Recruitment during Apoptosis.” Apoptosis. Springer Nature, 2021. https://doi.org/10.1007/s10495-020-01654-w.","ama":"Grosser JA, Maes ME, Nickells RW. Characteristics of intracellular propagation of mitochondrial BAX recruitment during apoptosis. Apoptosis. 2021;26(2):132-145. doi:10.1007/s10495-020-01654-w","ista":"Grosser JA, Maes ME, Nickells RW. 2021. Characteristics of intracellular propagation of mitochondrial BAX recruitment during apoptosis. Apoptosis. 26(2), 132–145.","apa":"Grosser, J. A., Maes, M. E., & Nickells, R. W. (2021). Characteristics of intracellular propagation of mitochondrial BAX recruitment during apoptosis. Apoptosis. Springer Nature. https://doi.org/10.1007/s10495-020-01654-w","ieee":"J. A. Grosser, M. E. Maes, and R. W. Nickells, “Characteristics of intracellular propagation of mitochondrial BAX recruitment during apoptosis,” Apoptosis, vol. 26, no. 2. Springer Nature, pp. 132–145, 2021."},"publication":"Apoptosis","article_processing_charge":"No","day":"01","scopus_import":"1","volume":26,"date_updated":"2023-08-07T13:32:40Z","date_created":"2021-01-17T23:01:11Z","author":[{"first_name":"Joshua A.","last_name":"Grosser","full_name":"Grosser, Joshua A."},{"full_name":"Maes, Margaret E","id":"3838F452-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9642-1085","first_name":"Margaret E","last_name":"Maes"},{"last_name":"Nickells","first_name":"Robert W.","full_name":"Nickells, Robert W."}],"publisher":"Springer Nature","department":[{"_id":"SaSi"}],"publication_status":"published","pmid":1,"year":"2021","acknowledgement":"This work was supported by National Institute of Health grants R01 EY030123, P30 EY016665, and T32 GM081061, an unrestricted research grant from Research to Prevent Blindness, Inc., and the Frederick A. Davis Endowment from the Department of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison.","language":[{"iso":"eng"}],"doi":"10.1007/s10495-020-01654-w","quality_controlled":"1","isi":1,"external_id":{"pmid":["33426618"],"isi":["000606722600001"]},"main_file_link":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082518/","open_access":"1"}],"oa":1,"publication_identifier":{"issn":["1360-8185"],"eissn":["1573-675X"]},"month":"02"},{"intvolume":" 36","status":"public","ddc":["570"],"title":"Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain","_id":"9642","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","oa_version":"Published Version","file":[{"creator":"cziletti","content_type":"application/pdf","file_size":56388540,"file_name":"2021_CellReports_Venturino.pdf","access_level":"open_access","date_updated":"2021-07-19T13:32:17Z","date_created":"2021-07-19T13:32:17Z","success":1,"checksum":"f056255f6d01fd9a86b5387635928173","file_id":"9693","relation":"main_file"}],"type":"journal_article","issue":"1","abstract":[{"text":"Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.","lang":"eng"}],"article_type":"original","citation":{"short":"A. Venturino, R. Schulz, H. De Jesús-Cortés, M.E. Maes, B. Nagy, F. Reilly-Andújar, G. Colombo, R.J. Cubero, F.E. Schoot Uiterkamp, M.F. Bear, S. Siegert, Cell Reports 36 (2021).","mla":"Venturino, Alessandro, et al. “Microglia Enable Mature Perineuronal Nets Disassembly upon Anesthetic Ketamine Exposure or 60-Hz Light Entrainment in the Healthy Brain.” Cell Reports, vol. 36, no. 1, 109313, Elsevier, 2021, doi:10.1016/j.celrep.2021.109313.","chicago":"Venturino, Alessandro, Rouven Schulz, Héctor De Jesús-Cortés, Margaret E Maes, Balint Nagy, Francis Reilly-Andújar, Gloria Colombo, et al. “Microglia Enable Mature Perineuronal Nets Disassembly upon Anesthetic Ketamine Exposure or 60-Hz Light Entrainment in the Healthy Brain.” Cell Reports. Elsevier, 2021. https://doi.org/10.1016/j.celrep.2021.109313.","ama":"Venturino A, Schulz R, De Jesús-Cortés H, et al. Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell Reports. 2021;36(1). doi:10.1016/j.celrep.2021.109313","ieee":"A. Venturino et al., “Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain,” Cell Reports, vol. 36, no. 1. Elsevier, 2021.","apa":"Venturino, A., Schulz, R., De Jesús-Cortés, H., Maes, M. E., Nagy, B., Reilly-Andújar, F., … Siegert, S. (2021). Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell Reports. Elsevier. https://doi.org/10.1016/j.celrep.2021.109313","ista":"Venturino A, Schulz R, De Jesús-Cortés H, Maes ME, Nagy B, Reilly-Andújar F, Colombo G, Cubero RJ, Schoot Uiterkamp FE, Bear MF, Siegert S. 2021. Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell Reports. 36(1), 109313."},"publication":"Cell Reports","date_published":"2021-07-06T00:00:00Z","scopus_import":"1","article_processing_charge":"No","has_accepted_license":"1","day":"06","department":[{"_id":"SaSi"}],"publisher":"Elsevier","publication_status":"published","pmid":1,"year":"2021","acknowledgement":"We thank the scientific service units at IST Austria, especially the IST bioimaging facility, the preclinical facility, and, specifically, Michael Schunn and Sonja Haslinger for excellent support; Plexxikon for the PLX food; the Csicsvari group for advice and equipment for in vivo recording; Jürgen Siegert for the light-entrainment design; Marco Benevento, Soledad Gonzalo Cogno, Pat King, and all Siegert group members for constant feedback on the project and manuscript; Lorena Pantano (PILM Bioinformatics Core) for assisting with sample-size determination for OD plasticity