title: VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease.
abstract: 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.
authors: Department of Physiology &Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Xing
authors: X
authors: Guo
authors: Department of Physiology &Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: XiaoYan
authors: X
authors: Sun
authors: Department of Physiology &Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Di
authors: D
authors: Hu
authors: Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Ya-Juan
authors: YJ
authors: Wang
authors: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Hisashi
authors: H
authors: Fujioka
authors: Department of Physiology &Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Rajan
authors: R
authors: Vyas
authors: Department of Physiology &Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Sudha
authors: S
authors: Chakrapani
authors: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94043, USA.
authors: Amit Umesh
authors: AU
authors: Joshi
authors: Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Yu
authors: Y
authors: Luo
authors: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94043, USA.
authors: Daria
authors: D
authors: Mochly-Rosen
authors: Department of Physiology &Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.|Center for Mitochondrial Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Xin
authors: 0000-0002-9578-3890
authors: X
authors: Qi
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy; D050505:Mutant Proteins / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D061251:Primary Cell Culture; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D040901:Proteomics; D051381:Rats; D000074405:Valosin Containing Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D010455:Peptides; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse