BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

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)
  • Received : 2022.10.23
  • Accepted : 2023.01.02
  • Published : 2023.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

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.

Keywords

Acknowledgement

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.

References

  1. Pan L and Feigin A (2021) Huntington's disease: new frontiers in therapeutics. Curr Neurol Neurosci Rep 21, 10  https://doi.org/10.1007/s11910-020-01089-5
  2. Ghosh R and Tabrizi SJ (2018) Clinical features of Huntington's disease. Adv Exp Med Biol 1049, 1-28  https://doi.org/10.1007/978-3-319-71779-1_1
  3. Arrowsmith CH, Bountra C, Fish PV, Lee K and Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11, 384-400  https://doi.org/10.1038/nrd3674
  4. Kazantsev AG and Thompson LM (2008) Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7, 854-868  https://doi.org/10.1038/nrd2681
  5. Bishton MJ, Harrison SJ, Martin BP et al (2011) Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia. Blood 117, 3658-3668  https://doi.org/10.1182/blood-2010-11-318055
  6. Subramanian S, Bates SE, Wright JJ, Espinoza-Delgado I and Piekarz RL (2010) Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals (Basel) 3, 2751-2767  https://doi.org/10.3390/ph3092751
  7. Noack M, Leyk J and Richter-Landsberg C (2014) HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes. Glia 62, 535-547  https://doi.org/10.1002/glia.22624
  8. Zhang Y, Li N, Caron C et al (2003) HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J 22, 1168-1179  https://doi.org/10.1093/emboj/cdg115
  9. Reed NA, Cai D, Blasius TL et al (2006) Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16, 2166-2172  https://doi.org/10.1016/j.cub.2006.09.014
  10. Trushina E, Dyer RB, Badger JD 2nd et al (2004) Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 24, 8195-8209  https://doi.org/10.1128/MCB.24.18.8195-8209.2004
  11. Dompierre JP, Godin JD, Charrin BC et al (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J Neurosci 27, 3571-3583  https://doi.org/10.1523/JNEUROSCI.0037-07.2007
  12. Zhang Y, Kwon S, Yamaguchi T et al (2008) Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol 28, 1688-1701  https://doi.org/10.1128/MCB.01154-06
  13. Hinckelmann MV, Zala D and Saudou F (2013) Releasing the brake: restoring fast axonal transport in neurodegenerative disorders. Trends Cell Biol 23, 634-643  https://doi.org/10.1016/j.tcb.2013.08.007
  14. Govindarajan N, Rao P, Burkhardt S et al (2013) Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease. EMBO Mol Med 5, 52-63  https://doi.org/10.1002/emmm.201201923
  15. Selenica ML, Benner L, Housley SB et al (2014) Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition. Alzheimers Res Ther 6, 12 
  16. d'Ydewalle C, Krishnan J, Chiheb DM et al (2011) HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med 17, 968-974  https://doi.org/10.1038/nm.2396
  17. Yang SS, Zhang R, Wang G and Zhang YF (2017) The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer's disease. Transl Neurodegener 6, 19 
  18. Reddy RG, Surineni G, Bhattacharya D et al (2019) Crafting carbazole-based vorinostat and tubastatin-a-like histone deacetylase (HDAC) inhibitors with potent in vitro and in vivo neuroactive functions. ACS Omega 4, 17279-17294  https://doi.org/10.1021/acsomega.9b01950
  19. Choi H, Kim HJ, Yang J et al (2020) Acetylation changes tau interactome to degrade tau in Alzheimer's disease animal and organoid models. Aging Cell 19, e13081 
  20. Ha N, Choi YI, Jung N et al (2020) A novel histone deacetylase 6 inhibitor improves myelination of Schwann cells in a model of Charcot-Marie-Tooth disease type 1A. Br J Pharmacol 177, 5096-5113  https://doi.org/10.1111/bph.15231
  21. Crook ZR and Housman D (2011) Huntington's disease: can mice lead the way to treatment? Neuron 69, 423-435  https://doi.org/10.1016/j.neuron.2010.12.035
  22. Sapp E, Valencia A, Li X et al (2012) Native mutant huntingtin in human brain: evidence for prevalence of full-length monomer. J Biol Chem 287, 13487-13499  https://doi.org/10.1074/jbc.M111.286609
  23. Slow EJ, van Raamsdonk J, Rogers D et al (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12, 1555-1567  https://doi.org/10.1093/hmg/ddg169
  24. Joshi PR, Wu NP, Andre VM et al (2009) Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease. J Neurosci 29, 2414-2427  https://doi.org/10.1523/JNEUROSCI.5687-08.2009
  25. Butler KV, Kalin J, Brochier C, Vistoli G, Langley B and Kozikowski AP (2010) Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc 132, 10842-10846  https://doi.org/10.1021/ja102758v
  26. Choi D, Li D and Raisman G (2002) Fluorescent retrograde neuronal tracers that label the rat facial nucleus: a comparison of Fast Blue, Fluoro-ruby, Fluoroemerald, Fluoro-Gold and DiI. J Neurosci Methods 117, 167-172  https://doi.org/10.1016/S0165-0270(02)00098-5
  27. Fernandez-Nogales M, Cabrera JR, Santos-Galindo M et al (2014) Huntington's disease is a four-repeat tauopathy with tau nuclear rods. Nat Med 20, 881-885  https://doi.org/10.1038/nm.3617
  28. Avila J, Lucas JJ, Perez M and Hernandez F (2004) Role of tau protein in both physiological and pathological conditions. Physiol Rev 84, 361-384 https://doi.org/10.1152/physrev.00024.2003