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@ARTICLE{Sadikoglou:282293,
author = {Sadikoglou, Eldem and Domingo-Fernández, Daniel and
Savytska, Natalia and Fernandes, Noemia and Rizzu, Patrizia
and Illarionova, Anastasia and Strauß, Tabea and Schwarz,
Sigrid and Kodamullil, Alpha and Höglinger, Günter U and
Dhingra, Ashutosh and Gasser, Thomas and Heutink, Peter},
title = {{C}hr:17q21.31 locus risk haplotype {H}1 susceptibility to
ferroptosis is mediated by endolysosomal pathway.},
journal = {Cell death $\&$ disease},
volume = {16},
number = {1},
issn = {2041-4889},
address = {London [u.a.]},
publisher = {Nature Publishing Group},
reportid = {DZNE-2025-01263},
pages = {828},
year = {2025},
abstract = {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.},
keywords = {Humans / Lysosomes: metabolism / Ferroptosis: genetics /
Haplotypes: genetics / Neurons: metabolism / Neurons:
pathology / Oxidative Stress / Genetic Predisposition to
Disease / Endosomes: metabolism / Induced Pluripotent Stem
Cells: metabolism / Reactive Oxygen Species: metabolism /
Neurodegenerative Diseases: genetics / Neurodegenerative
Diseases: pathology / Reactive Oxygen Species (NLM
Chemicals)},
cin = {AG Heutink / AG Bansal / AG Rizzu / ICRU / Clinical
Research (Munich) / AG Gasser},
ddc = {570},
cid = {I:(DE-2719)1210002 / I:(DE-2719)1210013 /
I:(DE-2719)1210009 / I:(DE-2719)1240005 / I:(DE-2719)1111015
/ I:(DE-2719)1210000},
pnm = {354 - Disease Prevention and Healthy Aging (POF4-354) / 353
- Clinical and Health Care Research (POF4-353) / 899 - ohne
Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-354 / G:(DE-HGF)POF4-353 /
G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41238560},
pmc = {pmc:PMC12618564},
doi = {10.1038/s41419-025-08147-1},
url = {https://pub.dzne.de/record/282293},
}