| First Author | Weinert S | Year | 2020 |
| Journal | EMBO J | Volume | 39 |
| Issue | 9 | Pages | e103358 |
| PubMed ID | 32118314 | Mgi Jnum | J:297238 |
| Mgi Id | MGI:6441641 | Doi | 10.15252/embj.2019103358 |
| Citation | Weinert S, et al. (2020) Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO J 39(9):e103358 |
| abstractText | 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. |
