Epigenetic Mechanisms in Neurodegenerative Disease

Susceptibility to complex neurodegenerative diseases such as Alzheimer’s disease (AD) and Multiple Sclerosis (MS) can result from both genetic and environmental influences. Different types of external environmental influences such as exposure to toxins and malnutrition as well as environmental stresses within a cell, such as oxidative damage and excitotoxicity, can alter gene transcription through epigenetic mechanisms. Two of these epigenetic mechanisms are histone acetylation and methylation of cytosine residues of DNA. Although these mechanisms have been investigated in other diseases, their role in neurodegenerative disease remains unknown. Changes in gene expression due to changes in histone acetylation and methylation status were examined as a novel system for understanding the physiology of AD, MS and other neuropathologies. Treatment of mice with the histone deacetylase inhibitor trichostatin A (TSA) led to increases in acetyl-L-lysine protein levels and differential gene expression. Genes susceptible to acetylation imbalances induced by trichostatin A were examined for overlaps with cellular pathways and human disease. Overlaps were found with DNA repair, chromatin remodeling, and methionine metabolism pathways, as well as other microarray studies that examined early-onset AD. Treatment of mice with L-methionine led to an increase in DNA (cytosine-5)-methyltransferase 3A (DNMT3A) but not Methionine adenosyltransferase I, alpha (MAT1A). Microarray expression analysis of L-methionine treated mice was also performed, but the results were inconclusive. Studies were also performed to examine methylation differences in the GAD1 promoter region between MS and control frontal, parietal, and motor cortex. Bisulfite sequencing identified three variably methylated CpG sites, and quantitative PCR was performed on immunoprecipitated methylation-enriched DNA fractions to determine differences in GAD1 promoter region methylation; however, no significant differences in GAD1 promoter methylation were found. These studies offer the first characterization of the role epigenetic mechanisms play in neurodegenerative disease.