Reference : Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modula...
Scientific journals : Article
Human health sciences : Neurology
Systems Biomedicine
http://hdl.handle.net/10993/53882
Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition.
English
Mahoney-Sanchez, Laura [> >]
Bouchaoui, Hind [> >]
Boussaad, Ibrahim mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services]
Jonneaux, Aurélie [> >]
Timmerman, Kelly [> >]
Berdeaux, Olivier [> >]
Ayton, Scott [> >]
Krüger, Rejko mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Duce, James A. [> >]
Devos, David [> >]
Devedjian, Jean-Christophe [> >]
23-Aug-2022
Cell reports
40
8
111231
Yes
International
2211-1247
United States
[en] Dopaminergic Neurons/metabolism ; Ferroptosis ; Humans ; Parkinson Disease/metabolism ; Phospholipid Ethers/metabolism ; alpha-Synuclein/metabolism ; CP: Molecular biology ; CP: Neuroscience ; Parkinson's disease ; alpha synuclein ; cell death ; ether phospholipids ; ferroptosis ; lipid peroxidation
[en] There is a continued unmet need for treatments that can slow Parkinson's disease progression due to the lack of understanding behind the molecular mechanisms underlying neurodegeneration. Since its discovery, ferroptosis has been implicated in several diseases and represents a therapeutic target in Parkinson's disease. Here, we use two highly relevant human dopaminergic neuronal models to show that endogenous levels of α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing α-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated α-synuclein expression in patients' small-molecule-derived neuronal precursor cells with SNCA triplication causes an increased vulnerability to lipid peroxidation and ferroptosis. Lipid profiling reveals that ferroptosis resistance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of α-synuclein (α-syn). These results provide a molecular mechanism linking α-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance.
http://hdl.handle.net/10993/53882
10.1016/j.celrep.2022.111231
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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