Chr:17q21.31 locus risk haplotype H1 susceptibility to ferroptosis is mediated by endolysosomal pathway

Human chr:17q21.31 locus is a complex genomic region of high linkage disequilibrium with two main haplotypes, named H1 and H2. The H1 haplotype is genetically associated with a wide spectrum of neurodegenerative diseases (NDs), including tauopathies and synucleinopathies, with the underlying mechanism remaining unknown. We investigated the interplay of environmental and genetic risk factors on neurons derived from iPSCs of both haplotypes under Mild Chronic Oxidative Stress (MCOS) conditions. The observed increased susceptibility of H1 neurons to MCOS leading to an earlier neuronal death, was mediated by ferroptosis. Characterization of the phenotype revealed spatiotemporal propagation and spreading of axonal deterioration and neuronal death in accordance with NDs pathology. Transcriptional profiling pointed to ferroptosis hallmarks and endo-lysosomal vesicles as implicated pathways, while FDA-approved drugs prevented the induced death in H1 neurons. Finally, ROS and lysosomal dynamics during the neuronal maturation shed further light to the differential response of haplotypes to MCOS, which could explain the risk association of the H1 haplotype with NDs.