Browse > Article
http://dx.doi.org/10.14348/molcells.2022.5005

Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor, in a Zebrafish Model of Neuromuscular Junction Disorders  

Jeong, Hui Su (Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University)
Kim, Hye Jin (Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University)
Kim, Deok-Ho (Department of Biomedical Engineering, Johns Hopkins University)
Chung, Ki Wha (Department of Biological Sciences, Kongju National University)
Choi, Byung-Ok (Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University)
Lee, Ji Eun (Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University)
Publication Information
Molecules and Cells / v.45, no.4, 2022 , pp. 231-242 More about this Journal
Abstract
The neuromuscular junction (NMJ), which is a synapse for signal transmission from motor neurons to muscle cells, has emerged as an important region because of its association with several peripheral neuropathies. In particular, mutations in GARS that affect the formation of NMJ result in Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. These disorders are mainly considered to be caused by neuronal axon abnormalities; however, no treatment is currently available. Therefore, in order to determine whether the NMJ could be targeted to treat neurodegenerative disorders, we investigated the NMJ recovery effect of HDAC6 inhibitors, which have been used in the treatment of several peripheral neuropathies. In the present study, we demonstrated that HDAC6 inhibition was sufficient to enhance movement by restoring NMJ impairments observed in a zebrafish disease model. We found that CKD-504, a novel HDAC6 inhibitor, was effective in repairing NMJ defects, suggesting that treatment of neurodegenerative diseases via NMJ targeting is possible.
Keywords
CKD-504; GARS; HDAC6 inhibitor; neuromuscular junction; zebrafish;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Cirrincione, A.M., Pellegrini, A.D., Dominy, J.R., Benjamin, M.E., Utkina-Sosunova, I., Lotti, F., Jergova, S., Sagen, J., and Rieger, S. (2020). Paclitaxel-induced peripheral neuropathy is caused by epidermal ROS and mitochondrial damage through conserved MMP-13 activation. Sci. Rep. 10, 3970.   DOI
2 Grice, S.J., Sleigh, J.N., Motley, W.W., Liu, J.L., Burgess, R.W., Talbot, K., and Cader, M.Z. (2015). Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology. Hum. Mol. Genet. 24, 4397-4406.   DOI
3 Ha, N., Choi, Y.I., Jung, N., Song, J.Y., Bae, D.K., Kim, M.C., Lee, Y.J., Song, H., Kwak, G., Jeong, S., 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.   DOI
4 He, W., Bai, G., Zhou, H., Wei, N., White, N.M., Lauer, J., Liu, H., Shi, Y., Dumitru, C.D., Lettieri, K., et al. (2015). CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526, 710-714.   DOI
5 Lee, H.J., Park, J., Nakhro, K., Park, J.M., Hur, Y.M., Choi, B.O., and Chung, K.W. (2012). Two novel mutations of GARS in Korean families with distal hereditary motor neuropathy type V. J. Peripher. Nerv. Syst. 17, 418-421.   DOI
6 Janke, C. and Bulinski, J.C. (2011). Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat. Rev. Mol. Cell Biol. 12, 773-786.   DOI
7 Antonellis, A., Lee-Lin, S.Q., Wasterlain, A., Leo, P., Quezado, M., Goldfarb, L.G., Myung, K., Burgess, S., Fischbeck, K.H., and Green, E.D. (2006). Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. J. Neurosci. 26, 10397-10406.   DOI
8 Licciardi, P.V. and Karagiannis, T.C. (2012). Regulation of immune responses by histone deacetylase inhibitors. ISRN Hematol. 2012, 690901.   DOI
9 Mann, B.S., Johnson, J.R., Cohen, M.H., Justice, R., and Pazdur, R. (2007). FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12, 1247-1252.   DOI
10 Niehues, S., Bussmann, J., Steffes, G., Erdmann, I., Kohrer, C., Sun, L., Wagner, M., Schafer, K., Wang, G., Koerdt, S.N., et al. (2015). Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. Nat. Commun. 6, 7520.   DOI
11 Morena, J., Gupta, A., and Hoyle, J.C. (2019). Charcot-Marie-Tooth: from molecules to therapy. Int. J. Mol. Sci. 20, 3419.   DOI
12 Vilmont, V., Cadot, B., Vezin, E., Le Grand, F., and Gomes, E.R. (2016). Dynein disruption perturbs post-synaptic components and contributes to impaired MuSK clustering at the NMJ: implication in ALS. Sci. Rep. 6, 27804.   DOI
