Журнал болезни Альцгеймера и паркинсонизма

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

Ramón Cacabelos

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.