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 Clcn3unc/unc mice in which ClC-3 is converted into a Cl- channel. Unlike Clcn3-/- mice, Clcn3unc/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 Clcn3unc/unc mice because ClC-3unc binds and stabilizes ClC-4 like wild-type ClC-3. Although mice lacking ClC-4 appear healthy, its absence in Clcn3unc/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 Clcn3unc/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.

中文翻译：

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内体CLC氯化物/质子交换的解偶联导致严重的神经变性。

CLC氯化物/质子交换剂可支持溶酶体的酸化并提高其腔内Cl浓度。内体ClC-3的破坏引起严重的神经变性。为了评估ClC-3 Cl- / H +交换的重要性，我们现在生成了Clcn3unc / unc小鼠，其中ClC-3转换为Cl-通道。与Clcn3-/-小鼠不同，Clcn3unc / unc小鼠由于ClC-4与ClC-3形成异聚体的补偿而显得正常。ClCl-4蛋白水平在Clcn3-/-中会大大降低，但在Clcn3unc / unc小鼠中不会降低，因为ClC-3unc像野生型ClC-3一样结合并稳定了ClC-4。尽管缺乏ClC-4的小鼠看起来很健康，但与Clcn3-/-小鼠相比，Clcn3unc / unc / Clcn4-/-小鼠中缺乏它会导致更强的神经变性。在突触小泡中发现了一部分ClC-3，