experiments; and Ana Morello from MIT for technical assistance with VEPs recordings. This research was supported by a DOC Fellowship from the Austrian Academy of Sciences at the Institute of Science and Technology Austria to R.S., from the European Union Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions program (grants 665385 to G.C.; 754411 to R.J.A.C.), the European Research Council (grant 715571 to S.S.), and the National Eye Institute of the National Institutes of Health under award numbers R01EY029245 (to M.F.B.) and R01EY023037 (diversity supplement to H.D.J-C.).","volume":36,"date_updated":"2023-08-10T14:09:39Z","date_created":"2021-07-11T22:01:16Z","related_material":{"link":[{"url":"https://ist.ac.at/en/news/the-twinkle-and-the-brain/","relation":"press_release","description":"News on IST Homepage"}]},"author":[{"last_name":"Venturino","first_name":"Alessandro","orcid":"0000-0003-2356-9403","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","full_name":"Venturino, Alessandro"},{"first_name":"Rouven","last_name":"Schulz","id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-5297-733X","full_name":"Schulz, Rouven"},{"last_name":"De Jesús-Cortés","first_name":"Héctor","full_name":"De Jesús-Cortés, Héctor"},{"full_name":"Maes, Margaret E","id":"3838F452-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9642-1085","first_name":"Margaret E","last_name":"Maes"},{"full_name":"Nagy, Balint","last_name":"Nagy","first_name":"Balint","id":"93C65ECC-A6F2-11E9-8DF9-9712E6697425"},{"first_name":"Francis","last_name":"Reilly-Andújar","full_name":"Reilly-Andújar, Francis"},{"full_name":"Colombo, Gloria","first_name":"Gloria","last_name":"Colombo","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9434-8902"},{"id":"850B2E12-9CD4-11E9-837F-E719E6697425","orcid":"0000-0003-0002-1867","first_name":"Ryan J","last_name":"Cubero","full_name":"Cubero, Ryan J"},{"id":"3526230C-F248-11E8-B48F-1D18A9856A87","last_name":"Schoot Uiterkamp","first_name":"Florianne E","full_name":"Schoot Uiterkamp, Florianne E"},{"first_name":"Mark F.","last_name":"Bear","full_name":"Bear, Mark F."},{"orcid":"0000-0001-8635-0877","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","last_name":"Siegert","first_name":"Sandra","full_name":"Siegert, Sandra"}],"article_number":"109313","ec_funded":1,"file_date_updated":"2021-07-19T13:32:17Z","project":[{"name":"International IST Doctoral Program","call_identifier":"H2020","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385"},{"_id":"260C2330-B435-11E9-9278-68D0E5697425","grant_number":"754411","call_identifier":"H2020","name":"ISTplus - Postdoctoral Fellowships"},{"grant_number":"715571","_id":"25D4A630-B435-11E9-9278-68D0E5697425","name":"Microglia action towards neuronal circuit formation and function in health and disease","call_identifier":"H2020"}],"quality_controlled":"1","isi":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"external_id":{"isi":["000670188500004"],"pmid":["34233180"]},"language":[{"iso":"eng"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"}],"doi":"10.1016/j.celrep.2021.109313","publication_identifier":{"eissn":["22111247"]},"month":"07"},{"type":"journal_article","issue":"7","abstract":[{"lang":"eng","text":"The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs. "}],"intvolume":" 10","ddc":["570"],"status":"public","title":"The influence of mitochondrial dynamics and function on retinal ganglion cell susceptibility in optic nerve disease","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","_id":"9761","oa_version":"Published Version","file":[{"date_updated":"2021-08-04T14:01:30Z","date_created":"2021-08-04T14:01:30Z","success":1,"checksum":"e0497ce5c77fa3b65a538c7d6e0f6c66","file_id":"9768","relation":"main_file","creator":"cziletti","file_size":4555611,"content_type":"application/pdf","file_name":"2021_Cells_Muench.pdf","access_level":"open_access"}],"scopus_import":"1","has_accepted_license":"1","article_processing_charge":"Yes","day":"25","article_type":"original","citation":{"ama":"Muench NA, Patel S, Maes ME, Donahue RJ, Ikeda A, Nickells RW. The influence of mitochondrial dynamics and function on retinal ganglion cell susceptibility in optic nerve disease. Cells. 2021;10(7). doi:10.3390/cells10071593","apa":"Muench, N. A., Patel, S., Maes, M. E., Donahue, R. J., Ikeda, A., & Nickells, R. W. (2021). The influence of mitochondrial dynamics and function on retinal ganglion cell susceptibility in optic nerve disease. Cells. MDPI. https://doi.org/10.3390/cells10071593","ieee":"N. A. Muench, S. Patel, M. E. Maes, R. J. Donahue, A. Ikeda, and R. W. Nickells, “The influence of mitochondrial dynamics and function on retinal ganglion cell susceptibility in optic nerve disease,” Cells, vol. 10, no. 7. MDPI, 2021.","ista":"Muench NA, Patel S, Maes ME, Donahue RJ, Ikeda A, Nickells RW. 2021. The influence of mitochondrial dynamics and function on retinal ganglion cell susceptibility in optic nerve disease. Cells. 10(7), 1593.","short":"N.A. Muench, S. Patel, M.E. Maes, R.J. Donahue, A. Ikeda, R.W. Nickells, Cells 10 (2021).","mla":"Muench, Nicole A., et al. “The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease.” Cells, vol. 10, no. 7, 1593, MDPI, 2021, doi:10.3390/cells10071593.","chicago":"Muench, Nicole A., Sonia Patel, Margaret E Maes, Ryan J. Donahue, Akihiro Ikeda, and Robert W. Nickells. “The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease.” Cells. MDPI, 2021. https://doi.org/10.3390/cells10071593."