Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration.

Abstract

CLC chloride/proton exchangers may support acidification of endolysosomes and raise their luminal Clconcentration. Disruption of endosomal ClC-3 causes severe neurodegeneration. To assess the importance of ClC-3 Cl/Hexchange, we now generate Clcn3mice in which ClC-3 is converted into a Clchannel. Unlike Clcn3mice, Clcn3mice 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 Clcn3mice because ClC-3binds and stabilizes ClC-4 like wild-type ClC-3. Although mice lacking ClC-4 appear healthy, its absence in Clcn3/Clcn4mice entails even stronger neurodegeneration than observed in Clcn3mice. A fraction of ClC-3 is found on synaptic vesicles, but miniature postsynaptic currents and synaptic vesicle acidification are not affected in Clcn3or Clcn3mice 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.