Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Overview

Journal Front Pharmacol

Date 2020 May 12

PMID 32390854

Citations 105

Authors

Surabhi Shukla

Babu L Tekwani

Affiliations

Soon will be listed here.

Abstract

Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.

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References

Chang J, Hsieh-Li H, Jong Y, Wang N, Tsai C, Li H . Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci U S A. 2001; 98(17):9808-13. PMC: 55534. DOI: 10.1073/pnas.171105098. View

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

Hockly E, Richon V, Woodman B, Smith D, Zhou X, Rosa E . Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003; 100(4):2041-6. PMC: 149955. DOI: 10.1073/pnas.0437870100. View

Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai L . Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007; 447(7141):178-82. DOI: 10.1038/nature05772. View

Marks P, Xu W . Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem. 2009; 107(4):600-8. PMC: 2766855. DOI: 10.1002/jcb.22185. View

Wiech N, Fisher J, Helquist P, Wiest O . Inhibition of histone deacetylases: a pharmacological approach to the treatment of non-cancer disorders. Curr Top Med Chem. 2009; 9(3):257-71. DOI: 10.2174/156802609788085241. View

Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon S . HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev. 2007; 21(17):2172-81. PMC: 1950856. DOI: 10.1101/gad.436407. View

Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl F, Raschke H, Blumcke I . Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet. 2003; 12(19):2481-9. DOI: 10.1093/hmg/ddg256. View

Harrison I, Crum W, Vernon A, Dexter D . Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson's is associated with histone acetylation and up-regulation of neurotrophic factors. Br J Pharmacol. 2015; 172(16):4200-15. PMC: 4543623. DOI: 10.1111/bph.13208. View

10.

Lillico R, Zhou T, Ahmad T, Stesco N, Gozda K, Truong J . Increased Post-Translational Lysine Acetylation of Myelin Basic Protein Is Associated with Peak Neurological Disability in a Mouse Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis. J Proteome Res. 2017; 17(1):55-62. DOI: 10.1021/acs.jproteome.7b00270. View

11.

Dubey H, Gulati K, Ray A . Recent studies on cellular and molecular mechanisms in Alzheimer's disease: focus on epigenetic factors and histone deacetylase. Rev Neurosci. 2018; 29(3):241-260. DOI: 10.1515/revneuro-2017-0049. View

12.

Maretina M, Zheleznyakova G, Lanko K, Egorova A, Baranov V, Kiselev A . Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates. Curr Genomics. 2018; 19(5):339-355. PMC: 6030859. DOI: 10.2174/1389202919666180101154916. View

13.

Poplawski S, Garbett K, McMahan R, Kordasiewicz H, Zhao H, Kennedy A . An Antisense Oligonucleotide Leads to Suppressed Transcription of Hdac2 and Long-Term Memory Enhancement. Mol Ther Nucleic Acids. 2020; 19:1399-1412. PMC: 7047133. DOI: 10.1016/j.omtn.2020.01.027. View

14.

Sun G, Yu R, Evans R, Shi Y . Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proc Natl Acad Sci U S A. 2007; 104(39):15282-7. PMC: 2000559. DOI: 10.1073/pnas.0704089104. View

15.

Sanchez-Arias J, Rabal O, Cuadrado-Tejedor M, de Miguel I, Perez-Gonzalez M, Ugarte A . Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease. ACS Chem Neurosci. 2016; 8(3):638-661. DOI: 10.1021/acschemneuro.6b00370. View

16.

Mahady L, Nadeem M, Malek-Ahmadi M, Chen K, Perez S, Mufson E . HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease. Neuropathol Appl Neurobiol. 2018; 45(4):380-397. PMC: 6433556. DOI: 10.1111/nan.12518. View

17.

Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage F . Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A. 2004; 101(47):16659-64. PMC: 527137. DOI: 10.1073/pnas.0407643101. View

18.

Neuwald A, Landsman D . GCN5-related histone N-acetyltransferases belong to a diverse superfamily that includes the yeast SPT10 protein. Trends Biochem Sci. 1997; 22(5):154-5. DOI: 10.1016/s0968-0004(97)01034-7. View

19.

Jung G, Yoon J, Moon B, Yang D, Kim H, Lee S . Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway. BMC Cell Biol. 2008; 9:66. PMC: 2639384. DOI: 10.1186/1471-2121-9-66. View

20.

Wu J, Lessard J, Olave I, Qiu Z, Ghosh A, Graef I . Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron. 2007; 56(1):94-108. DOI: 10.1016/j.neuron.2007.08.021. View