Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex

• Published in: Acta pharmacologica Sinica 2021-10, Vol.42 (10), p.1556-1566
• Main Authors: Li, Xiao-jing, Zhang, Yuan-yuan, Fu, Yu-hua, Zhang, Hao, Li, He-xuan, Li, Quan-fu, Li, Hai-ling, Tan, Ren-ke, Jiang, Chen-xiao, Jiang, Wei, Li, Zeng-xia, Luo, Cheng, Lu, Bo-xun, Dang, Yong-jun
• Format: Article
• Language: English
• Subjects: Acetic acid; Adenosine triphosphatase; Animal models; Animals; Autophagy; Autophagy - drug effects; Biomedical and Life Sciences; Biomedicine; Degradation; Drosophila; Enzymatic activity; Enzyme Inhibitors - therapeutic use; Female; Gossypol; Gossypol - therapeutic use; HEK293 Cells; HeLa Cells; Hereditary diseases; High-throughput screening; Humans; Huntingtin; Huntingtin Protein - chemistry; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - drug therapy; Huntington's disease; Huntingtons disease; Immunology; Internal Medicine; Male; Medical Microbiology; Mice; Microtubule-Associated Proteins - metabolism; Mutants; Mutation; Neostriatum; Neurodegenerative diseases; Neuroprotective Agents - therapeutic use; Patients; Phagocytosis; Pharmacology/Toxicology; Phenotypes; Proteasomes; Protein Multimerization - drug effects; Proteins; Proteolysis - drug effects; Vaccine; Valosin Containing Protein - antagonists & inhibitors; Valosin Containing Protein - metabolism; Valosin-containing protein
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-00605-0

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by toxic aggregates of mutant huntingtin protein (mHTT) in the brain. Decreasing mHTT is a potential strategy for therapeutic purpose of HD. Valosin-containing protein (VCP/p97) is a crucial regulator of proteostasis, which regulates the degradation of damaged protein through proteasome and autophagy pathway. Since VCP has been implicated in pathogenesis of HD as well as other neurodegenerative diseases, small molecules that specifically regulate the activity of VCP may be of therapeutic benefits for HD patients. In this study we established a high-throughput screening biochemical assay for VCP ATPase activity measurement and identified gossypol, a clinical approved drug in China, as a novel modulator of VCP. Gossypol acetate dose-dependently inhibited the enzymatic activity of VCP in vitro with IC 50 of 6.53±0.6 μM. We further demonstrated that gossypol directly bound to the interface between the N and D1 domains of VCP. Gossypol acetate treatment not only lowered mHTT levels and rescued HD-relevant phenotypes in HD patient iPS-derived Q47 striatal neurons and HD knock-in mouse striatal cells, but also improved motor function deficits in both Drosophila and mouse HD models. Taken together, gossypol acetate acted through a gain-of-function way to induce the formation of VCP-LC3-mHTT ternary complex, triggering autophagic degradation of mHTT. This study reveals a new strategy for treatment of HD and raises the possibility that an existing drug can be repurposed as a new treatment of neurodegenerative diseases.