A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders - PubMed (original) (raw)

Xuting Wang et al. Cell Rep. 2016.

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.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1

Study design and summary of candidates. (A) Overview of workflow for identifying functional ARE SNPs associated with disease; (B) The significance of GWAS SNPs linked to ARE SNPs.

Figure 2

Figure 2

Characteristics of rs242561. (A) location relative to risk SNP for PSP and PD and ChIP-seq signals, (B) position in ARE motif, (C) conservation, (D) allele-specific binding, (E) allele specific transactivation, (F) RT-PCR of MAPT levels in human IMR32 neuroblastoma cells treated with t-BHQ or vehicle, (G) Nrf2 +/+ and Nrf2 −/− mice were exposed to oxidative stress induced by hyperoxia and Mapt gene expression level was measured in mRNA from cerebellum by RT-PCR. See also Figure S3 and Tables S4–S5.

Figure 3

Figure 3

Association of rs242561 genotypes with MAPT mRNA levels in humans. (A) Map of rs242561 and eQTL SNPs with LD correlations (R2) within the MAPT gene; (B) MAPT mRNA levels and genotypes of rs242561 in human brain temporal cortex as measured by Affymetrix Exon array (UKBEC). TT is the stronger binding genotype. See also Figure S3.

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