13 Bremer, J., Skinner, J., and Granato, M. (2017). A small molecule screen identifies in vivo modulators of peripheral nerve regeneration in zebrafish. PLoS One 12, e0178854.   DOI
14 Mariadason, J.M. (2008). HDACs and HDAC inhibitors in colon cancer. Epigenetics 3, 28-37.   DOI
15 Menelaou, E., Husbands, E.E., Pollet, R.G., Coutts, C.A., Ali, D.W., and Svoboda, K.R. (2008). Embryonic motor activity and implications for regulating motoneuron axonal pathfinding in zebrafish. Eur. J. Neurosci. 28, 1080-1096.   DOI
16 Mo, Z., Zhao, X., Liu, H., Hu, Q., Chen, X.Q., Pham, J., Wei, N., Liu, Z., Zhou, J., Burgess, R.W., et al. (2018). Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy. Nat. Commun. 9, 1007.   DOI
17 Namdar, M., Perez, G., Ngo, L., and Marks, P.A. (2010). Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents. Proc. Natl. Acad. Sci. U. S. A. 107, 20003-20008.   DOI
18 Ponomareva, O.Y., Eliceiri, K.W., and Halloran, M.C. (2016). Charcot-Marie-Tooth 2b associated Rab7 mutations cause axon growth and guidance defects during vertebrate sensory neuron development. Neural Dev. 11, 2.   DOI
19 Rodriguez Cruz, P.M., Cossins, J., Beeson, D., and Vincent, A. (2020). The neuromuscular junction in health and disease: molecular mechanisms governing synaptic formation and homeostasis. Front. Mol. Neurosci. 13, 610964.   DOI
20 Simoes-Pires, C., Zwick, V., Nurisso, A., Schenker, E., Carrupt, P.A., and Cuendet, M. (2013). HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? Mol. Neurodegener. 8, 7.   DOI
21 Holloway, M.P., DeNardo, B.D., Phornphutkul, C., Nguyen, K., Davis, C., Jackson, C., Richendrfer, H., Creton, R., and Altura, R.A. (2016). An asymptomatic mutation complicating severe chemotherapy-induced peripheral neuropathy (CIPN): a case for personalised medicine and a zebrafish model of CIPN. NPJ Genom. Med. 1, 16016.   DOI
22 Seburn, K.L., Nangle, L.A., Cox, G.A., Schimmel, P., and Burgess, R.W. (2006). An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron 51, 715-726.   DOI
23 Osseni, A., Ravel-Chapuis, A., Thomas, J.L., Gache, V., Schaeffer, L., and Jasmin, B.J. (2020). HDAC6 regulates microtubule stability and clustering of AChRs at neuromuscular junctions. J. Cell Biol. 219, e201901099.   DOI
24 Ennerfelt, H., Voithofer, G., Tibbo, M., Miller, D., Warfield, R., Allen, S., and Kennett Clark, J. (2019). Disruption of peripheral nerve development in a zebrafish model of hyperglycemia. J. Neurophysiol. 122, 862-871.   DOI
25 Howard, J.F., Jr. (2018). Myasthenia gravis: the role of complement at the neuromuscular junction. Ann. N. Y. Acad. Sci. 1412, 113-128.   DOI
26 Jung, J., Choi, I., Ro, H., Huh, T.L., Choe, J., and Rhee, M. (2020). march5 governs the convergence and extension movement for organization of the telencephalon and diencephalon in zebrafish embryos. Mol. Cells 43, 76-85.   DOI
27 Chapela, D., Sousa, S., Martins, I., Cristovao, A.M., Pinto, P., Corte-Real, S., and Saude, L. (2019). A zebrafish drug screening platform boosts the discovery of novel therapeutics for spinal cord injury in mammals. Sci. Rep. 9, 10475.   DOI
28 Banerjee, S. and Riordan, M. (2018). Coordinated regulation of axonal microtubule organization and transport by Drosophila neurexin and BMP pathway. Sci. Rep. 8, 17337.   DOI
29 Benoy, V., Van Helleputte, L., Prior, R., d'Ydewalle, C., Haeck, W., Geens, N., Scheveneels, W., Schevenels, B., Cader, M.Z., Talbot, K., et al. (2018). HDAC6 is a therapeutic target in mutant GARS-induced Charcot-MarieTooth disease. Brain 141, 673-687.   DOI
30 Borg, K. and Ericson-Gripenstedt, U. (2002). Muscle biopsy abnormalities differ between Charcot-Marie-Tooth type 1 and 2: reflect different pathophysiology? Exerc. Sport Sci. Rev. 30, 4-7.   DOI
31 Chen, S., Owens, G.C., Makarenkova, H., and Edelman, D.B. (2010). HDAC6 regulates mitochondrial transport in hippocampal neurons. PLoS One 5, e10848.   DOI
32 d'Ydewalle, C., Krishnan, J., Chiheb, D.M., Van Damme, P., Irobi, J., Kozikowski, A.P., Vanden Berghe, P., Timmerman, V., Robberecht, W., and Van Den Bosch, L. (2011). HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat. Med. 17, 968-974.   DOI
