@article{111f3e10a8944425a5103c78e3753903,
title = "Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition",
abstract = "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{\textquoteright} 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.",
keywords = "alpha synuclein, cell death, CP: Molecular biology, CP: Neuroscience, ether phospholipids, ferroptosis, lipid peroxidation, Parkinson's disease",
author = "Laura Mahoney-Sanchez and Hind Bouchaoui and Ibrahim Boussaad and Aur{\'e}lie Jonneaux and Kelly Timmerman and Olivier Berdeaux and Scott Ayton and Rejko Kr{\"u}ger and Duce, {James A.} and David Devos and Devedjian, {Jean Christophe}",
note = "Funding Information: The authors wish to thank the BioImaging Center Lille (BiCel) platform, and in particular Nathalie Jouy, for the support given in the flow cytometry experiments. The authors wish to thank the support of the Lille University Hospital and NS-Park/FCRIN clinical research network, the European commission for grant no. 633190 of the H2020 program, NCT02655315. This work was supported in part by European funds Network of Centres of Excellence in Neurodegeneration (CoEN) PRION-IRON and European funds (H2020, Eurostar) for preclinical research E-PD-IRONSYN. The work of I.B. and R.K. was supported by grants from Luxembourg National Research Fund ( FNR ) for the PEARL program ( FNR /P13/6682797 to R.K.), MotaSYN (12719684), and MAMasyn. Funding Information: D.D. has received PHRC grants from the French Ministry of Health and research funding from the ARSLA charity, France Parkinson charity, and the Credit Agricole Foundation. He has led two pilot investigator-driven studies with DFP provided for free by ApoPharma (FAIRPARK-I and SAFE-FAIR ALS-I). He is leading two large investigator-driven studies with DFP provided for free by ApoPharma (FAIRPARK-II and FAIR ALS-II). He served on advisory boards, served as a consultant, and has given lectures for pharmaceutical companies such as Orkyn, Aguettant, Abbvie, Medtronic, Novartis, Teva, UCB, and Lundbeck. J.A.D. has received research funding from Alzheimer{\textquoteright}s Society, Alzheimer{\textquoteright}s Research UK, European Commission, Parkinson{\textquoteright}s UK, and NHMRC. He serves as a scientific advisor on the FAIR-PARK II but has no financial disclosures. The remaining authors have nothing to declare. Funding Information: The authors wish to thank the BioImaging Center Lille (BiCel) platform, and in particular Nathalie Jouy, for the support given in the flow cytometry experiments. The authors wish to thank the support of the Lille University Hospital and NS-Park/FCRIN clinical research network, the European commission for grant no. 633190 of the H2020 program, NCT02655315. This work was supported in part by European funds Network of Centres of Excellence in Neurodegeneration (CoEN) PRION-IRON and European funds (H2020, Eurostar) for preclinical research E-PD-IRONSYN. The work of I.B. and R.K. was supported by grants from Luxembourg National Research Fund (FNR) for the PEARL program (FNR/P13/6682797 to R.K.), MotaSYN (12719684), and MAMasyn. Conceptualization, D.D. J.-C.D. L.M.-S. and J.A.D; methodology, A.J. K.T. L.M.-S. and J.-C.D.; investigation, L.M.-S. I.D. and H.B.; formal analysis, O.B.; writing – original draft, L.M.-S.; writing – review & editing, J.A.D. D.D. R.K. and S.A.; supervision, J.A.D. D.D. and J.-C.D.; funding acquisition, D.D. and R.K. D.D. has received PHRC grants from the French Ministry of Health and research funding from the ARSLA charity, France Parkinson charity, and the Credit Agricole Foundation. He has led two pilot investigator-driven studies with DFP provided for free by ApoPharma (FAIRPARK-I and SAFE-FAIR ALS-I). He is leading two large investigator-driven studies with DFP provided for free by ApoPharma (FAIRPARK-II and FAIR ALS-II). He served on advisory boards, served as a consultant, and has given lectures for pharmaceutical companies such as Orkyn, Aguettant, Abbvie, Medtronic, Novartis, Teva, UCB, and Lundbeck. J.A.D. has received research funding from Alzheimer's Society, Alzheimer's Research UK, European Commission, Parkinson's UK, and NHMRC. He serves as a scientific advisor on the FAIR-PARK II but has no financial disclosures. The remaining authors have nothing to declare. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = aug,
day = "23",
doi = "10.1016/j.celrep.2022.111231",
language = "English",
volume = "40",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}