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Autophagic degradation of Mutant Huntingtin by Enhancement of the Complex of VCP/p97-LC3-mHTT
  • +11
  • Xiaojing Li,
  • Yuanyuan Zhang,
  • Yuhua Fu,
  • Hao Zhang,
  • Hexuan Li,
  • Quanfu Li,
  • Hailing Li,
  • Renke Tan,
  • Chenxiao Jiang,
  • Wei Jiang,
  • Zengxia Li,
  • Cheng Luo,
  • Boxun Lu,
  • Yongjun DangOrcid
Xiaojing Li
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Yuanyuan Zhang
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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Yuhua Fu
Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China
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Hao Zhang
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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Hexuan Li
Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China
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Quanfu Li
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Hailing Li
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Renke Tan
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Chenxiao Jiang
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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Wei Jiang
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Zengxia Li
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Cheng Luo
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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Boxun Lu
Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China
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Yongjun Dang
Orcid
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Abstract

Background and Purpose Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by cytotoxicity of mutant huntingtin protein (mHTT). Decrease of mHTT will be a potential strategy for therapeutic purpose of HD. VCP has been reported and functioned in HD. Finding of novel small molecules specifically regulates the activity of VCP, which may be benefited to HD patients. Experimental Approach In-house screening drug library against VCP enzymatic activity was performed and a leading candidate was studied for its mechanism of the degradation of mHTT and its effect on HD animal models. Key Results We identified gossypol, a clinical approved drug in China, as a novel modulator of VCP. Gossypol acetate acted through a gain-of-function way to induce the formation of VCP-LC3-mHTT ternary complex, triggering autophagic degradation of mHTT. Gossypol interfered with VCP’s enzymatic activity through its direct binding to interface between VCP’s N and D1 domains. Gossypol acetate not only lowered mHTT levels and rescued HD-relevant phenotypes in patient induced pluripotent stem cell (iPS)-derived neurons and HD knockin mouse striatal cell, but also improved motor function deficits in both Drosophila and mouse HD models. Conclusions and Implications Taken together, these findings revealed a new strategy for treating HD by gossypol that targets mHTT through VCP and LC3 to the autophagic pathway and raised the possibility that an existing drug can be repurposed as a new treatment of HD.