**2.2 Epigenetic enzymes implicated in neurodegenerative disorders**

Recently, genomic profiling studies and molecular investigations have delineated the impact of epigenetic alterations on neurodegeneration. Neurodegenerative diseases encompass the gradual loss of cognitive and/or motor functions in humans. Examples include but are not limited to Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS) [58]. It has been reported that the DNA methylation of AD-associated genes, such as the β-secretase (BACE), amyloid precursor protein (APP), and presenilin 1 (PS1) genes, is dramatically decreased in AD cell models and results in the exacerbation of AD pathology [59]. In a genome-wide study conducted by Huynh and colleagues on MS patients' brains, several differential methylated regions in the DNA were observed. Genes that are critical to oligodendrocyte regulation, such as BCL2L2 and NDRG1, were found to be hypermethylated and showed decreased expression levels [60]. Also, given that HATs like p300/CBP are involved in memory formation, its loss has been shown to lead to different neurological dysfunction, which is characteristic of HD, Rubinstein-Taybi syndrome, and AD [61, 62]. Thus, HDAC inhibitors can be used as a therapeutic strategy to offset the imbalanced role of HATs in the aforementioned neurodegenerative diseases. On the contrary, the downregulation of p300 levels by native α-synuclein (αsyn) exerts neuroprotective function in the brain. Thus, it has been suggested that misfolded αsyn, a major phenotype of PD, may lead to enhanced p300/CBP activity, thereby causing impaired motor function [63]. In ALS, reduced p300/CBP has been found to cause the hypoacetylation of the cyclin D1 gene, a critical gene for cell cycle progression [64]. Similarly, increased methylation marks on histones have been linked with aging, an important risk factor in neurodegeneration [65]. In ataxia-telangiectasia, the loss of A-T mutated (ATM) increases the tri-methylation of H3K27 *via* EZH2 stabilization, thereby affecting neuronal survival [66]. Also, overexpression of an

#### *Repurposing Market Drugs to Target Epigenetic Enzymes in Human Diseases DOI: http://dx.doi.org/10.5772/intechopen.101397*

H3K9 methyltransferase, ERG-associated protein with SET domain (ESET, also known as SET domain bifurcated 1, SETDB1), is shown to be markedly increased in HD patients, and the inhibition of ESET was reported to restore the normal behavioral and neuronal function in HD mice [67]. Moreover, PRMT1 was reported to play a neuroprotective role in ALS *via* asymmetric dimethylation of H4R3, a methylation mark that aids histone acetylation, and consequently, transcription of survival genes [64]. Collectively, this brief overview shows that chromatin modification *via* epigenetic processes is critical to neuronal function.
