title: Neuroprotection of α-synuclein under acute and chronic rotenone and maneb treatment is abolished by its familial Parkinson's disease mutations A30P, A53T and E46K.
abstract: α-Synuclein (α-Syn) plays a crucial role in the pathophysiology of Parkinson's disease (PD). α-Syn has been extensively studied in many neuronal cell-based PD models but has yielded mixed results. The objective of this study was to re-evaluate the dual cytotoxic/protective roles of α-Syn in dopaminergic SH-SY5Y cells. Stable SH-SY5Y cells overexpressing wild type or familial α-Syn mutants (A30P, E46K and A53T) were subjected to acute and chronic rotenone and maneb treatment. Compared with untransfected SH-SY5Y cells, wild type α-Syn attenuated rotenone and maneb-induced cell death along with an attenuation of toxin-induced mitochondrial membrane potential changes and Reactive Oxygen Species level, whereas the mutant α-Syn constructs exacerbated environmental toxins-induced cytotoxicity. After chronic treatment, wild type α-Syn but not the mutant variants was found to rescue cells from subsequent acute hydrogen peroxide insult. These results suggest that the fundamental property of wild type α-Syn may be protective, and such property may be lost by its familial PD mutations.
authors.affiliation: Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, 31900 Kampar, Perak, Malaysia.
authors.forename: Chi-Jing
authors.initials: CJ
authors.lastname: Choong
authors.forename: Yee-How
authors.initials: YH
authors.lastname: Say
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008344:Maneb / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity*; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C497604:SNCA protein, human; D051844:alpha-Synuclein; D012402:Rotenone; D008344:Maneb; D006861:Hydrogen Peroxide; D004298:Dopamine