title: Lipid peroxidation is essential for α-synuclein-induced cell death.
abstract: Parkinson's disease is the second most common neurodegenerative disease and its pathogenesis is closely associated with oxidative stress. Deposition of aggregated α-synuclein (α-Syn) occurs in familial and sporadic forms of Parkinson's disease. Here, we studied the effect of oligomeric α-Syn on one of the major markers of oxidative stress, lipid peroxidation, in primary co-cultures of neurons and astrocytes. We found that oligomeric but not monomeric α-Syn significantly increases the rate of production of reactive oxygen species, subsequently inducing lipid peroxidation in both neurons and astrocytes. Pre-incubation of cells with isotope-reinforced polyunsaturated fatty acids (D-PUFAs) completely prevented the effect of oligomeric α-Syn on lipid peroxidation. Inhibition of lipid peroxidation with D-PUFAs further protected cells from cell death induced by oligomeric α-Syn. Thus, lipid peroxidation induced by misfolding of α-Syn may play an important role in the cellular mechanism of neuronal cell loss in Parkinson's disease. We have found that aggregated α-synuclein-induced production of reactive oxygen species (ROS) that subsequently stimulates lipid peroxidation and cell death in neurons and astrocytes. Specific inhibition of lipid peroxidation by incubation with reinforced polyunsaturated fatty acids (D-PUFAs) completely prevented the effect of α-synuclein on lipid peroxidation and cell death.
authors.affiliation: UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Plamena R
authors.initials: PR
authors.lastname: Angelova
authors.forename: Mathew H
authors.initials: MH
authors.lastname: Horrocks
authors.forename: David
authors.initials: D
authors.lastname: Klenerman
authors.forename: Sonia
authors.initials: S
authors.lastname: Gandhi
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.forename: Mikhail S
authors.initials: MS
authors.lastname: Shchepinov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D004996:Ethidium / Q000031:analogs & derivatives / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D005231:Fatty Acids, Unsaturated; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; C067883:dihydroethidium; D004996:Ethidium
keywords: deuterated PUFA; lipid peroxidation; oxidative stress; α-synuclein