{"external_id":{"pmid":["32118314"]},"quality_controlled":"1","_id":"7586","abstract":[{"lang":"eng","text":"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."}],"volume":39,"date_published":"2020-03-02T00:00:00Z","file_date_updated":"2020-07-14T12:48:00Z","file":[{"checksum":"82750a7a93e3740decbce8474004111a","relation":"main_file","content_type":"application/pdf","creator":"dernst","file_id":"7615","date_created":"2020-03-23T13:51:11Z","date_updated":"2020-07-14T12:48:00Z","file_size":12243278,"access_level":"open_access","file_name":"2020_EMBO_Weinert.pdf"}],"department":[{"_id":"GaNo"}],"intvolume":"        39","oa":1,"language":[{"iso":"eng"}],"publication":"EMBO Journal","year":"2020","type":"journal_article","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","article_type":"original","publication_identifier":{"eissn":["14602075"],"issn":["02614189"]},"article_number":"e103358","oa_version":"Published Version","tmp":{"name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"has_accepted_license":"1","citation":{"ista":"Weinert S, Gimber N, Deuschel D, Stuhlmann T, Puchkov D, Farsi Z, Ludwig CF, Novarino G, López-Cayuqueo KI, Planells-Cases R, Jentsch TJ. 2020. Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal. 39, e103358.","apa":"Weinert, S., Gimber, N., Deuschel, D., Stuhlmann, T., Puchkov, D., Farsi, Z., … Jentsch, T. J. (2020). Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. <i>EMBO Journal</i>. EMBO Press. <a href=\"https://doi.org/10.15252/embj.2019103358\">https://doi.org/10.15252/embj.2019103358</a>","mla":"Weinert, Stefanie, et al. “Uncoupling Endosomal CLC Chloride/Proton Exchange Causes Severe Neurodegeneration.” <i>EMBO Journal</i>, vol. 39, e103358, EMBO Press, 2020, doi:<a href=\"https://doi.org/10.15252/embj.2019103358\">10.15252/embj.2019103358</a>.","chicago":"Weinert, Stefanie, Niclas Gimber, Dorothea Deuschel, Till Stuhlmann, Dmytro Puchkov, Zohreh Farsi, Carmen F. Ludwig, et al. “Uncoupling Endosomal CLC Chloride/Proton Exchange Causes Severe Neurodegeneration.” <i>EMBO Journal</i>. EMBO Press, 2020. <a href=\"https://doi.org/10.15252/embj.2019103358\">https://doi.org/10.15252/embj.2019103358</a>.","short":"S. Weinert, N. Gimber, D. Deuschel, T. Stuhlmann, D. Puchkov, Z. Farsi, C.F. Ludwig, G. Novarino, K.I. López-Cayuqueo, R. Planells-Cases, T.J. Jentsch, EMBO Journal 39 (2020).","ama":"Weinert S, Gimber N, Deuschel D, et al. Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. <i>EMBO Journal</i>. 2020;39. doi:<a href=\"https://doi.org/10.15252/embj.2019103358\">10.15252/embj.2019103358</a>","ieee":"S. Weinert <i>et al.</i>, “Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration,” <i>EMBO Journal</i>, vol. 39. EMBO Press, 2020."},"pmid":1,"author":[{"last_name":"Weinert","full_name":"Weinert, Stefanie","first_name":"Stefanie"},{"last_name":"Gimber","full_name":"Gimber, Niclas","first_name":"Niclas"},{"first_name":"Dorothea","full_name":"Deuschel, Dorothea","last_name":"Deuschel"},{"full_name":"Stuhlmann, Till","last_name":"Stuhlmann","first_name":"Till"},{"first_name":"Dmytro","last_name":"Puchkov","full_name":"Puchkov, Dmytro"},{"first_name":"Zohreh","last_name":"Farsi","full_name":"Farsi, Zohreh"},{"first_name":"Carmen F.","last_name":"Ludwig","full_name":"Ludwig, Carmen F."},{"full_name":"Novarino, Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"},{"last_name":"López-Cayuqueo","full_name":"López-Cayuqueo, Karen I.","first_name":"Karen I."},{"first_name":"Rosa","last_name":"Planells-Cases","full_name":"Planells-Cases, Rosa"},{"first_name":"Thomas J.","last_name":"Jentsch","full_name":"Jentsch, Thomas J."}],"acknowledgement":"We thank T. Stauber and T. Breiderhoff for cloning expression constructs; K. Räbel, S. Hohensee, and C. Backhaus for technical assistance; R. Jahn (MPIbpc, Göttingen) for providing the equipment required for SV purification; and A\r\nWoehler (MDC, Berlin) for assistance with SV imaging. Supported, in part, by grants from the Deutsche Forschungsgemeinschaft (JE164/9-2, SFB740 TP C5, FOR 2625 (JE164/14-1), NeuroCure Cluster of Excellence), the European Research Council Advanced Grant CYTOVOLION (ERC 294435) and the Prix Louis-Jeantet de Médecine to TJJ, and Peter and Traudl Engelhorn fellowship to ZF.","title":"Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration","day":"02","publisher":"EMBO Press","article_processing_charge":"No","publication_status":"published","status":"public","month":"03","ddc":["570"],"date_created":"2020-03-15T23:00:55Z","date_updated":"2021-01-12T08:14:21Z","doi":"10.15252/embj.2019103358","scopus_import":"1"}