Mechanism Description

Recent research has observed an mtHtt-dependent association of Valosin-containing protein (VCP) with mitochondria. It was demonstrated that mtHtt recruits VCP to the mitochondria in various Huntington's Disease (HD) experimental models and HD patient brain tissue, where VCP initiates mitochondrial dysfunction and HD-associated neuropathology. Additionally, VCP contains an LC3 binding motif that mediates the interaction between mitochondria-accumulated VCP and LC3 (an autophagosome protein). This suggests that the mtHtt-induced accumulation of VCP on mitochondria recruits LC3-decorated autophagosomes to engulf mitochondria.

Based on the discovery that VCP mitochondrial accumulation is required for mtHtt-induced mitochondrial defects and subsequent neuronal injury, the JQ-H3 peptide inhibitor was identified to selectively block the VCP-mtHtt interaction. This peptide inhibited VCP recruitment to mitochondrial-bound mtHtt, reducing aberrant mitophagy and cell death. Consequently, inhibitors of mtHtt-VCP interactions hold promise for retarding or preventing HD in genetically susceptible individuals and reducing neuropathology in those affected.