Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration.

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.

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