Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic 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, 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.

Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release

“…In addition to the extensive preclinical data supporting a key role of Nrf2 disruption in PD neurodegeneration, recent epidemiological studies have suggested Nrf2 genetic variants modify PD susceptibility and onset (Todorovic et al 2015, von Otter et al, 2014). From a therapeutic standpoint this astrocytic Nrf2-orchestrated defense system may offer an attractive drug target in several neurodegenerative diseases and other neurological disorders.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…These results were supported by four new independent European case-control studies (von Otter et al, 2014), but were not replicated in a Taiwanese population , suggesting disparity in ethnicities and environmental factors. As an alternative approach, PD cells derived from olfactory mucosa were exposed to smoke extract or pesticide to assess gene-environment interaction, and several SNPs were identified that affect the susceptibility to these toxins (Todorovic et al, 2015). Altogether, it is possible that a slight activation of NRF2, such as that found for some functional haplotypes of the NFE2L2 gene, should be enough to trigger protective mechanisms in the brain.…”

Sustained Effects of Neonatal Systemic Lipopolysaccharide on IL-1β and Nrf2 in Adult Rat Substantia Nigra Are Partly Normalized by a <b><i>Spirulina</i></b>-Enriched Diet

“…An association has been found between a haplotype in the Nrf2-gene and risk to develop PD [26–28]. This indicates that variations in the NFE2L2 gene could contribute to the pathology of Parkinson`s disease [29]. In addition, Nrf2 levels decrease with aging, which is the main risk factor for PD and several other neurodegenerative diseases [30].…”