},"publication":"Cells","date_published":"2021-06-25T00:00:00Z","article_number":"1593","file_date_updated":"2021-08-04T14:01:30Z","publisher":"MDPI","department":[{"_id":"SaSi"}],"publication_status":"published","pmid":1,"year":"2021","acknowledgement":"The authors are grateful to Kazuya Oikawa and Gillian McLellan for generously sharing some of their data for this review, and to Janis Eells for helpful comments on the manuscript.","volume":10,"date_created":"2021-08-01T22:01:22Z","date_updated":"2023-08-10T14:14:53Z","author":[{"last_name":"Muench","first_name":"Nicole A.","full_name":"Muench, Nicole A."},{"first_name":"Sonia","last_name":"Patel","full_name":"Patel, Sonia"},{"last_name":"Maes","first_name":"Margaret E","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","full_name":"Maes, Margaret E"},{"full_name":"Donahue, Ryan J.","last_name":"Donahue","first_name":"Ryan J."},{"first_name":"Akihiro","last_name":"Ikeda","full_name":"Ikeda, Akihiro"},{"last_name":"Nickells","first_name":"Robert W.","full_name":"Nickells, Robert W."}],"publication_identifier":{"eissn":["20734409"]},"month":"06","quality_controlled":"1","isi":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"external_id":{"pmid":["34201955"],"isi":["000678193300001"]},"language":[{"iso":"eng"}],"doi":"10.3390/cells10071593"},{"file_date_updated":"2022-05-13T07:40:15Z","article_number":"14","author":[{"full_name":"Schmitt, Heather M.","first_name":"Heather M.","last_name":"Schmitt"},{"first_name":"Rachel L.","last_name":"Fehrman","full_name":"Fehrman, Rachel L."},{"full_name":"Maes, Margaret E","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","last_name":"Maes","first_name":"Margaret E"},{"last_name":"Yang","first_name":"Huan","full_name":"Yang, Huan"},{"full_name":"Guo, Lian Wang","first_name":"Lian Wang","last_name":"Guo"},{"full_name":"Schlamp, Cassandra L.","last_name":"Schlamp","first_name":"Cassandra L."},{"last_name":"Pelzel","first_name":"Heather R.","full_name":"Pelzel, Heather R."},{"full_name":"Nickells, Robert W.","first_name":"Robert W.","last_name":"Nickells"}],"date_updated":"2023-08-14T06:35:17Z","date_created":"2021-09-12T22:01:23Z","volume":62,"year":"2021","acknowledgement":"The authors thank Joel Dietz for maintaining the mice used in this study, Satoshi Kinoshita and the Translational Research Initiative in Pathology Laboratory at the University of Wisconsin-Madison for cutting retinal sections analyzed in this study, and Mark Banghart for statistical review of the data analysis. Supported by National Eye Institute Grants R01 EY012223 (RWN), R01 EY030123 (RWN), R01 EY029809 (LWG), R01 EY029809 (LWG) and a Vision Research CORE grant P30 EY016665, NRSA grant T32 GM081061, by an unrestricted research grant from Research to Prevent Blindness, Inc., and by a University of Wisconsin-Madison Vilas Life Cycle award and the Frederick A. Davis Research Chair (RWN). ","pmid":1,"publication_status":"published","department":[{"_id":"SaSi"}],"publisher":"Association for Research in Vision and Ophthalmology","month":"08","publication_identifier":{"eissn":["1552-5783"],"issn":["0146-0404"]},"doi":"10.1167/IOVS.62.10.14","language":[{"iso":"eng"}],"tmp":{"name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png"},"external_id":{"pmid":["34398198"],"isi":["000695230000014"]},"oa":1,"quality_controlled":"1","isi":1,"abstract":[{"lang":"eng","text":"Inhibition or targeted deletion of histone deacetylase 3 (HDAC3) is neuroprotective in a variety neurodegenerative conditions, including retinal ganglion cells (RGCs) after acute optic nerve damage. Consistent with this, induced HDAC3 expression in cultured cells shows selective toxicity to neurons. Despite an established role for HDAC3 in neuronal pathology, little is known regarding the mechanism of this pathology."}],"issue":"10","type":"journal_article","oa_version":"Published Version","file":[{"checksum":"c430967746f653aa1ae84ee617f62b73","success":1,"date_created":"2022-05-13T07:40:15Z","date_updated":"2022-05-13T07:40:15Z","relation":"main_file","file_id":"11369","file_size":19707796,"content_type":"application/pdf","creator":"dernst","access_level":"open_access","file_name":"2021_IOVS_Schmitt.pdf"}],"_id":"10000","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","title":"Increased susceptibility and intrinsic apoptotic signaling in neurons by induced HDAC3 expression","ddc":["570"],"status":"public","intvolume":" 62","day":"16","article_processing_charge":"Yes","has_accepted_license":"1","scopus_import":"1","date_published":"2021-08-16T00:00:00Z","publication":"Investigative Ophthalmology and Visual Science","citation":{"apa":"Schmitt, H. M., Fehrman, R. L., Maes, M. E., Yang, H., Guo, L. W., Schlamp, C. L., … Nickells, R. W. (2021). Increased susceptibility and intrinsic apoptotic signaling in neurons by induced HDAC3 expression. Investigative Ophthalmology and Visual Science. Association for Research in Vision and Ophthalmology. https://doi.org/10.1167/IOVS.62.10.14","ieee":"H. M. Schmitt et al., “Increased susceptibility and intrinsic apoptotic signaling in neurons by induced HDAC3 expression,” Investigative Ophthalmology and Visual Science, vol. 62, no. 10. Association for Research in Vision and Ophthalmology, 2021.","ista":"Schmitt HM, Fehrman RL, Maes ME, Yang H, Guo LW, Schlamp CL, Pelzel HR, Nickells RW. 2021. Increased susceptibility and intrinsic apoptotic signaling in neurons by induced HDAC3 expression. Investigative Ophthalmology and Visual Science. 