@misc{10481/95426,
year = {2022},
month = {12},
url = {https://hdl.handle.net/10481/95426},
abstract = {Increased brain iron content has been consistently reported in sporadic Parkinson’s disease (PD) patients, and an increase in
cytosolic free iron is known to cause oxidative stress and cell death. However, whether iron also accumulates in susceptible brain
areas in humans or in mouse models of familial PD remains unknown. In addition, whilst the lysosome functions as a critical
intracellular iron storage organelle, little is known about the mechanisms underlying lysosomal iron release and how this process is
influenced by lysosome biogenesis and/or lysosomal exocytosis. Here, we report an increase in brain iron content also in PD
patients due to the common G2019S-LRRK2 mutation as compared to healthy age-matched controls, whilst differences in iron
content are not observed in G2019S-LRRK2 knockin as compared to control mice. Chemically triggering iron overload in cultured
cells causes cytotoxicity via the endolysosomal release of iron which is mediated by TRPML1. TFEB expression reverts the iron
overload-associated cytotoxicity by causing lysosomal exocytosis, which is dependent on a TRPML1-mediated increase in cytosolic
calcium levels. Therefore, approaches aimed at increasing TFEB levels, or pharmacological TRPML1 activation in conjunction with
iron chelation may prove beneficial against cell death associated with iron overload conditions such as those associated with PD.},
organization = {Biobank HUB-ICO-IDIBELL
(PT17/0015/0024), integrated into the Spanish Biobank Network},
organization = {European Regional Development Fund (FEDER) Research Project UNGR15-CE-3380},
organization = {Junta de Andalucia (B-CTS-386-UGR18, F.G. and S.H.), intramural funds from
the CSIC (S.H.)},
organization = {intramural funds from Rutgers University (S.H.)},
publisher = {Springer Nature},
title = {Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB},
doi = {10.1038/s41419-022-05504-2},
author = {Fernández López, María Belén and Olmedo Palma, Pablo and Gil, Fernando and Fernández, Elena and Naaldijk, Yahaira and Rivero Ríos, María del Pilar and Bracher, Franz and Grimm, Christian and C. Churchill, Grant and Navarro Hilfiker, Sabine Nicole},
}