A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson's disease

Abstract

With increased histone deacetylase (HDAC) activity and histone hypoacetylation being implicated in neurodegeneration, HDAC inhibitors have been reported to have considerable therapeutic potential. Yet, existing inhibitors lack specificity and may show substantial adverse effect. In this study, we identified a novel HDAC1/2 isoform-specific inhibitor, K560, with protective effects against 1-methyl-4-phenylpyridinium (MPP(+))- and/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal death in both in vitro and in vivo Parkinson's disease model. K560 attenuated cell death induced by MPP(+) in differentiated SH-SY5Y cells through the sustained expression of an antiapoptotic protein, X-linked inhibitor of apoptosis (XIAP). Inhibition of XIAP expression by locked nucleic acid antisense oligonucleotides abolished the protective effect of K560. Inactivation of mitogen-activated protein kinase cascades, reduced p53 phosphorylation, and down-regulation of p53-upregulated modulator of apoptosis on K560 treatment were also observed. Furthermore, pre- and post-oral administration of K560 to mice prevented MPTP-induced loss of dopaminergic neurons in substantia nigra, suggesting that selective inhibition of HDAC1 and HDAC2 by K560 may pave the way to new strategies for Parkinson's disease treatment.

Impaired Mitophagy and Protein Acetylation Levels in Fibroblasts from Parkinson’s Disease Patients

“…How histones are hypoacetylated in IPD cells remains unclear. Studies in vivo and in vitro on oxidative stress models of PD have demonstrated that acetylation levels are reduced with MPP + /MPTP and paraquat because of the increase in HDAC activity [58,59]. In IPD cells, total HDAC activity was notably reduced, which was not correlated with the acetylation status of proteins.…”

“…Therefore, SIRT activity is abrogated in IPD cells and leads to a compensatory increase in class I and II HDACs (Fig.6E) that are responsible for the hypoacetylation of proteins [56]. It would be interesting to explore whether specific inhibitors of class I HDACs [58] are beneficial in IPD cells.…”

Complex neuroprotective and neurotoxic effects of histone deacetylases

“…Specific Hdac1/2 ablation inhibited this apoptotic pathway by impairing the crucial acetylation status of p53 and reducing PUMA expression, thereby contributing to the ensuing enhanced neuroprotection. In another study, a newly identified but relatively uncharacterized HDAC1/HDAC2selective inhibitor, K560, had protective effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuronal death in both in vitro and in vivo Parkinson's disease models (Choong et al 2016). Treatment with K560 caused a sustained increase in expression of X-linked inhibitor of apoptosis, an anti-apoptotic protein, leading to beneficial effects (Choong et al 2016).…”

Stop for tea? Enzyme inhibitors from tea – what good are they?

“…Kim et al (2010) found that administration of EGCG attenuated the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced activation of iNOS in both anterior halves of midbrain and striatum. After derangement of histone deacetylase (HDAC), neuronal cell death occurs and pathologies of PD will develop (Choong et al, 2016). A neuroprotective effect of HDAC inhibitor had been observed in PD mice (Gebremedhin & Rademacher, 2016), and caffeine treatment could lower the activity of HDAC in 6-OHDA-lesioned rats (Machado-Filho et al, 2014).…”