Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration

EMBO J. 2020 May 4;39(9):e103358. doi: 10.15252/embj.2019103358. Epub 2020 Mar 2.


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.

Keywords: VGLUT1; anion transport; anion-proton exchanger; intracellular trafficking; retina.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chloride Channels / genetics*
  • Chloride Channels / metabolism*
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Endosomes / metabolism*
  • Mice
  • Mutation
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Synaptic Vesicles / metabolism


  • CLC-5 chloride channel
  • Chloride Channels
  • ClC-3 channel