62(10), 14.","ama":"Schmitt HM, Fehrman RL, Maes ME, et al. Increased susceptibility and intrinsic apoptotic signaling in neurons by induced HDAC3 expression. Investigative Ophthalmology and Visual Science. 2021;62(10). doi:10.1167/IOVS.62.10.14","chicago":"Schmitt, Heather M., Rachel L. Fehrman, Margaret E Maes, Huan Yang, Lian Wang Guo, Cassandra L. Schlamp, Heather R. Pelzel, and Robert W. Nickells. “Increased Susceptibility and Intrinsic Apoptotic Signaling in Neurons by Induced HDAC3 Expression.” Investigative Ophthalmology and Visual Science. Association for Research in Vision and Ophthalmology, 2021. https://doi.org/10.1167/IOVS.62.10.14.","short":"H.M. Schmitt, R.L. Fehrman, M.E. Maes, H. Yang, L.W. Guo, C.L. Schlamp, H.R. Pelzel, R.W. Nickells, Investigative Ophthalmology and Visual Science 62 (2021).","mla":"Schmitt, Heather M., et al. “Increased Susceptibility and Intrinsic Apoptotic Signaling in Neurons by Induced HDAC3 Expression.” Investigative Ophthalmology and Visual Science, vol. 62, no. 10, 14, Association for Research in Vision and Ophthalmology, 2021, doi:10.1167/IOVS.62.10.14."},"article_type":"original"},{"has_accepted_license":"1","article_processing_charge":"Yes","day":"10","scopus_import":"1","date_published":"2021-12-10T00:00:00Z","page":"210-224","article_type":"original","citation":{"chicago":"Maes, Margaret E, Gabriele M. Wögenstein, Gloria Colombo, Raquel Casado Polanco, and Sandra Siegert. “Optimizing AAV2/6 Microglial Targeting Identified Enhanced Efficiency in the Photoreceptor Degenerative Environment.” Molecular Therapy - Methods and Clinical Development. Elsevier, 2021. https://doi.org/10.1016/j.omtm.2021.09.006.","short":"M.E. Maes, G.M. Wögenstein, G. Colombo, R. Casado Polanco, S. Siegert, Molecular Therapy - Methods and Clinical Development 23 (2021) 210–224.","mla":"Maes, Margaret E., et al. “Optimizing AAV2/6 Microglial Targeting Identified Enhanced Efficiency in the Photoreceptor Degenerative Environment.” Molecular Therapy - Methods and Clinical Development, vol. 23, Elsevier, 2021, pp. 210–24, doi:10.1016/j.omtm.2021.09.006.","ieee":"M. E. Maes, G. M. Wögenstein, G. Colombo, R. Casado Polanco, and S. Siegert, “Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment,” Molecular Therapy - Methods and Clinical Development, vol. 23. Elsevier, pp. 210–224, 2021.","apa":"Maes, M. E., Wögenstein, G. M., Colombo, G., Casado Polanco, R., & Siegert, S. (2021). Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment. Molecular Therapy - Methods and Clinical Development. Elsevier. https://doi.org/10.1016/j.omtm.2021.09.006","ista":"Maes ME, Wögenstein GM, Colombo G, Casado Polanco R, Siegert S. 2021. Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment. Molecular Therapy - Methods and Clinical Development. 23, 210–224.","ama":"Maes ME, Wögenstein GM, Colombo G, Casado Polanco R, Siegert S. Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment. Molecular Therapy - Methods and Clinical Development. 2021;23:210-224. doi:10.1016/j.omtm.2021.09.006"},"publication":"Molecular Therapy - Methods and Clinical Development","abstract":[{"text":"Adeno-associated viruses (AAVs) are widely used to deliver genetic material in vivo to distinct cell types such as neurons or glial cells, allowing for targeted manipulation. Transduction of microglia is mostly excluded from this strategy, likely due to the cells’ heterogeneous state upon environmental changes, which makes AAV design challenging. Here, we established the retina as a model system for microglial AAV validation and optimization. First, we show that AAV2/6 transduced microglia in both synaptic layers, where layer preference corresponds to the intravitreal or subretinal delivery method. Surprisingly, we observed significantly enhanced microglial transduction during photoreceptor degeneration. Thus, we modified the AAV6 capsid to reduce heparin binding by introducing four point mutations (K531E, R576Q, K493S, and K459S), resulting in increased microglial transduction in the outer plexiform layer. Finally, to improve microglial-specific transduction, we validated a Cre-dependent transgene delivery cassette for use in combination with the Cx3cr1CreERT2 mouse line. Together, our results provide a foundation for future studies optimizing AAV-mediated microglia transduction and highlight that environmental conditions influence microglial transduction efficiency.\r\n","lang":"eng"}],"type":"journal_article","file":[{"creator":"cchlebak","file_size":4794147,"content_type":"application/pdf","file_name":"2021_MolTherMethodsClinDev_Maes.pdf","access_level":"open_access","date_updated":"2022-01-24T07:43:09Z","date_created":"2022-01-24T07:43:09Z","success":1,"checksum":"77dc540e8011c5475031bdf6ccef20a6","file_id":"10657","relation":"main_file"}],"oa_version":"Published Version","intvolume":" 23","title":"Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment","status":"public","ddc":["570"],"user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","_id":"10655","publication_identifier":{"eissn":["2329-0501"]},"month":"12","language":[{"iso":"eng"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"doi":"10.1016/j.omtm.2021.09.006","project":[{"name":"Microglia action towards