Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Abstract

The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

“…While HDAC inhibitors have previously been shown to induce neurite growth in these cells (Collins et al 2015;Yuan et al 2001), this is the first report documenting the ability of a HAT activator to promote SH-SY5Y neurite growth. This is an important finding considering the limited number of HAT activators which have been produced (Schneider et al 2013), and the corresponding paucity of studies investigating their neurotrophic potential. The ability of p300/CBP activity to promote neurite growth has been reported in other neuronal populations (Gaub et al 2011;Gaub et al 2010;Lee et al 2009), while small molecule-mediated activation of p300/CBP promotes the growth of neurons in the adult mouse dentate gyrus in vivo (Chatterjee et al 2013).…”

“…We and others have shown that pan-and class-specific HDAC inhibitors can protect DA neurons (Chen et al 2006;Chen et al 2007;Collins et al 2015;Gardian et al 2004;Kidd and Schneider 2010;Kidd and Schneider 2011;Kontopoulos et al 2006;Outeiro et al 2007;St Laurent et al 2013;Wu et al 2008;Zhu et al 2014) and sympathetic neurons (Collins et al 2015) in experimental models of PD. The potential of this approach for clinical translation is highlighted by an ongoing Phase I clinical trial of the FDA-approved drug Glycerol Phenylbutyrate (a HDAC inhibitor) which is exploring the potential of this drug to increase the removal of α-synuclein from the brain (NCT02046434) (for recent reviews see Harrison and Dexter 2013;Schneider et al 2013;Valor et al 2013). An alternative epigenetic approach for the broad, yet selective, activation of gene expression is the induction of HAT activity, instead of HDAC inhibition.…”

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…5). CBP belongs to 1 of the 5 major HAT groups: CBP/ p300; Gcn5-related N-acetyltransferases (including Gcn5 and p300/CBP-associated factor); MYST (MOZ, Ybf2, Sas2, and Tip60); nuclear receptor-associated HATs; and transcription factor-related HATs [177]. On the other side, HDACs function to remove acetyl groups from histone lysines, repressing gene transcription.…”

Looking Above but Not Beyond the Genome for Therapeutics in Neurology and Psychiatry: Epigenetic Proteins and RNAs Find a New Focus

“…One way to bias histone acetylation in favor of transcription is via histone acetyltransferase (HAT) activity. In the review by Schneider et al (p. XX) [7], a detailed description of the most promising HAT activators is reported.…”