TY  - JOUR
AU  - Sadikoglou, Eldem
AU  - Domingo-Fernández, Daniel
AU  - Savytska, Natalia
AU  - Fernandes, Noemia
AU  - Rizzu, Patrizia
AU  - Illarionova, Anastasia
AU  - Strauß, Tabea
AU  - Schwarz, Sigrid
AU  - Kodamullil, Alpha
AU  - Höglinger, Günter U
AU  - Dhingra, Ashutosh
AU  - Gasser, Thomas
AU  - Heutink, Peter
TI  - Chr:17q21.31 locus risk haplotype H1 susceptibility to ferroptosis is mediated by endolysosomal pathway.
JO  - Cell death & disease
VL  - 16
IS  - 1
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2025-01263
SP  - 828
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Lysosomes: metabolism
KW  - Ferroptosis: genetics
KW  - Haplotypes: genetics
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Oxidative Stress
KW  - Genetic Predisposition to Disease
KW  - Endosomes: metabolism
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Reactive Oxygen Species: metabolism
KW  - Neurodegenerative Diseases: genetics
KW  - Neurodegenerative Diseases: pathology
KW  - Reactive Oxygen Species (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41238560
C2  - pmc:PMC12618564
DO  - DOI:10.1038/s41419-025-08147-1
UR  - https://pub.dzne.de/record/282293
ER  -