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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
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.
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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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