A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders

The NRF2/sMAF protein complex regulates the oxidative stress response by occupying cis-acting enhancers containing an antioxidant response element (ARE). Integrating genome-wide maps of NRF2/sMAF occupancy with disease-susceptibility loci, we discovered eight polymorphic AREs linked to 14 highly ranked disease-risk SNPs in individuals of European ancestry. Among these SNPs was rs242561, located within a regulatory region of the MAPT gene (encoding microtubule-associated protein Tau). It was consistently occupied by NRF2/sMAF in multiple experiments and its strong-binding allele associated with higher mRNA levels in cell lines and human brain tissue. Induction of MAPT transcription by NRF2 was confirmed using a human neuroblastoma cell line and a Nrf2-deficient mouse model. Most importantly, rs242561 displayed complete linkage disequilibrium with a highly protective allele identified in multiple GWASs of progressive supranuclear palsy, Parkinson’s disease, and corticobasal degeneration. These observations suggest a potential role for NRF2/sMAF in tauopathies and a possible role for NRF2 pathway activators in disease prevention. [Display omitted] •Genome-wide NRF2/sMAF occupancy defines highly ranked disease-associated SNPs•SNPs in NRF2 binding sites are rare in the human genome due to negative selection•A SNP in MAPT shows allele-specific binding to NRF2, enhanced MAPT transcription•Strong NRF2 binding site is linked with reduced risk of parkinsonian diseases Wang et al. find that a polymorphic NRF2/sMAF binding site in MAPT is strongly associated with differential risk for parkinsonian disorders and provide evidence that it is occupied by NRF2/sMAF proteins in human and mouse cells. The stronger-binding allele enhances MAPT expression in the human brain and associates with a protective effect in GWAS analyses.