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Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration
Author(s) -
Weinert Stefanie,
Gimber Niclas,
Deuschel Dorothea,
Stuhlmann Till,
Puchkov Dmytro,
Farsi Zohreh,
Ludwig Carmen F,
Novarino Gaia,
LópezCayuqueo Karen I,
PlanellsCases Rosa,
Jentsch Thomas J
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103358
Subject(s) - endosome , biology , neurodegeneration , microbiology and biotechnology , biochemistry , receptor , medicine , disease
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.