Assessing the Role of the Oxidative Stress Response ‘Master Regulator’ Nrf2 in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown. However, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model, generated from biopsies of the olfactory mucosa, termed hONS cells. These cells have demonstrated disease-specific differences in gene expression and metabolic activity associated with the Nrf2-mediated antioxidant defence pathway. To date, few studies have examined the role of the Nrf2 encoding gene, NFE2L2, in PD. This thesis comprehensibly assessed whether rare and common NFE2L2 genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1,338; controls=1,379). We employed a haplotype-tagging approach that identified an association with the tagging SNP rs2364725 and PD (OR = 0.849 (0.760-0.948), P = 0.004). Further genetic screening for rare variants in patient-derived cell lines produced no obvious pathogenic variants in the coding regions of NFE2L2. In addition, we were able to identify some age-at-onset modifying SNPs and replicate an ‘early-onset’ haplotype that contains a previously identified ‘functional promoter’ SNP (rs6721961).