Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration

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 (n.d.) e103358.

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Abstract
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.
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Date Published
2020-03-02
Journal Title
EMBO Journal
Article Number
e103358
ISSN
eISSN
IST-REx-ID

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Weinert S, Gimber N, Deuschel D, et al. Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal.:e103358. doi:10.15252/embj.2019103358
Weinert, S., Gimber, N., Deuschel, D., Stuhlmann, T., Puchkov, D., Farsi, Z., … Jentsch, T. J. (n.d.). Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal, e103358. https://doi.org/10.15252/embj.2019103358
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, n.d., e103358. https://doi.org/10.15252/embj.2019103358.
S. Weinert et al., “Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration,” EMBO Journal, p. e103358.
Weinert S, Gimber N, Deuschel D, Stuhlmann T, Puchkov D, Farsi Z, Ludwig CF, Novarino G, López-Cayuqueo KI, Planells-Cases R, Jentsch TJ. Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal., e103358.
Weinert, Stefanie, et al. “Uncoupling Endosomal CLC Chloride/Proton Exchange Causes Severe Neurodegeneration.” EMBO Journal, EMBO Press, p. e103358, doi:10.15252/embj.2019103358.
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