Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition

Autor: Laura Mahoney-Sanchez, Hind Bouchaoui, Ibrahim Boussaad, Aurélie Jonneaux, Kelly Timmerman, Olivier Berdeaux, Scott Ayton, Rejko Krüger, James A. Duce, David Devos, Jean-Christophe Devedjian
Přispěvatelé: Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Luxembourg [Luxembourg], Plateforme Chemosens [Dijon], Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), University of Melbourne, Julien, Sabine
Jazyk: angličtina
Rok vydání: 2022
Předmět:
History
Molecular biology [CP]
Polymers and Plastics
Neurology [D14] [Human health sciences]
Parkinson's disease
ether phospholipids
Industrial and Manufacturing Engineering
General Biochemistry
Genetics and Molecular Biology
Dopaminergic Neurons/metabolism
alpha-Synuclein/metabolism
alpha synuclein
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Business and International Management
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Neurologie [D14] [Sciences de la santé humaine]
Neuroscience [CP]
Dopaminergic Neurons
Phospholipid Ethers
Parkinson Disease
lipid peroxidation
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Parkinson Disease/metabolism
ferroptosis
cell death
Phospholipid Ethers/metabolism
alpha-Synuclein
Zdroj: Cell Reports
Cell Reports, 2022, 40 (8), pp.111231. ⟨10.1016/j.celrep.2022.111231⟩
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2022.111231⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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