Sensitization of Neuronal Cells to Oxidative Stress with Mutated Human α‐Synuclein

• Published in: Journal of neurochemistry Vol. 75; no. 6; pp. 2546 - 2554
• Main Authors: Ko, Li‐wen, Mehta, Nitin D., Farrer, Matthew, Easson, Colin, Hussey, Jennifer, Yen, Samuel, Hardy, John, Yen, Shu‐Hui C.
• Format: Journal Article
• Language: English
• Published: Oxford UK Blackwell Science Ltd 01.12.2000; Blackwell
• Subjects: a-Synuclein; alpha-Synuclein; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Humans; Immunoblotting; Kidney - cytology; Kidney - drug effects; Kidney - metabolism; Medical sciences; Menadione; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - pharmacology; Neurology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Parkinson Disease - genetics; Parkinson's disease; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Sulfhydryl Compounds - metabolism; Synucleins; Tetrazolium Salts; Thiazoles; Transfection; Vitamin K - pharmacology; α‐Synuclein; Human; Oxidative stress; Nervous system diseases; Central nervous system disease; Parkinson disease; Degenerative disease; Mutation; Synuclein; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2000.0752546.x

: Linkage of α‐synuclein (α‐SN) mutations tofamilial Parkinson's disease (PD) and presence of α‐SN as a majorconstituent of Lawy body in both sporadic and familial PD implicate α‐SNabnormality in PD pathogenesis. Here we demonstrate that overexpression ofwild‐type or mutant α‐SN does not cause any deleterious effect on thegrowth or continued propagation of transfected human cells, but overproductionof mutant α‐SN heightens their sensitivity to menadione‐inducedoxidative injury. Such enhanced vulnerability is more pronounced in neuronaltransfectants than in their nonneuronal counterparts and is associated withincreased production of reactive oxygen species. The data suggest that mutatedα‐SN, especially with an alanine‐to‐proline substitution at residue 30,sensitizes neuronal cells to oxidative damage.