ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 51 citations in OpenAlex.
- The accessory protein ORF3a hijacks the CLCC1 chloride channel to disrupt ER homeostasis in betacoronavirus pathogenesis.Cell discovery · 2026Article
- The identity crisis of cryptic lncRNAs: when non-coding RNAs translate into small peptides.The EMBO journal · 2026Review
- PIGBOS-CLCC1 interaction shapes cellular calcium dynamics and energy metabolism.Cell communication and signaling : CCS · 2026Article
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- ER protein CLCC1 promotes nuclear envelope fusion in herpesviral and host processes.Nature communications · 2025Article
- Emerging roles for microproteins as critical regulators of endoplasmic reticulum function and cellular homeostasis.Seminars in cell & developmental biology · 2025Review
- Unravelling axonal transcriptional landscapes: insights from induced pluripotent stem cell-derived cortical neurons and implications for motor neuron degeneration.Open biology · 2025Article
- Mutation and clinical analysis of the CLCC1 gene in amyotrophic lateral sclerosis patients from Central South China.Annals of clinical and translational neurology · 2024Article
- Ultrasonic vocalization phenotypes in the Ts65Dn and Dp(16)1Yey mouse models of Down syndrome.Physiology & behavior · 2023Article
- Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies.Cell research · 2023Article
- Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees.Human molecular genetics · 2023Article
- Electrical signals in the ER are cell type and stimulus specific with extreme spatial compartmentalization in neurons.Cell reports · 2023Article
- SARS-CoV-2PeerJ · 2023Article
- A Superfolder Green Fluorescent Protein-Based Biosensor Allows Monitoring of Chloride in the Endoplasmic Reticulum.ACS sensors · 2022Article
- Microproteins in skeletal muscle: hidden keys in muscle physiology.Journal of cachexia, sarcopenia and muscle · 2022Review
- SARS-CoV-2 nucleocapsid protein binds host mRNAs and attenuates stress granules to impair host stress response.iScience · 2022Article
- CLCC1 c. 75C>A Mutation in Pakistani Derived Retinitis Pigmentosa Families Likely Originated With a Single Founder Mutation 2,000-5,000 Years Ago.Frontiers in genetics · 2022Article
- In silico analysis of the aggregation propensity of the SARS-CoV-2 proteome: Insight into possible cellular pathologies.Biochimica et biophysica acta. Proteins and proteomics · 2021Article
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Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.