Epigenetics-Based Therapeutics for Neurodegenerative Disorders

Abstract

Epigenetic regulation, such as DNA methylation and histone modification, is implicated in the aberrant changes in gene expression that occur during the progression of neurodegeneration. Many epigenetics-based drugs have been developed recently for the treatment of some neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Here we review recent studies that highlight the role of epigenetic modifications in neurodegeneration, among them DNA methylation and demethylation and histone acetylation and deacetylation; we also explore the possibility of using epigenetics-based therapeutics to treat neurodegenerative disorders.

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

“…In vivo and in vitro experiments on such DNMT inhibitors show a reduction in total DNMT enzyme activity and reduction in the DNA hypermethylation in the RELN and GAD1 gene promoters, hence normalizing the GABAergic neurotransmission [107]. The most commonly studied compounds are azacitidine and decitabine, which form an irreversible complex with DNMT1 and inhibit CpG methylation [129,130]. These inhibitors have been used in cancer cells in vivo and in vitro to downregulate cell division, but the effects are questionable in postmitotic differentiated neurons.…”

Bridging the Genetical Environmental Gap in Parkinson's Disease through Epigenetics

“…They incorporate themselves into DNA following activation by a triphosphate moiety, with enzyme degradation taking place following the formation of an irreversible complex with DNMT1. This is responsible for the prevention of daughter DNA methylation in CpG islands during DNA replication [28].…”

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

“…Several drugs that target epigenetic alterations are known and well studied (Table 1). Such inhibitors of HDACs and DNMTs are currently approved and available for clinical investigation [67]. One effective epigenetic pharmacological strategy for the selective reduction of genes could involve methylating cytosine bases in the promoter regions of their DNA by increasing the endogenous levels SAM, the methyl donor used in DNA methylation reactions, via exogenous delivery of methionine, choline, folates, and vitamin B12 [67].…”

“…Such inhibitors of HDACs and DNMTs are currently approved and available for clinical investigation [67]. One effective epigenetic pharmacological strategy for the selective reduction of genes could involve methylating cytosine bases in the promoter regions of their DNA by increasing the endogenous levels SAM, the methyl donor used in DNA methylation reactions, via exogenous delivery of methionine, choline, folates, and vitamin B12 [67]. The selectivity of the latter epigenetic therapeutic strategy depends on increasing DNA methylation, thereby interfering with the binding of transcription factors to the promoter regions that contain a high guanine-cytosine content of CpG-enriched dinucleotides.…”

“…DNMT inhibitors, also referred to as demethylating agents have been under preclinical and clinical investigation for a long period of time. The most widely studied inhibitors are the cytidine nucleoside analogs, which incorporate into DNA after activation by a triphosphate moiety [67]. After the formation of an irreversible complex with DNMT1, enzyme degradation occurs, which prevents the methylation of daughter DNA in CpG islands during DNA replication.…”