A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders
Xuting Wang,
Michelle R. Campbell,
Sarah E. Lacher,
Hye-Youn Cho,
Ma Wan,
Christopher L. Crowl,
Brian N. Chorley,
Gareth L. Bond,
Steven R. Kleeberger,
Matthew Slattery,
Douglas A. Bell
Affiliations
Xuting Wang
Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Michelle R. Campbell
Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Sarah E. Lacher
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA
Hye-Youn Cho
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Ma Wan
Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Christopher L. Crowl
Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Brian N. Chorley
Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Gareth L. Bond
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK
Steven R. Kleeberger
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Matthew Slattery
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA
Douglas A. Bell
Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
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.
