title: A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders.
abstract: 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.
authors.affiliation: Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. Electronic address: wang21@niehs.nih.gov.
authors.forename: Xuting
authors.initials: X
authors.lastname: Wang
authors.affiliation: Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Campbell
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA; Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lacher
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.affiliation: Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Ma
authors.initials: M
authors.lastname: Wan
authors.affiliation: Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Crowl
authors.affiliation: Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Chorley
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Bond
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA; Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Slattery
authors.affiliation: Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. Electronic address: bell1@niehs.nih.gov.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell