Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration.

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^-/- m

SUBMITTER: Weinert S 

PROVIDER: S-EPMC7196918 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature