VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington’s disease

Xing Guo, XiaoYan Sun, Di Hu, Ya-Juan Wang, Hisashi Fujioka, Rajan Vyas, Sudha Chakrapani, Amit Umesh Joshi, Yu Luo, Daria Mochly-Rosen and Xin Qi ()
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Xing Guo: Case Western Reserve University School of Medicine
XiaoYan Sun: Case Western Reserve University School of Medicine
Di Hu: Case Western Reserve University School of Medicine
Ya-Juan Wang: Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine
Hisashi Fujioka: Case Western Reserve University School of Medicine
Rajan Vyas: Case Western Reserve University School of Medicine
Sudha Chakrapani: Case Western Reserve University School of Medicine
Amit Umesh Joshi: Stanford University School of Medicine
Yu Luo: Case Western Reserve University School of Medicine
Daria Mochly-Rosen: Stanford University School of Medicine
Xin Qi: Case Western Reserve University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12646

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