A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders
Open accessAbstract
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.
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GWAS have identified >2000 single-nucleotide polymorphisms (SNPs) associated with human diseases.
“GWAS have identified >2000 single-nucleotide polymorphisms (SNPs) associated with human diseases61.”
From Key points for the development of antioxidant cocktails to prevent cellular stress and damage caused by reactive oxygen species (ROS) during manned space missions (2021) · cites this paper as [61]
The Introduction says GWASs identified approximately 2,000 SNPs significantly associated with susceptibility to more than 70 human diseases. It supports the general point, but “approximately 2,000” does not establish the claim’s specific threshold of more than 2,000. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOne SNP (rs242561) located in the regulatory region of the microtubule-associated protein Tau gene induced a strong binding of the NRF2/sMAF complex, leading to increased transcription and a reduced risk of parkinsonian diseases.
“One of these SNPs (rs242561) was located in the regulatory region of the microtubule-associated protein Tau gene, which induced a strong binding of the NRF2/sMAF complex, leading to increased transcription and a reduced risk of parkinsonian diseases61,62.”
From Key points for the development of antioxidant cocktails to prevent cellular stress and damage caused by reactive oxygen species (ROS) during manned space missions (2021) · cites this paper as [61]
The Results section identifies rs242561 in a MAPT regulatory region, documents NRF2/sMAF occupancy, and associates its stronger-binding T allele with higher MAPT expression. It also reports that this allele is in strong linkage disequilibrium with a protective allele for parkinsonian disorders. The paper proposes, rather than establishes, that rs242561 itself causes the reduced disease risk; the Discussion describes the protective mechanism as a hypothesis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEight polymorphic ARE are linked to a higher disease risk in individuals of European ancestry.
“It has been shown that eight polymorphic ARE are linked to a higher disease risk in individuals of European ancestry.”
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References 56 · Cited by 49
Research works printed but not linked: 43
- Allen M Kachadoorian M Quicksall Z Zou F Chai HS Younkin C Crook JE Pankratz VS Carrasquillo MM Krishnan S Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels Alzheimers Res Ther 2014 6 39 25324900 PMC4198935
- Boyle AP Hong EL Hariharan M Cheng Y Schaub MA Kasowski M Karczewski KJ Park J Hitz BC Weng S Annotation of functional variation in personal genomes using RegulomeDB Genome Res 2012 22 1790 1797 22955989 PMC3431494
- Caffrey TM Joachim C Wade-Martins R Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus Neurobiology of Aging 2008 29 1923 1929 17602795 PMC2801070
- Cho HY Kleeberger SR Association of Nrf2 with airway pathogenesis: lessons learned from genetic mouse models Arch Toxicol 2015 89 1931 1957 26194645 PMC6779142
- Chorley BN Campbell MR Wang X Karaca M Sambandan D Bangura F Xue P Pi J Kleeberger SR Bell DA Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha Nucleic Acids Res 2012 40 7416 7429 22581777 PMC3424561
- Consortium EP An integrated encyclopedia of DNA elements in the human genome Nature 2012 489 57 74 22955616 PMC3439153
- Consortium G Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans Science (New York, NY) 2015a 348 648 660 PMC4547484 25954001
- Consortium RE Integrative analysis of 111 reference human epigenomes Nature 2015b 518 317 330 25693563 PMC4530010
- Dobin A Davis CA Schlesinger F Drenkow J Zaleski C Jha S Batut P Chaisson M Gingeras TR STAR: ultrafast universal RNA-seq aligner Bioinformatics 2013 29 15 21 23104886 PMC3530905
- Dubois PC Trynka G Franke L Hunt KA Romanos J Curtotti A Zhernakova A Heap GA Adany R Aromaa A Multiple common variants for celiac disease influencing immune gene expression Nature genetics 2010 42 295 302 20190752 PMC2847618
- Farh KK Marson A Zhu J Kleinewietfeld M Housley WJ Beik S Shoresh N Whitton H Ryan RJ Shishkin AA Genetic and epigenetic fine mapping of causal autoimmune disease variants Nature 2015 518 337 343 25363779 PMC4336207
- Genomes Project C Abecasis GR Auton A Brooks LD DePristo MA Durbin RM Handsaker RE Kang HM Marth GT McVean GA An integrated map of genetic variation from 1,092 human genomes Nature 2012 491 56 65 23128226 PMC3498066
- Hayes JD Dinkova-Kostova AT The Nrf2 regulatory network provides an interface between redox and intermediary metabolism Trends Biochem Sci 2014 39 199 218 24647116
- Hayes JD McMahon M Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention Cancer Lett 2001 174 103 113 11689285
- Hoglinger GU Melhem NM Dickson DW Sleiman PMA Wang LS Klei L Rademakers R de Silva R Litvan I Riley DE Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy Nature genetics 2011 43 699 U125 21685912 PMC3125476
- Hybertson BM Gao B Role of the Nrf2 signaling system in health and disease Clin Genet 2014 86 447 452 25099075
- Itoh K Chiba T Takahashi S Ishii T Igarashi K Katoh Y Oyake T Hayashi N Satoh K Hatayama I An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements Biochem Biophys Res Commun 1997 236 313 322 9240432
- Ittner A Ke YD van Eersel J Gladbach A Gotz J Ittner LM Brief update on different roles of tau in neurodegeneration IUBMB Life 2011 63 495 502 21698753