neuronal circuit formation and function in health and disease","call_identifier":"H2020","_id":"25D4A630-B435-11E9-9278-68D0E5697425","grant_number":"715571"}],"quality_controlled":"1","isi":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"external_id":{"isi":["000748748500019"]},"ec_funded":1,"file_date_updated":"2022-01-24T07:43:09Z","volume":23,"date_created":"2022-01-23T23:01:28Z","date_updated":"2023-11-16T13:12:03Z","author":[{"full_name":"Maes, Margaret E","first_name":"Margaret E","last_name":"Maes","id":"3838F452-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9642-1085"},{"full_name":"Wögenstein, Gabriele M.","first_name":"Gabriele M.","last_name":"Wögenstein"},{"full_name":"Colombo, Gloria","orcid":"0000-0001-9434-8902","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","last_name":"Colombo","first_name":"Gloria"},{"first_name":"Raquel","last_name":"Casado Polanco","id":"15240fc1-dbcd-11ea-9d1d-ac5a786425fd","orcid":"0000-0001-8293-4568","full_name":"Casado Polanco, Raquel"},{"id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8635-0877","first_name":"Sandra","last_name":"Siegert","full_name":"Siegert, Sandra"}],"publisher":"Elsevier","department":[{"_id":"SaSi"},{"_id":"SiHi"}],"publication_status":"published","year":"2021","acknowledgement":"This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 715571). The research was supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Bioimaging Facility, the Life Science Facility, and the Pre-Clinical Facility, namely Sonja Haslinger and Michael Schunn for their animal colony management and support. We would also like to thank Chakrabarty Lab for sharing the plasmids for AAV2/6 production. Finally, we would like to thank the Siegert team members for discussion about the manuscript."},{"day":"01","article_processing_charge":"No","scopus_import":"1","date_published":"2020-02-01T00:00:00Z","publication":"Molecular Neurobiology","citation":{"short":"R. Donahue, M.E. Maes, J. Grosser, R. Nickells, Molecular Neurobiology 57 (2020) 1070–1084.","mla":"Donahue, RJ, et al. “BAX-Depleted Retinal Ganglion Cells Survive and Become Quiescent Following Optic Nerve Damage.” Molecular Neurobiology, vol. 57, no. 2, Springer Nature, 2020, pp. 1070–1084, doi:10.1007/s12035-019-01783-7.","chicago":"Donahue, RJ, Margaret E Maes, JA Grosser, and RW Nickells. “BAX-Depleted Retinal Ganglion Cells Survive and Become Quiescent Following Optic Nerve Damage.” Molecular Neurobiology. Springer Nature, 2020. https://doi.org/10.1007/s12035-019-01783-7.","ama":"Donahue R, Maes ME, Grosser J, Nickells R. BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Molecular Neurobiology. 2020;57(2):1070–1084. doi:10.1007/s12035-019-01783-7","apa":"Donahue, R., Maes, M. E., Grosser, J., & Nickells, R. (2020). BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Molecular Neurobiology. Springer Nature. https://doi.org/10.1007/s12035-019-01783-7","ieee":"R. Donahue, M. E. Maes, J. Grosser, and R. Nickells, “BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage,” Molecular Neurobiology, vol. 57, no. 2. Springer Nature, pp. 1070–1084, 2020.","ista":"Donahue R, Maes ME, Grosser J, Nickells R. 2020. BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Molecular Neurobiology. 57(2), 1070–1084."},"article_type":"original","page":"1070–1084","abstract":[{"lang":"eng","text":"Removal of the Bax gene from mice completely protects the somas of retinal ganglion cells (RGCs) from apoptosis following optic nerve injury. This makes BAX a promising therapeutic target to prevent neurodegeneration. In this study, Bax+/− mice were used to test the hypothesis that lowering the quantity of BAX in RGCs would delay apoptosis following optic nerve injury. RGCs were damaged by performing optic nerve crush (ONC) and then immunostaining for phospho-cJUN, and quantitative PCR were used to monitor the status of the BAX activation mechanism in the months following injury. The apoptotic susceptibility of injured cells was directly tested by virally introducing GFP-BAX into Bax−/− RGCs after injury. The competency of quiescent RGCs to reactivate their BAX activation mechanism was tested by intravitreal injection of the JNK pathway agonist, anisomycin. Twenty-four weeks after ONC, Bax+/− mice had significantly less cell loss in their RGC layer than Bax+/+ mice 3 weeks after ONC. Bax+/− and Bax+/+ RGCs exhibited similar patterns of nuclear phospho-cJUN accumulation immediately after ONC, which persisted in Bax+/− RGCs for up to 7 weeks before abating. The transcriptional activation of BAX-activating genes was similar in Bax+/− and Bax+/+ RGCs following ONC. Intriguingly, cells deactivated their BAX activation mechanism between 7 and 12 weeks after crush. Introduction of GFP-BAX into Bax−/− cells at 4 weeks after ONC showed that these cells had a nearly normal capacity to activate this protein, but this capacity was lost 8 weeks after crush. Collectively, these data suggest that 8–12 weeks after crush, damaged cells no longer displayed increased susceptibility to BAX activation relative to their naïve counterparts. In this same timeframe, retinal glial activation and the signaling of the pro-apoptotic JNK pathway also abated. Quiescent RGCs did not show a timely reactivation of their JNK pathway following intravitreal injection with anisomycin. These findings demonstrate that lowering the quantity of BAX in RGCs is neuroprotective after acute injury. Damaged RGCs enter a quiescent state months after injury and are no longer responsive to an apoptotic stimulus. Quiescent RGCs will require rejuvenation to reacquire functionality."