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

Xing Guo,Yu Luo,Rajan Vyas,Xiaoyan Sun,Sudha Chakrapani,Daria Mochly-Rosen,Ya-Juan Wang,Di Hu,Xin Qi,Amit Umesh Joshi,Hisashi Fujioka

doi:10.1038/ncomms12646

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.

Highlights

Mutant Huntingtin causes neurodegeneration in Huntington’s disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive
Because altered binding of huntingtin protein (Htt) with target proteins can significantly contribute to the pathogenesis of HD11, we recently profiled the proteins that bind to Mutant Huntingtin (mtHtt) on mitochondria and identified valosin-containing protein (VCP) as a high-abundance mtHtt-interacting protein on mitochondria (Supplementary Fig. 1)
Our results suggest that VCP recruitment to mitochondria by mtHtt is a crucial step in the initiation of neuropathology in HD

Summary

Results

VCP is recruited to mitochondria by mtHtt in HD. We used HD mouse striatal HdhQ111 (mutant) and HdhQ7 (wild-type, wt) cells to profile the interactors of mtHtt on the mitochondria (Fig. 1a, Supplementary Fig. 1). Tandem mass spectrometry analysis following affinity purification identified 9 proteins that putatively bound to mitochondria-associated mtHtt in HdhQ111 but not wt Htt in HdhQ7 cells (Fig. 1a, Supplementary Fig. 1b). We found that treatment with either MG132 (a proteasome inhibitor that prevents protein degradation) or Eeyarestatin I (Eer I, an inhibitor that blocks VCP substrate degradation33), did not affect Htt or mtHtt protein levels in HdhQ or HdhQ111 cells, respectively (Supplementary Fig. 3) These data exclude the possibility that Htt or mtHtt is a substrate of VCP on the mitochondria. In YAC128 mice, which express a full-length human mtHtt, the treatment blocked VCP translocation to mitochondria in the striatum at the age of 6 months relative to YAC128 mice treated with control peptide TAT (Fig. 3h, treatment timeline in Supplementary Fig. 5a). The neuroprotective effects of HV-3 were consistently a Similarity: Identity: 100% 67%

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Discussion

Methods