Epigenetic role of sirtuins in neurodegenerative brain disorders

Abstract

Sirtuins, a family of NAD+-dependent class III histone deacetylases (HDACs), are known to deacetylate some histone and nonhistone proteins including various transcription and cell signaling factors, thereby helping to regulate expression of many genes under a variety of stress challenges, and therefore they are referred to as important epigenetic regulators of the cell functions. This is in line with the classical Zn2+-dependent class I and class II HDACs, first recognized as protein level epigenetic regulators, which by modulating chromatin dynamics could affect DNA functions. All together, seven cell organelle-specific mammalian sirtuin homologues are known with distinct metabolic roles. SIRT 1, 6, and 7 are predominantly localized in the nucleus; SIRT 3, 4, and 5 are mitochondrial; while SIRT2 is found in the cytoplasm. The research during the past decade could characterize a good number of protein targets like histone H3 (H3K9), PGC1α, FOX03a, p53, and NF-κB type transcription factors for SIRT1 and SOD2, IDH2, LCAD, AceCS2, FOX03a etc. for mitochondrial SIRT3, which are now argued to be critically associated with the cell survival versus cell death mechanisms. As dysregulation of gene expression and mitochondrial dysfunction constitutes the base line of pathogenesis of many neurodegenerative brain disorders, like Alzheimer’s disease, Parkinson’s disease, Huntington’s, stroke etc., it is argued that SIRT1 and SIRT3 are likely to be the logical hot spots for exploring pathogenesis and therapeutic options against these brain disorders. Indeed some findings describe that SIRT1 and/or SIRT3 overexpression/activation could impart neuroprotection, whereas their inactivation/suppression could correlate with the neuronal derangements associated with aging and excitotoxic brain disorders. Thus sirtuin biochemistry seems to be an evolving concept in discerning the neuropathology of brain disorders. © 2021 Elsevier Inc. All rights reserved.