}],"issue":"2","type":"journal_article","oa_version":"Submitted Version","_id":"7033","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","status":"public","title":"BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage","intvolume":" 57","month":"02","publication_identifier":{"eissn":["1559-1182"],"issn":["0893-7648"]},"doi":"10.1007/s12035-019-01783-7","language":[{"iso":"eng"}],"oa":1,"main_file_link":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035206/","open_access":"1"}],"external_id":{"pmid":["31673950"],"isi":["000493754200001"]},"isi":1,"quality_controlled":"1","author":[{"full_name":"Donahue, RJ","last_name":"Donahue","first_name":"RJ"},{"orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","last_name":"Maes","first_name":"Margaret E","full_name":"Maes, Margaret E"},{"full_name":"Grosser, JA","first_name":"JA","last_name":"Grosser"},{"full_name":"Nickells, RW","first_name":"RW","last_name":"Nickells"}],"date_updated":"2023-08-17T14:05:48Z","date_created":"2019-11-18T14:18:39Z","volume":57,"year":"2020","acknowledgement":"This work was supported by National Eye Institute grants R01 EY012223 (RWN), R01 EY030123 (RWN), T32 EY027721 (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), and a Vision Science Core grant P30 EY016665 (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), an unrestricted funding grant from Research to Prevent Blindness (Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison), the Frederick A. Davis Endowment (RWN), and the Mr. and Mrs. George Taylor Foundation (RWN).","pmid":1,"publication_status":"published","department":[{"_id":"SaSi"}],"publisher":"Springer Nature"},{"publication_identifier":{"issn":["0304-3940"]},"month":"08","language":[{"iso":"eng"}],"doi":"10.1016/j.neulet.2019.134310","project":[{"_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385","name":"International IST Doctoral Program","call_identifier":"H2020"},{"_id":"25D4A630-B435-11E9-9278-68D0E5697425","grant_number":"715571","call_identifier":"H2020","name":"Microglia action towards neuronal circuit formation and function in health and disease"},{"_id":"267F75D8-B435-11E9-9278-68D0E5697425","name":"Modulating microglia through G protein-coupled receptor (GPCR) signaling"}],"quality_controlled":"1","isi":1,"external_id":{"isi":["000486094600037"],"pmid":["31158432"]},"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"ec_funded":1,"file_date_updated":"2020-07-14T12:47:33Z","article_number":"134310","volume":707,"date_created":"2019-06-05T13:16:24Z","date_updated":"2023-08-28T09:30:57Z","author":[{"full_name":"Maes, Margaret E","last_name":"Maes","first_name":"Margaret E","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Colombo, Gloria","first_name":"Gloria","last_name":"Colombo","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9434-8902"},{"full_name":"Schulz, Rouven","orcid":"0000-0001-5297-733X","id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87","last_name":"Schulz","first_name":"Rouven"},{"full_name":"Siegert, Sandra","first_name":"Sandra","last_name":"Siegert","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8635-0877"}],"department":[{"_id":"SaSi"}],"publisher":"Elsevier","publication_status":"published","pmid":1,"year":"2019","has_accepted_license":"1","article_processing_charge":"No","day":"10","scopus_import":"1","date_published":"2019-08-10T00:00:00Z","article_type":"original","citation":{"short":"M.E. Maes, G. Colombo, R. Schulz, S. Siegert, Neuroscience Letters 707 (2019).","mla":"Maes, Margaret E., et al. “Targeting Microglia with Lentivirus and AAV: Recent Advances and Remaining Challenges.” Neuroscience Letters, vol. 707, 134310, Elsevier, 2019, doi:10.1016/j.neulet.2019.134310.","chicago":"Maes, Margaret E, Gloria Colombo, Rouven Schulz, and Sandra Siegert. “Targeting Microglia with Lentivirus and AAV: Recent Advances and Remaining Challenges.” Neuroscience Letters. Elsevier, 2019. https://doi.org/10.1016/j.neulet.2019.134310.","ama":"Maes ME, Colombo G, Schulz R, Siegert S. Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges. Neuroscience Letters. 2019;707. doi:10.1016/j.neulet.2019.134310","apa":"Maes, M. E., Colombo, G., Schulz, R., & Siegert, S. (2019). Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges. Neuroscience Letters. Elsevier. https://doi.org/10.1016/j.neulet.2019.134310","ieee":"M. E. Maes, G. Colombo, R. Schulz, and S. Siegert, “Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges,” Neuroscience Letters, vol. 707. Elsevier, 2019.","ista":"Maes ME, Colombo G, Schulz R, Siegert S. 2019. Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges. Neuroscience Letters. 707, 134310."},"publication":"Neuroscience Letters","abstract":[{"lang":"eng","text":"Microglia have emerged as a critical component of neurodegenerative diseases. Genetic manipulation of microglia can elucidate their functional impact in disease. In neuroscience, recombinant viruses such as lentiviruses and adeno-associated viruses (AAVs) have been successfully used to target various cell types in the brain, although effective transduction of microglia is rare. In this review, we provide a short background of lentiviruses and AAVs, and strategies for designing recombinant viral vectors. Then, we will summarize recent literature on successful microglial transductions in vitro and in vivo, and discuss the current challenges. Finally, we provide guidelines for reporting the efficiency and specificity of viral targeting in microglia, which will enable the microglial research community to assess and improve methodologies for future studies."