Histone Methylation Regulation in Neurodegenerative Disorders

Abstract

Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; Parkinson’s disease; epigenetics; neuronal loss and alcohol.

Figure 1

A schematic depiction of chromatin histone protein lysine methylation and demethylation by the mammalian histone methyltransferase (KMTs) and histone demethylase (KDMs) enzyme families. The HMT and HDM for each lysine methylation are also represented with their methylation/demethylation state specificities (Me1, monomethylation; Me2, dimethylation; Me3, trimethylation), X, inhibition.

Figure 2

Graphical summary of histone methylation-specific epigenetic defects in ND disorders. Neurodegeneration-inducing conditions have been shown to affect DNA-associated histone methylation via specific KMTs and KDMs, followed by several changes in gene and protein expression that are important for cognitive and other ND-related brain pathologies.