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생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
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A novel HDAC6 inhibitor, CKD-504, is effective in treating preclinical models of huntington's disease

  • Endan Li (Department of Biomedical Science, CHA University) ;
  • Jiwoo Choi (Department of Biomedical Science, CHA University) ;
  • Hye-Ri Sim (CKD Research Institute, Chong Kun Dang Pharmaceutical Corp.) ;
  • Jiyeon Kim (Department of Biomedical Science, CHA University) ;
  • Jae Hyun Jun (CKD Research Institute, Chong Kun Dang Pharmaceutical Corp.) ;
  • Jangbeen Kyung (CKD Research Institute, Chong Kun Dang Pharmaceutical Corp.) ;
  • Nina Ha (CKD Research Institute, Chong Kun Dang Pharmaceutical Corp.) ;
  • Semi Kim (CKD Research Institute, Chong Kun Dang Pharmaceutical Corp.) ;
  • Keun Ho Ryu (CKD Research Institute, Chong Kun Dang Pharmaceutical Corp.) ;
  • Seung Soo Chung (Department of Physiology, Yonsei University College of Medicine) ;
  • Hyun Sook Kim (Department of Neurology, CHA Bundang Medical Center, CHA University) ;
  • Sungsu Lee (iPS Bio Inc.) ;
  • Wongi Seol (iPS Bio Inc.) ;
  • Jihwan Song (Department of Biomedical Science, CHA University)
  • 투고 : 2022.10.23
  • 심사 : 2023.01.02
  • 발행 : 2023.03.31
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초록

Huntington's disease (HD) is a neurodegenerative disorder, of which pathogenesis is caused by a polyglutamine expansion in the amino-terminus of huntingtin gene that resulted in the aggregation of mutant HTT proteins. HD is characterized by progressive motor dysfunction, cognitive impairment and neuropsychiatric disturbances. Histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase, has been shown to induce transport- and release-defect phenotypes in HD models, whilst treatment with HDAC6 inhibitors ameliorates the phenotypic effects of HD by increasing the levels of α-tubulin acetylation, as well as decreasing the accumulation of mutant huntingtin (mHTT) aggregates, suggesting HDAC6 inhibitor as a HD therapeutics. In this study, we employed in vitro neural stem cell (NSC) model and in vivo YAC128 transgenic (TG) mouse model of HD to test the effect of a novel HDAC6 selective inhibitor, CKD-504, developed by Chong Kun Dang (CKD Pharmaceutical Corp., Korea). We found that treatment of CKD-504 increased tubulin acetylation, microtubule stabilization, axonal transport, and the decrease of mutant huntingtin protein in vitro. From in vivo study, we observed CKD-504 improved the pathology of Huntington's disease: alleviated behavioral deficits, increased axonal transport and number of neurons, restored synaptic function in corticostriatal (CS) circuit, reduced mHTT accumulation, inflammation and tau hyperphosphorylation in YAC128 TG mouse model. These novel results highlight CKD-504 as a potential therapeutic strategy in HD.

키워드

과제정보

This work was supported by an internal funding from the CKD Research Institute and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021M3A9G2015885) and by the Technological Innovation R&D Program (S3305828) funded by the Ministry of SMEs and Startups (MSS, Korea). We thank Dongchul Shin (iPS Bio) for the interpretation of electrophysiological data analysis.

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