Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. (2nd March 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO journal. Volume 39:Number 9(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-03-02
• Subjects: anion transport -- anion–proton exchanger -- intracellular trafficking -- retina -- VGLUT1; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2019103358
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: The importance of intracellular ClC‐3 channel conductance versus chloride/proton exchange activity for endosome and synaptic vesicle function remain unclear. Here, study of a new ClC‐3 uncoupling mouse mutant ( Clcn3 unc/unc ) reveals that proton transport by ClC‐3/ClC‐4 heterodimers is crucial for central nervous system integrity. Clcn3 unc/unc mice devoid of channel function do not exhibit neurodegeneration. ClC‐3 forms heterodimers with ClC‐4 and stabilizes it. Depletion of ClC‐4 in Clcn3 unc/unc mice causes severe neurodegeneration. ClC‐3 has no functional role in synaptic vesicles. Abstract : ClC‐3 antiporter activity and heterodimerization with ClC‐4 are critical for endolysosomal acidification and central nervous system integrity.