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Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration

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Item Type:Article
Title:Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration
Creators Name:Weinert, S. and Gimber, N. and Deuschel, D. and Stuhlmann, T. and Puchkov, D. and Farsi, Z. and Ludwig, C.F. and Novarino, G. and López-Cayuqueo, K.I. and Planells-Cases, R. and Jentsch, T.J.
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 Clcn3(unc/unc) mice in which ClC-3 is converted into a Cl(-) channel. Unlike Clcn3(-/-) mice, Clcn3(unc/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 Clcn3(unc/unc) mice because ClC-3(unc) binds and stabilizes ClC-4 like wild-type ClC-3. Although mice lacking ClC-4 appear healthy, its absence in Clcn3(unc/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 Clcn3(unc/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.
Keywords:Anion Transport, Anion-Proton Exchanger, Intracellular Trafficking, Retina, VGLUT1, Animals, Mice
Source:EMBO Journal
Publisher:EMBO Press
Page Range:e103358
Date:4 May 2020
Official Publication:https://doi.org/10.15252/embj.2019103358
PubMed:View item in PubMed

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