VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington’s disease
Open accessAbstract
Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington’s disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD.
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- Authors
- Guo, X., Sun, X., Hu, D., Wang, Y.-J., Fujioka, H., Vyas, R., Chakrapani, S., Joshi, A. U., Luo, Y., Mochly-Rosen, D., & Qi, X.
- Affiliations
- Case Western Reserve University (US)
- Stanford Medicine (US)
- Corresponding author
- Qi, Xin
- ORCID
- Venue
- Nature Communications
- Published
- 2016-08-26
- Volume
- 7
- Issue
- 1
- Pages
- 12646-12646
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5007466
- OpenAlex
- W2516126943
- Cited by
- 200
- References
- 70
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 26 · 2023: 23 · 2022: 24 · 2021: 24 · 2020: 25 · 2019: 20 · 2018: 17 · 2017: 8 · 2016: 3
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association (12SDG12070069)
- Shenyang Pharmaceutical University
- National Institutes of Health (NIH-R01, NS088192)
- National Heart, Lung, and Blood Institute (R01HL052141)
- National Institute of General Medical Sciences (R01GM108921)
- National Institute of Neurological Disorders and Stroke (R01NS088192, R01NS091213)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Huntington's disease, VCP, mutant huntingtin, mitophagy, mitochondrial translocation, neurodegeneration, neuronal cell death, peptide therapeutics, mitochondrial proteomics, transgenic mouse model
- MeSH terms
- Huntingtin Protein, Valosin Containing Protein, Adult, Animals, Behavior, Animal, Cell Line, Corpus Striatum, Disease Models, Animal, Fibroblasts, Humans, Huntington Disease, Male, Mice, Transgenic, Mitochondria, Neurons, Peptides, Protein Binding, Apoptosis, Protein Transport, Proteomics, Mutant Proteins, Mice, Rats, Primary Cell Culture, Mitophagy
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