| dc.description.abstract | Alzheimer's disease (AD) and Huntington’s disease (HD) are two severe neurodegenerative diseases with distinct epidemiological profiles and aetiologies. AD is the leading cause of dementia and genetic risk factors only explain a third of cases. In contrast, HD is a rare disorder, the cause of which is fully explained by an autosomal dominant CAG trinucleotide repeat expansion in the Huntingtin gene. Environmental factors modulate the risk of developing AD, suggesting epigenetic processes may mediate this risk. This hypothesis has been supported through epigenome wide association studies that have found robust and reproducible differences in DNA methylation in AD. What these studies have thus far lacked is comprehensive coverage of the genes to which associations have been made. This is due to the reduced coverage of the genome that microarray technology, used in most of these studies, offers. Although a genetic disorder, variation in HD, including the age of onset and disease severity, has been partly attributed to environmental factors, raising the possibility that epigenetic mechanisms play a role in its phenotypic profile. Despite this, epigenetic studies of the disease are sparse and have been beset by a host of experimental problems. The aim of this thesis was to use methodological approaches that would increase the breadth and depth of the current understanding of DNA methylation changes in the brain, associated with these diseases. Either through full profiling of previously associated genes in the context of Alzheimer’s disease, or through epigenome-wide profiling of Huntington’s disease to nominate new potential associations. In addition, this work attempted to address specificity of a HD nominated locus, PTGDS, found to be associated during this thesis, by examining the locus in AD and other neurodegenerative diseases. The results revealed new DNA methylation associations with AD using targeted bisulfite sequencing, and that PTGDS is subject to differential methylation, specifically in HD. In summary, this work confirms that different methodological approaches can uncover new DNA methylation associations, even in well characterised loci, and nominates a novel association with Huntington’s disease, PTGDS, which should be further interrogated in a multi-omic and cell-specific context to understand how this association relates to the development of the condition. | en_GB |