33 Butler, K.V., Kalin, J., Brochier, C., Vistoli, G., Langley, B., and Kozikowski, A.P. (2010). Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J. Am. Chem. Soc. 132, 10842-10846.   DOI
34 Cirrincione, A.M. and Rieger, S. (2020). Analyzing chemotherapy-induced peripheral neuropathy in vivo using non-mammalian animal models. Exp. Neurol. 323, 113090.   DOI
35 Kalebic, N., Martinez, C., Perlas, E., Hublitz, P., Bilbao-Cortes, D., Fiedorczuk, K., Andolfo, A., and Heppenstall, P.A. (2013). Tubulin acetyltransferase alphaTAT1 destabilizes microtubules independently of its acetylation activity. Mol. Cell. Biol. 33, 1114-1123.   DOI
36 Choi, H., Kim, H.J., Yang, J., Chae, S., Lee, W., Chung, S., Kim, J., Choi, H., Song, H., Lee, C.K., et al. (2020). Acetylation changes tau interactome to degrade tau in Alzheimer's disease animal and organoid models. Aging Cell 19, e13081.   DOI
37 Dompierre, J.P., Godin, J.D., Charrin, B.C., Cordelieres, F.P., King, S.J., Humbert, S., and Saudou, F. (2007). Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J. Neurosci. 27, 3571-3583.   DOI
38 Loprest, L.J., Pericak-Vance, M.A., Stajich, J., Gaskell, P.C., Lucas, A.M., Lennon, F., Yamaoka, L.H., Roses, A.D., and Vance, J.M. (1992). Linkage studies in Charcot-Marie-Tooth disease type 2: evidence that CMT types 1 and 2 are distinct genetic entities. Neurology 42(3 Pt 1), 597-601.   DOI
39 Antonellis, A., Ellsworth, R.E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L.T., et al. (2003). Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293-1299.   DOI
40 Asthana, J., Kapoor, S., Mohan, R., and Panda, D. (2013). Inhibition of HDAC6 deacetylase activity increases its binding with microtubules and suppresses microtubule dynamic instability in MCF-7 cells. J. Biol. Chem. 288, 22516-22526.   DOI
41 Wong, V.S.C., Picci, C., Swift, M., Levinson, M., Willis, D., and Langley, B. (2018). alpha-tubulin acetyltransferase is a novel target mediating neurite growth inhibitory effects of chondroitin sulfate proteoglycans and myelin-associated glycoprotein. eNeuro 5, ENEURO.0240-17.2018.
42 Kesner, V.G., Oh, S.J., Dimachkie, M.M., and Barohn, R.J. (2018). Lambert-Eaton myasthenic syndrome. Neurol. Clin. 36, 379-394.   DOI
43 Sleigh, J.N., Dawes, J.M., West, S.J., Wei, N., Spaulding, E.L., Gomez-Martin, A., Zhang, Q., Burgess, R.W., Cader, M.Z., Talbot, K., et al. (2017). Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. Proc. Natl. Acad. Sci. U. S. A. 114, E3324-E3333.
44 Smith, A., Kim, J.H., Chun, C., Gharai, A., Moon, H.W., Kim, E.Y., Nam, S.H., Ha, N., Song, J.Y., Chung, K.W., et al. (2022). HDAC6 inhibition corrects electrophysiological and axonal transport deficits in a human stem cell-based model of Charcot-Marie-Tooth disease (type 2D). Adv. Biol. (Weinh.) 6, e2101308.
45 Sleigh, J.N., Grice, S.J., Burgess, R.W., Talbot, K., and Cader, M.Z. (2014). Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice. Hum. Mol. Genet. 23, 2639-2650.   DOI
46 Sivakumar, K., Kyriakides, T., Puls, I., Nicholson, G.A., Funalot, B., Antonellis, A., Sambuughin, N., Christodoulou, K., Beggs, J.L., Zamba-Papanicolaou, E., et al. (2005). Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain 128, 2304-2314.   DOI
47 Sleigh, J.N., Mech, A.M., and Schiavo, G. (2020). Developmental demands contribute to early neuromuscular degeneration in CMT2D mice. Cell Death Dis. 11, 564.   DOI
48 Son, I.H., Chung, I.M., Lee, S.I., Yang, H.D., and Moon, H.I. (2007). Pomiferin, histone deacetylase inhibitor isolated from the fruits of Maclura pomifera. Bioorg. Med. Chem. Lett. 17, 4753-4755.   DOI
49 Valenzuela-Fernandez, A., Cabrero, J.R., Serrador, J.M., and Sanchez-Madrid, F. (2008). HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol. 18, 291-297.   DOI
50 Wenzel, E.D., Speidell, A., Flowers, S.A., Wu, C., Avdoshina, V., and Mocchetti, I. (2019). Histone deacetylase 6 inhibition rescues axonal transport impairments and prevents the neurotoxicity of HIV-1 envelope protein gp120. Cell Death Dis. 10, 674.   DOI
51 Zhang, Y., Li, N., Caron, C., Matthias, G., Hess, D., Khochbin, S., and Matthias, P. (2003). HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J. 22, 1168-1179.   DOI