The role of demographic, genetic and environmental factors in DNA methylation of microtubule-associated protein tau (MAPT) and their implications for neurodegenerative disease.

Abstract

Neurodegenerative diseases involve the progressive damage or death of neurons leading to a range of symptoms that can include cognitive deficits, behavioural changes and movement difficulties. Idiopathic neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, are complex disorders the genetic origins of which remain to be determined. Many studies have identified genes associated with these conditions, but it remains unclear how they influence the disease process in the absence of mutations. DNA methylation is capable of influencing gene expression and is a potential mechanism by which variants in genes may influence an individual’s risk of developing a neurodegenerative condition. The microtubule-associated protein tau gene (MAPT) has been associated with multiple neurodegenerative conditions including progressive supranuclear palsy and Parkinson’s disease, but its role in disease aetiology is unclear. In this thesis epigenetic regulation of MAPT was examined to elucidate demographic, lifestyle and genetic factors influencing MAPT methylation, and how methylation of MAPT influences downstream gene expression. The role of MAPT methylation in Alzheimer’s and Parkinson’s disease was also examined. It was found that both cis- and trans-genetic elements are involved in regulation of MAPT methylation, with methylation of the MAPT promoter resulting in altered MAPT expression. Similarly, demographic and lifestyle factors alter MAPT methylation and expression. These alterations in methylation were associated with altered disease risk in idiopathic Parkinson’s disease and PSEN1 mutant carriers. Amelioration of disease risk by altering MAPT methylation is possible via dietary intervention, as was demonstrated for the MAPT H2 haplotype. This thesis represents an in-depth examination of methylation of the MAPT promoter and its role in gene expression and neurodegenerative disease. This work highlights areas for future investigation in nutrigenomic therapies targeting methylation and gene-gene/gene-protein interactions that influence methylation.