Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

Abstract

The worldwide prevalence of movement disorders is increasing day by day. Parkinson's disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in both in vivo and in vitro models of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity

“…Reduction in histone H3 acetylation level has been reported in various animal and cell culture models of PD [2,26]. In the present study, 6-OHDA induced neuronal damage was associated with reduced global histone H3 acetylation.…”

“…Various HDAC inhibitors have been tested for their possible therapeutic potential in cell culture and animal models of PD ((for review) [2,26]). Although many of these inhibitors have shown neuroprotective potential, however, the molecular mechanisms involved are still elusive.…”

A novel tool for monitoring endogenous alpha-synuclein transcription by NanoLuciferase tag insertion at the 3′end using CRISPR-Cas9 genome editing technique

“…4). Hyper-acetylation of histone is expected to unwind underlying DNA, which in turn favors transcription1920. To test whether HDAC inhibition in 293T- SNCA -3′NL cells would faithfully monitor transcription in response to histone hyper-acetylation, cells were treated with sodium butyrate (class I and IIa inhibitor of HDAC) at concentrations 2.5 mM and 5.0 mM for 24 hours19.…”

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

“…Benzamides represent an exciting class of HDACIs due to their high selectivity (Sharma and Taliyan, 2015). The most commonly used drug in this class is N-(2-aminophenyl)-4-benzamide derivative (MS-275), which is currently in clinical trials for the treatment of cancers (Grayson et al, 2010).…”

“…Individual cyclic peptide HDACIs specifically inhibit different HDAC isoforms, given that the chemical structures of different peptides vary significantly. Thus, cyclic peptide HDACIs can be used as templates for the development of highly selective HDACIs (Chuang et al, 2009;Sharma and Taliyan, 2015). Two types of drugs in this class are available, including apicidin (which selectively targets HDAC2 and HDAC3) and romidepsin (also called desipeptide or FK-228, which selectively inhibits HDAC1 and HDAC2).…”