Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

Abstract

Over 80% of brain disorders are associated with multiple genomic defects in conjunction with environmental factors and epigenetic phenomena. Classical epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs) regulation, are among the major regulatory elements that control metabolic pathways at the molecular level, with epigenetic modifications controlling gene expression transcriptionally and miRNAs suppressing gene expression post-transcriptionally. Epigenetic modifications are related to disease development, environmental exposure, drug treatment and aging. Epigenetic changes are reversible and can be potentially targeted by pharmacological intervention. Both hypermethylation and hypomethylation of DNA, chomatin changes and miRNA dysregulation are common in age-related disorders and in many neuropsychiatric, neurodevelopmental and neurodegenerative disorders. Major epigenetic mechanisms may contribute to Alzheimer's disease (AD) pathology. Several pathogenic genes and many other AD-related susceptibility genes contain methylated CpG sites. AD brains exhibit a genome-wide decrease in DNA methylation. Pathogenic histone modifications are present in AD. Alterations in epigentically regulated miRNAs may contribute to the abnormal expression of pathogenic genes in AD. Epigenetic drugs can reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Individual differences in drug response are associated with genetic and epigenetic variability and disease determinants. Pharmacoepigenomics deals with the influence that epigenetic alterations may exert on genes involved in the pharmacogenomic network (pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes) responsible for the pharmacokinetics and pharmacodynamics of drugs (efficacy and safety), as well as the effects that drugs may have on the epigenetic machinery. family), AID/APOBEC family, and the VER glycosylase family [9]. Histone acetylation is achieved by histone acetyltransferase (HAT); and histone deacetylation is produced by histone deacetylases (HDACs) (class I: HDAC1, 2, 3, and 8; class IIa: HDAC4, 5,7, and 9; class IIb: HDAC6 and 10; class III: SIRT1, 2, 6, 7; class IV: HDAC11) [9].Long non-coding (lnc) RNAs are non-protein-coding RNAs, distinct from housekeeping RNAs (tRNAs, rRNAs, and snRNAs) and independent from small RNAs with specific molecular processing machinery. Over 95% of the eukaryotic genome is transcribed into non-coding RNAs and less than 5% is translated. LncRNA-mediated epigenetic regulation depends on lcnRNA interactions with proteins or genomic DNA via RNA secondary structures [10].Epigenomic modifications are involved in a great variety of physiological and pathological conditions; of major importance are those related with major problems of health such as cardiovascular disorders, obesity, cancer, inflammatory processes, and brain disorders [11,12]. A good paradigm on the influence of epigenetic factors on human pathology is the oncogenic ...

Clinical Advances in Sex- and Gender-Informed Medicine to Improve the Health of All

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