ReferenceID 2001
Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex
Acta Pharmacol Sin
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 o
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Record Fields
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- Reference Id
- 2001
- Evidence Id
- 18591
- Core Evidence Id
- 18591
- Source Reference Id
- 4019
- Herb2 Reference Id
- HBREF004816
- Subject Paper Key
- HBIN028351_33495516
- Pubmed Id
- 33495516
- Doi
- 10.1038/s41401-020-00605-0
- Paper Title
- Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex
- Paper Abstract
- 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 IC50 of 6.53+-0.6 muM. 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.
- Journal
- Acta Pharmacol Sin
- Publish Year
- 2021
- Experiment Subject
- mouse; patient; drosophila; hd knock-in mouse striatal cells; hd patient ips-derived q47 striatal neurons
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Autosomal Dominant Neurodegenerative Disorder; Neurodegenerative Diseases; Huntington's Disease
- Paper Title Cn
- Paper Title En
- Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex
- Bilingual Status
- semi_complete