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| Item Type: | Article |
|---|---|
| Title: | Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration |
| Creators Name: | Weinert, S. and Gimber, N. and Deuschel, D. and Stuhlmann, T. and Puchkov, D. and Farsi, Z. and Ludwig, C.F. and Novarino, G. and López-Cayuqueo, K.I. and Planells-Cases, R. and Jentsch, T.J. |
| 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(-/-) 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. |
| Keywords: | Anion Transport, Anion-Proton Exchanger, Intracellular Trafficking, Retina, VGLUT1, Animals, Mice |
| Source: | EMBO Journal |
| ISSN: | 0261-4189 |
| Publisher: | EMBO Press / Wiley |
| Volume: | 39 |
| Number: | 9 |
| Page Range: | e103358 |
| Date: | 4 May 2020 |
| Official Publication: | https://doi.org/10.15252/embj.2019103358 |
| PubMed: | View item in PubMed |
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