A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders

Abstract

Summary 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 8 polymorphic AREs linked to 14 highly-ranked disease-risk SNPs in Caucasians. 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.

Axonal pathology in hPSC-based models of Parkinson’s disease results from loss of Nrf2 transcriptional activity at the Map1b gene locus

“…In our hPSC model, overexpression of Map1b or activation of its expression by treatment with the Nrf2 activator DMF resulted in rescue of neurite length deficits in A53T hNs. A recent study reported the Mapt gene is also regulated by binding of Nrf2 to an ARE within its first intron and that a single-nucleotide polymorphism associated with stronger Nrf2 binding results in increased expression of Tau protein and reduced risk of parkinsonian disorders (30). We examined Mapt in our system and found that gene expression was not significantly affected by the SNCA-A53T mutation, and its expression was not induced by treatment with the Nrf2 activator DMF.…”

“…Map1b is known to be an important regulator of both axonal and dendritic growth and guidance (29), while Tau is restricted to axons (10), and increased Tau expression is commonly associated with PD pathology (11,12). Mapt is a known target of Nrf2 (30) and was therefore an attractive candidate, but confirmation of the expression profile results by qPCR indicated no significant difference in expression between hiPSC-derived (SI Appendix, Fig. S5B) and hESC-derived (SI Appendix, Fig.…”

NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models

“…NRF2 deficiency leads to enhanced autophagic dysfunction (21), phosphorylated-Tau (22,44), and vulnerability to oxidative stress (45). Conversely, up-regulation of NRF2-ARE pathway protects neurons against oxidative proteotoxic stress (29,(46)(47)(48).…”

Tau Structures

“…Regarding the possible function of exons 2 and 3, it has been described that they might play a role in the association of tau protein with different cell membrane proteins like apolipoprotein ApoA1 (preferentially binding to tau with those exons) or synaptophysin (preferentially binding tau without those exons; Liu C. et al, 2016). Curiously, a binding site for NRF2, a transcription factor involved in antioxidant responses, is present in the first intron of the mapt gene and it may facilitate exon 3 inclusion in tau protein, an inclusion that could have a protective role (Wang et al, 2016). …”