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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 converte...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196918/ https://www.ncbi.nlm.nih.gov/pubmed/32118314 http://dx.doi.org/10.15252/embj.2019103358 |
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author | Weinert, Stefanie Gimber, Niclas Deuschel, Dorothea Stuhlmann, Till Puchkov, Dmytro Farsi, Zohreh Ludwig, Carmen F Novarino, Gaia López‐Cayuqueo, Karen I Planells‐Cases, Rosa Jentsch, Thomas J |
author_facet | Weinert, Stefanie Gimber, Niclas Deuschel, Dorothea Stuhlmann, Till Puchkov, Dmytro Farsi, Zohreh Ludwig, Carmen F Novarino, Gaia López‐Cayuqueo, Karen I Planells‐Cases, Rosa Jentsch, Thomas J |
author_sort | Weinert, Stefanie |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7196918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71969182020-05-04 Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration Weinert, Stefanie Gimber, Niclas Deuschel, Dorothea Stuhlmann, Till Puchkov, Dmytro Farsi, Zohreh Ludwig, Carmen F Novarino, Gaia López‐Cayuqueo, Karen I Planells‐Cases, Rosa Jentsch, Thomas J EMBO J Articles 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. John Wiley and Sons Inc. 2020-03-02 2020-05-04 /pmc/articles/PMC7196918/ /pubmed/32118314 http://dx.doi.org/10.15252/embj.2019103358 Text en © 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Weinert, Stefanie Gimber, Niclas Deuschel, Dorothea Stuhlmann, Till Puchkov, Dmytro Farsi, Zohreh Ludwig, Carmen F Novarino, Gaia López‐Cayuqueo, Karen I Planells‐Cases, Rosa Jentsch, Thomas J Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration |
title | Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration |
title_full | Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration |
title_fullStr | Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration |
title_full_unstemmed | Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration |
title_short | Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration |
title_sort | uncoupling endosomal clc chloride/proton exchange causes severe neurodegeneration |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196918/ https://www.ncbi.nlm.nih.gov/pubmed/32118314 http://dx.doi.org/10.15252/embj.2019103358 |
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