Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders

Reversal of aging symptoms and related disorders are the challenging task where epigenetic is a crucial player that includes DNA methylation, histone modification; chromatin remodeling and regulation that are linked to the progression of various neurodegenerative disorders (NDDs). Overexpression of various histone deacetylase (HDACs) can activate Glycogen synthase kinase 3 which promotes the hyperphosphorylation of tau and inhibits its degradation. While HDAC is important for maintaining the neuronal morphology and brain homeostasis, at the same time, these enzymes are promoting neurodegeneration, if it is deregulated. Different experimental models have also confirmed the neuroprotective effects caused by HDAC enzymes through the regulation of neuronal apoptosis, inflammatory response, DNA damage, cell cycle regulation, and metabolic dysfunction. Apart from transcriptional regulation, protein-protein interaction, histone post-translational modifications, deacetylation mechanism of non-histone protein and direct association with disease proteins have been linked to neuronal imbalance. Histone deacetylases inhibitors (HDACi) can be able to alter gene expression and shown its efficacy on experimental models, and in clinical trials for NDD's and found to be a very promising therapeutic agent with certain limitation, for instance, non-specific target effect, isoform-selectivity, specificity, and limited number of predicted biomarkers. Herein, we discussed (i) the catalytic mechanism of the deacetylation process of various HDAC's in in vivo and in vitro experimental models, (ii) how HDACs are participating in neuroprotection as well as in neurodegeneration, (iii) a comprehensive role of HDACi in maintaining neuronal homeostasis and (iv) therapeutic role of biomolecules to modulate HDACs.