}],"type":"journal_article","oa_version":"Published Version","file":[{"access_level":"open_access","file_name":"2019_Neuroscience_Maes.pdf","content_type":"application/pdf","file_size":1779287,"creator":"dernst","relation":"main_file","file_id":"6551","checksum":"553c9dbd39727fbed55ee991c51ca4d1","date_created":"2019-06-08T11:44:20Z","date_updated":"2020-07-14T12:47:33Z"}],"intvolume":" 707","ddc":["570"],"status":"public","title":"Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","_id":"6521"},{"language":[{"iso":"eng"}],"doi":"10.1038/s41598-019-53049-w","quality_controlled":"1","isi":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"external_id":{"pmid":["31719602"],"isi":["000495857600019"]},"oa":1,"month":"11","publication_identifier":{"eissn":["2045-2322"]},"date_created":"2019-11-25T07:45:17Z","date_updated":"2023-08-30T07:26:54Z","volume":9,"author":[{"orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","last_name":"Maes","first_name":"Margaret E","full_name":"Maes, Margaret E"},{"full_name":"Grosser, J. A.","last_name":"Grosser","first_name":"J. A."},{"first_name":"R. L.","last_name":"Fehrman","full_name":"Fehrman, R. L."},{"last_name":"Schlamp","first_name":"C. L.","full_name":"Schlamp, C. L."},{"full_name":"Nickells, R. W.","first_name":"R. W.","last_name":"Nickells"}],"publication_status":"published","publisher":"Springer Nature","department":[{"_id":"SaSi"}],"year":"2019","pmid":1,"file_date_updated":"2020-07-14T12:47:49Z","article_number":"16565","date_published":"2019-11-12T00:00:00Z","article_type":"original","publication":"Scientific Reports","citation":{"ista":"Maes ME, Grosser JA, Fehrman RL, Schlamp CL, Nickells RW. 2019. Completion of BAX recruitment correlates with mitochondrial fission during apoptosis. Scientific Reports. 9, 16565.","ieee":"M. E. Maes, J. A. Grosser, R. L. Fehrman, C. L. Schlamp, and R. W. Nickells, “Completion of BAX recruitment correlates with mitochondrial fission during apoptosis,” Scientific Reports, vol. 9. Springer Nature, 2019.","apa":"Maes, M. E., Grosser, J. A., Fehrman, R. L., Schlamp, C. L., & Nickells, R. W. (2019). Completion of BAX recruitment correlates with mitochondrial fission during apoptosis. Scientific Reports. Springer Nature. https://doi.org/10.1038/s41598-019-53049-w","ama":"Maes ME, Grosser JA, Fehrman RL, Schlamp CL, Nickells RW. Completion of BAX recruitment correlates with mitochondrial fission during apoptosis. Scientific Reports. 2019;9. doi:10.1038/s41598-019-53049-w","chicago":"Maes, Margaret E, J. A. Grosser, R. L. Fehrman, C. L. Schlamp, and R. W. Nickells. “Completion of BAX Recruitment Correlates with Mitochondrial Fission during Apoptosis.” Scientific Reports. Springer Nature, 2019. https://doi.org/10.1038/s41598-019-53049-w.","mla":"Maes, Margaret E., et al. “Completion of BAX Recruitment Correlates with Mitochondrial Fission during Apoptosis.” Scientific Reports, vol. 9, 16565, Springer Nature, 2019, doi:10.1038/s41598-019-53049-w.","short":"M.E. Maes, J.A. Grosser, R.L. Fehrman, C.L. Schlamp, R.W. Nickells, Scientific Reports 9 (2019)."},"day":"12","article_processing_charge":"No","has_accepted_license":"1","scopus_import":"1","file":[{"file_id":"7096","relation":"main_file","date_updated":"2020-07-14T12:47:49Z","date_created":"2019-11-25T07:49:52Z","checksum":"9ab397ed9c1c454b34bffb8cc863d734","file_name":"2019_ScientificReports_Maes.pdf","access_level":"open_access","creator":"dernst","file_size":6467393,"content_type":"application/pdf"}],"oa_version":"Published Version","status":"public","title":"Completion of BAX recruitment correlates with mitochondrial fission during apoptosis","ddc":["570"],"intvolume":" 9","_id":"7095","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","abstract":[{"text":"BAX, a member of the BCL2 gene family, controls the committed step of the intrinsic apoptotic program. Mitochondrial fragmentation is a commonly observed feature of apoptosis, which occurs through the process of mitochondrial fission. BAX has consistently been associated with mitochondrial fission, yet how BAX participates in the process of mitochondrial fragmentation during apoptosis remains to be tested. Time-lapse imaging of BAX recruitment and mitochondrial fragmentation demonstrates that rapid mitochondrial fragmentation during apoptosis occurs after the complete recruitment of BAX to the mitochondrial outer membrane (MOM). The requirement of a fully functioning BAX protein for the fission process was demonstrated further in BAX/BAK-deficient HCT116 cells expressing a P168A mutant of BAX. The mutant performed fusion to restore the mitochondrial network. but was not demonstrably recruited to the MOM after apoptosis induction. Under these conditions, mitochondrial fragmentation was blocked. Additionally, we show that loss of the fission protein, dynamin-like protein 1 (DRP1), does not temporally affect the initiation time or rate of BAX recruitment, but does reduce the final level of BAX recruited to the MOM during