- Johnson DA Johnson JA Nrf2-a therapeutic target for the treatment of neurodegenerative diseases Free Radic Biol Med 2015 PMC4809057 26281945
- Jun G Ibrahim-Verbaas CA Vronskaya M Lambert JC Chung J Naj AC Kunkle BW Wang LS Bis JC Bellenguez C A novel Alzheimer disease locus located near the gene encoding tau protein Mol Psychiatry 2015 PMC4573764 25778476
- Karczewski KJ Dudley JT Kukurba KR Chen R Butte AJ Montgomery SB Snyder M Systematic functional regulatory assessment of disease-associated variants Proceedings of the National Academy of Sciences of the United States of America 2013 110 9607 9612 23690573 PMC3677437
- Li H Handsaker B Wysoker A Fennell T Ruan J Homer N Marth G Abecasis G Durbin R The Sequence Alignment/Map format and SAMtools Bioinformatics 2009 25 2078 2079 19505943 PMC2723002
- Li H Ruan J Durbin R Mapping short DNA sequencing reads and calling variants using mapping quality scores Genome Res 2008 18 1851 1858 18714091 PMC2577856
- Li QH Brown JB Huang HY Bickel PJ Measuring Reproducibility of High-Throughput Experiments Annals of Applied Statistics 2011 5 1752 1779
- Machanick P Bailey TL MEME-ChIP: motif analysis of large DNA datasets Bioinformatics 2011 27 1696 1697 21486936 PMC3106185
- McKenna A Hanna M Banks E Sivachenko A Cibulskis K Kernytsky A Garimella K Altshuler D Gabriel S Daly M The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data Genome Res 2010 20 1297 1303 20644199 PMC2928508
- Muramatsu H Katsuoka F Toide K Shimizu Y Furusako S Yamamoto M Nrf2 deficiency leads to behavioral, neurochemical and transcriptional changes in mice Genes Cells 2013 18 899 908 23890231
- Nioi P McMahon M Itoh K Yamamoto M Hayes JD Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence Biochem J 2003 374 337 348 12816537 PMC1223621
- Ramasamy A Trabzuni D Gibbs JR Dillman A Hernandez DG Arepalli S Walker R Smith C Ilori GP Shabalin AA Resolving the polymorphism-in-probe problem is critical for correct interpretation of expression QTL studies Nucleic Acids Res 2013 41 e88 23435227 PMC3627570
- Rushmore TH Morton MR Pickett CB The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity J Biol Chem 1991 266 11632 11639 1646813
- Schaub MA Boyle AP Kundaje A Batzoglou S Snyder M Linking disease associations with regulatory information in the human genome Genome Res 2012 22 1748 1759 22955986 PMC3431491
- Stack C Jainuddin S Elipenahli C Gerges M Starkova N Starkov AA Jove M Portero-Otin M Launay N Pujol A Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity Human molecular genetics 2014 23 3716 3732 24556215 PMC4065148
- Stefansson H Helgason A Thorleifsson G Steinthorsdottir V Masson G Barnard J Baker A Jonasdottir A Ingason A Gudnadottir VG A common inversion under selection in Europeans Nature genetics 2005 37 129 137 15654335
- Trabzuni D Wray S Vandrovcova J Ramasamy A Walker R Smith C Luk C Gibbs JR Dillman A Hernandez DG MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies Human molecular genetics 2012 21 4094 4103 22723018 PMC3428157
- Wang X Tomso DJ Chorley BN Cho HY Cheung VG Kleeberger SR Bell DA Identification of polymorphic antioxidant response elements in the human genome Human molecular genetics 2007 16 1188 1200 17409198 PMC2805149
- Ward LD Kellis M HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants Nucleic Acids Research 2012 40 D930 D934 22064851 PMC3245002
- Wasserman WW Fahl WE Functional antioxidant responsive elements Proc Natl Acad Sci U S A 1997 94 5361 5366 9144242 PMC24683
- Welter D MacArthur J Morales J Burdett T Hall P Junkins H Klemm A Flicek P Manolio T Hindorff L The NHGRI GWAS Catalog, a curated resource of SNP-trait associations Nucleic Acids Res 2014 42 D1001 D1006 24316577 PMC3965119
- Yamazaki H Tanji K Wakabayashi K Matsuura S Itoh K Role of the Keap1/Nrf2 pathway in neurodegenerative diseases Pathol Int 2015 65 210 219 25707882
- Zeron-Medina J Wang X Repapi E Campbell MR Su D Castro-Giner F Davies B Peterse EF Sacilotto N Walker GJ A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection Cell 2013 155 410 422 24120139 PMC4171736
- Zhang Y Liu T Meyer CA Eeckhoute J Johnson DS Bernstein BE Nussbaum C Myers RM Brown M Li W Model-based Analysis of ChIP-Seq (MACS) Genome biology 2008 9 PMC2592715 18798982
- Zhong Q Congdon EE Nagaraja HN Kuret J Tau isoform composition influences rate and extent of filament formation J Biol Chem 2012 287 20711 20719 22539343 PMC3370253
- Zou FG Chai HS Younkin CS Allen M Crook J Pankratz VS Carrasquillo MM Rowley CN Nair AA Middha S Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants Plos Genetics 2012 8 PMC3369937 22685416
- Authors
- Wang, X., Campbell, M. R., Lacher, S. E., Cho, H.-Y., Wan, M., Crowl, C. L., Chorley, B. N., Bond, G. L., Kleeberger, S. R., Slattery, M., & Bell, D. A.
- Affiliations
- National Institutes of Health (US)
- University of Minnesota (US)
- University of Oxford (GB)
- Corresponding author
- Wang, Xuting
- Bell, Douglas A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 15
- Issue
- 4
- Pages
- 830-842
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5063658
- OpenAlex
- W2337969040
- Cited by
- 49
- References
- 56
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 3
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (Z01-ES100475)
- National Institute of Environmental Health Sciences (Z01ES046008, Z01ES100475)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- antioxidant response element, MAPT, tau protein, Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, tauopathy, oxidative stress response, cis-acting enhancer, linkage disequilibrium, transcriptional regulation, neuroprotection
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