A polymorphic antioxidant response element links NRF2/sMAF binding to enhanced MAPT expression and reduced risk of parkinsonian disorders

Research output: Contribution to journalArticlepeer-review

Authors

  • Xuting Wang
  • Michelle R Campbell
  • Sarah E Lacher
  • Hye-Youn Cho
  • Ma Wan
  • Christopher L Crowl
  • Brian N Chorley
  • Steven R Kleeberger
  • Matthew Slattery
  • Douglas A Bell

Colleges, School and Institutes

External organisations

  • Environmental Genomics Section, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • University of Minnesota Medical School
  • University of Minnesota

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.

Details

Original languageEnglish
Pages (from-to)830-842
Number of pages13
JournalCell Reports
Volume15
Issue number4
Early online date14 Apr 2016
Publication statusPublished - 26 Apr 2016