Abstract The microtubule associated protein tau (MAPT) chromosome 17q21.31 locus lies within a region of high linkage disequilibrium (LD) conferring two extended haplotypes commonly referred to as H1 and H2. The major haplotype, H1 has been genetically associated with an increased risk for multiple neurodegenerative disorders, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), APOE ε4-negative Alzheimer’s disease (AD) and Parkinson’s disease (PD). The mechanism causing this increased risk is largely unknown. Here, we investigated the role of Mild Chronic Oxidative Stress (MCOS) in neurogenin 2 ( NGN2 ) induced neurons (iNeurons) derived from iPS (induced pluripotent stem cells) from carriers of both haplotypes. We identified that iNeurons of the H1 homozygous haplotype showed an increased susceptibility to MCOS compared to homozygous H2 carriers, leading to cell death through ferroptosis. We performed a cellular screen in H1 iNeurons using a FDA-approved Drug Library and identified candidate molecules that rescued the increased susceptibility to MCOS and prevented ferroptosis in H1 iNeurons. Highlights Mild Chronic Oxidative Stress induces neurotoxicity via ferroptosis on iNGN2 neurons Axonal degeneration, disordered microtubules, blebs precede neurotoxicity MAPT-17q21.3 locus H1/H1, risk allele for NDD is more vulnerable to MCOS FDA-approved drugs reverse MCOS induced ferroptosis on H1/H1 risk allele Abstract Figure

Rescue of the increased susceptibility to Mild Chronic Oxidative Stress of iNeurons carrying the MAPT Chromosome 17q21.3 H1/H1 risk allele by FDA-approved compounds