title: Modulating epigenetic HAT activity for reinstating acetylation homeostasis: A promising therapeutic strategy for neurological disorders.
abstract: Epigenetic mechanisms are emerging as a fundamental regulatory switch in neuronal function. Acetylation homeostasis governed by the antagonistic activities of HATs and HDACs plays a critical role in neuronal gene activity. It is now becoming increasingly clear that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are caused by aberrant changes in chromatin acetylation. Several HATs have been shown to be vital for neuronal processes such as synaptic plasticity and memory formation. Thus not surprisingly, dysregulation of such HATs has been implicated in the pathogenesis of several neurodegenerative diseases including Huntington's disease (HD) and Alzheimer's disease (AD). The current therapeutic strategy involves the use of small-molecule histone deacetylase inhibitors to compensate the acetylation deficits arising due to loss of HAT activity. Despite the promising therapeutic effects, the lack of isoform (target) specificity of HDACi raises concerns regarding their applicability. Mounting evidences about the role of HATs in neuronal survival, learning and memory has triggered a new wave of modulating specific HATs as a novel therapeutic option to tackle neurodegenerative diseases. In this review we focus on different HAT families and the critical roles they play in neural development and how the altered acetylation homeostasis culminates in neurodegeneration. Further, we describe the HDACi-based therapeutic approach and its flip side in overcoming neurodegenerative diseases. Furthermore, we discuss the therapeutic potential of HAT modulators in reinstating acetylation homeostasis to ameliorate neurodegenerative disorders.
authors.affiliation: Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, 190006, India.
authors.forename: Shabir Ahmad
authors.initials: SA
authors.lastname: Ganai
authors.affiliation: Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, 190006, India.
authors.forename: Shahid
authors.initials: S
authors.lastname: Banday
authors.affiliation: Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, 190006, India.
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Farooq
authors.affiliation: Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, 190006, India. Electronic address: altafbhat@uok.edu.in.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Altaf
mesh_terms: D000107:Acetylation; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000503:physiopathology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: HAT modulators; HATs; HDACi; HDACs; Histone acetylation; Neurodegenerative diseases