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, in which the NRF2-mediated antioxidant response pathway genes were among the most differentially-expressed. To date, few studies have examined the role of the NRF2 encoding gene, NFE2L2, and PD. In this study, we comprehensibly assessed whether rare and common NFE2L2 genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1338, controls=1379). 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 in hONS cell lines produced no obvious pathogenic variants in the coding regions of NFE2L2. Finally, we investigated the relationship between xenobiotic exposures and NRF2 function, through gene-environment interactions, between NFE2L2 SNPs and smoking or pesticide exposure. Our results demonstrated a significant interaction between rs2706110 and pesticide exposure (OR = 0.597 (0.393-0.900), P = 0.014). 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). Our results suggest a role of NFE2L2 genetic variants in modifying PD susceptibility and onset. Our findings also support the utility of testing gene-environment interactions in genetic studies of PD.
Highlights
Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors
To assess for possible gene-environment interactions between NFE2L2 single nucleotide polymorphisms (SNPs) and xenobiotic exposures commonly associated with PD we examined the joint effects of genotype and exposure on PD risk using logistic regression models
While we identified two rare NFE2L2 coding variants from our hONS cell lines, it appears unlikely that they are pathogenic and are not likely the cause of NRF2-mediated pathway differences in PD hONS cell lines
Summary
Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. Nuclear factor erythroid-2-related factor 2 (protein: NRF2; gene: NFE2L2) is a transcription factor in the phase II antioxidant and xenobiotic response pathway and is termed a ‘master regulator’ of expression for many antioxidant and detoxification pathway genes [5]. KEAP1 forms a complex with CUL3-RBX1 and regulates NRF2 through targeted ubiquitination and subsequent degradation. The mode of action for NRF2 begins upon exposure to oxidative stress, xenobiotics, or electrophilic compounds. This causes the modification of cysteine-151 of KEAP1 and subsequent stabilisation and translocation of NRF2 to the nucleus where it binds to the antioxidant response element (ARE) of its target genes [5, 6]
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