title: Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration.
abstract: Folding of transmembrane and secretory proteins occurs in the lumen of the endoplasmic reticulum (ER) before transportation to the cell surface and is monitored by the unfolded protein response (UPR) signaling pathway. The accumulation of unfolded proteins in the ER activates the UPR that restores ER homeostasis by regulating gene expression that leads to an increase in the protein-folding capacity of the ER and a decrease in the ER protein-folding load. However, prolonged UPR activity has been associated with cell death in multiple pathological conditions, including neurodegeneration. Here, we report a spontaneous recessive mouse mutation that causes progressive cerebellar granule cell death and peripheral motor axon degeneration. By positional cloning, we identify the mutation in this strain as a retrotransposon insertion in the Clcc1 gene, which encodes a putative chloride channel localized to the ER. Furthermore, we demonstrate that the C3H/HeSnJ inbred strain has late onset cerebellar degeneration due to this mutation. Interestingly, acute knockdown of Clcc1 expression in cultured cells increases sensitivity to ER stress. In agreement, GRP78, the major HSP70 family chaperone in the ER, is upregulated in Clcc1-deficient granule cells in vivo, and ubiquitinated proteins accumulate in these neurons before their degeneration. These data suggest that disruption of chloride homeostasis in the ER disrupts the protein-folding capacity of the ER, leading to eventual neuron death.
authors.affiliation: Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Yichang
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jucius
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Cook
authors.affiliation: Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, Maine 04609 susan.ackerman@jax.org.
authors.forename: Susan L
authors.identifier: http://orcid.org/0000-0002-6740-593X
authors.initials: SL
authors.lastname: Ackerman
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology; D018118:Chloride Channels / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
chemical_list: D018118:Chloride Channels; C503392:Clcc1 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D012333:RNA, Messenger
keywords: ER stress; ataxia; cerebellum; degeneration; endoplasmic reticulum; granule cell