the late phase of BAX recruitment. These correlative observations suggest a model where late-stage BAX oligomers play a functional part of the mitochondrial fragmentation machinery in apoptotic cells.","lang":"eng"}],"type":"journal_article"},{"publist_id":"7254","file_date_updated":"2020-07-14T12:47:04Z","volume":58,"date_updated":"2023-10-10T14:06:18Z","date_created":"2018-12-11T11:47:10Z","author":[{"full_name":"Nickells, Robert","last_name":"Nickells","first_name":"Robert"},{"first_name":"Heather","last_name":"Schmitt","full_name":"Schmitt, Heather"},{"full_name":"Maes, Margaret E","orcid":"0000-0001-9642-1085","id":"3838F452-F248-11E8-B48F-1D18A9856A87","last_name":"Maes","first_name":"Margaret E"},{"first_name":"Cassandra","last_name":"Schlamp","full_name":"Schlamp, Cassandra"}],"publisher":"Association for Research in Vision and Ophthalmology","department":[{"_id":"SaSi"}],"publication_status":"published","year":"2017","publication_identifier":{"issn":["01460404"]},"month":"12","language":[{"iso":"eng"}],"doi":"10.1167/iovs.17-22634","quality_controlled":"1","oa":1,"tmp":{"name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png"},"issue":"14","abstract":[{"text":"PURPOSE. Gene therapy of retinal ganglion cells (RGCs) has promise as a powerful therapeutic for the rescue and regeneration of these cells after optic nerve damage. However, early after damage, RGCs undergo atrophic changes, including gene silencing. It is not known if these changes will deleteriously affect transduction and transgene expression, or if the therapeutic protein can influence reactivation of the endogenous genome. METHODS. Double-transgenic mice carrying a Rosa26-(LoxP)-tdTomato reporter, and a mutant allele for the proapoptotic Bax gene were reared. The Bax mutant blocks apoptosis, but RGCs still exhibit nuclear atrophy and gene silencing. At times ranging from 1 hour to 4 weeks after optic nerve crush (ONC), eyes received an intravitreal injection of AAV2 virus carrying the Cre recombinase. Successful transduction was monitored by expression of the tdTomato reporter. Immunostaining was used to localize tdTomato expression in select cell types. RESULTS. Successful transduction of RGCs was achieved at all time points after ONC using AAV2 expressing Cre from the phosphoglycerate kinase (Pgk) promoter, but not the CMV promoter. ONC promoted an increase in the transduction of cell types in the inner nuclear layer, including Müller cells and rod bipolar neurons. There was minimal evidence of transduction of amacrine cells and astrocytes in the inner retina or optic nerve. CONCLUSIONS. Damaged RGCs can be transduced and at least some endogenous genes can be subsequently activated. Optic nerve damage may change retinal architecture to allow greater penetration of an AAV2 virus to transduce several additional cell types in the inner nuclear layer.","lang":"eng"}],"type":"journal_article","oa_version":"Published Version","file":[{"file_name":"IST-2018-920-v1+1_i1552-5783-58-14-6091.pdf","access_level":"open_access","content_type":"application/pdf","file_size":2955559,"creator":"system","relation":"main_file","file_id":"5311","date_created":"2018-12-12T10:17:53Z","date_updated":"2020-07-14T12:47:04Z","checksum":"d7a7b6f1fa9211a04e5e65634a0265d9"}],"pubrep_id":"920","intvolume":" 58","status":"public","title":"AAV2 mediated transduction of the mouse retina after optic nerve injury","ddc":["576"],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","_id":"557","article_processing_charge":"No","has_accepted_license":"1","day":"14","scopus_import":"1","date_published":"2017-12-14T00:00:00Z","page":"6091 - 6104","citation":{"ama":"Nickells R, Schmitt H, Maes ME, Schlamp C. AAV2 mediated transduction of the mouse retina after optic nerve injury. Investigative Ophthalmology and Visual Science. 2017;58(14):6091-6104. doi:10.1167/iovs.17-22634","ista":"Nickells R, Schmitt H, Maes ME, Schlamp C. 2017. AAV2 mediated transduction of the mouse retina after optic nerve injury. Investigative Ophthalmology and Visual Science. 58(14), 6091–6104.","ieee":"R. Nickells, H. Schmitt, M. E. Maes, and C. Schlamp, “AAV2 mediated transduction of the mouse retina after optic nerve injury,” Investigative Ophthalmology and Visual Science, vol. 58, no. 14. Association for Research in Vision and Ophthalmology, pp. 6091–6104, 2017.","apa":"Nickells, R., Schmitt, H., Maes, M. E., & Schlamp, C. (2017). AAV2 mediated transduction of the mouse retina after optic nerve injury. Investigative Ophthalmology and Visual Science. Association for Research in Vision and Ophthalmology. https://doi.org/10.1167/iovs.17-22634","mla":"Nickells, Robert, et al. “AAV2 Mediated Transduction of the Mouse Retina after Optic Nerve Injury.” Investigative Ophthalmology and Visual Science, vol. 58, no. 14, Association for Research in Vision and Ophthalmology, 2017, pp. 6091–104, doi:10.1167/iovs.17-22634.","short":"R. Nickells, H. Schmitt, M.E. Maes, C. Schlamp, Investigative Ophthalmology and Visual Science 58 (2017) 6091–6104.","chicago":"Nickells, Robert, Heather Schmitt, Margaret E Maes, and Cassandra Schlamp. “AAV2 Mediated Transduction of the Mouse Retina after Optic Nerve Injury.” Investigative Ophthalmology and Visual Science. Association for Research in Vision and Ophthalmology, 2017. https://doi.org/10.1167/iovs.17-22634."},"publication":"Investigative Ophthalmology and Visual Science"}]