Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration

Autor: Carmen F Ludwig, Rosa Planells-Cases, Till Stuhlmann, Stefanie Weinert, Dorothea Deuschel, Dmytro Puchkov, Thomas J. Jentsch, Niclas Gimber, Gaia Novarino, Karen I. López-Cayuqueo, Zohreh Farsi
Jazyk: angličtina
Rok vydání: 2020
Předmět:
anion transport
retina
Endosome
intracellular trafficking
VGLUT1
Endosomes
macromolecular substances
Biology
Chloride
Synaptic vesicle
General Biochemistry
Genetics and Molecular Biology
Article
Mice
03 medical and health sciences
0302 clinical medicine
Chloride Channels
Chlorocebus aethiops
medicine
Animals
News & Views
Membrane & Intracellular Transport
Molecular Biology
030304 developmental biology
0303 health sciences
General Immunology and Microbiology
urogenital system
General Neuroscience
Neurodegeneration
fungi
Neurodegenerative Diseases
Articles
medicine.disease
Cell biology
Disease Models
Animal
nervous system
Cardiovascular and Metabolic Diseases
COS Cells
Mutation
Synaptic Vesicles
Technology Platforms
Function and Dysfunction of the Nervous System
030217 neurology & neurosurgery
anion–proton exchanger
medicine.drug
Neuroscience
Zdroj: The EMBO Journal
EMBO J
ISSN: 1460-2075
0261-4189
Popis: 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‐3unc 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.
ClC‐3 antiporter activity and heterodimerization with ClC‐4 are critical for endolysosomal acidification and central nervous system integrity.
Databáze: OpenAIRE
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