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ISDN2012_0216: Neuroprotection of α‐Synuclein under Parkinsonian pesticide and apoptotic stimulus staurosporine treatments is diminished by its familial Parkinson's disease mutations
Author(s) -
Choong C.J.,
Say Y.H.
Publication year - 2012
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2012.10.037
Subject(s) - neuroprotection , staurosporine , chemistry , neuroscience , psychology , library science , computer science , biochemistry , protein kinase c , enzyme
Department of Biomedical Science, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, Malaysia E-mail address: sayyh@utar.edu.my (Y.H. Say). -Synuclein ( -Syn) plays a crucial role in the pathophysiology of dopaminergic neurodegeneration that occurs in Parkinson’s disease (PD). -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 -Syn in dopaminergic human neuroblastoma SH-SY5Y cells. SH-SY5Y cells stably overexpressing wild type or familial Syn mutants (A30P, E46K and A53T) were subjected to acute and chronic Parkinsonian pesticides rotenone and maneb, or to apoptotic stimulus staurosporine treatments. MTT cell viability assay showed that compared with untransfected or mock-transfected SH-SY5Y cells, wild type -Syn attenuated rotenone, maneb and staurosporine-induced cell death, along with an attenuation of toxin-induced mitochondrial membrane potential changes and Reactive Oxygen Species level, whereas the mutant -Syn constructs exacerbated environmental toxins-induced cytotoxicity or staurosporine-induced apoptosis. After chronic treatment of rotenone and maneb, wild type -Syn but not the mutant variants was found to rescue cells from subsequent acute hydrogen peroxide insult. Under staurosporine treatment, wild type -Syn cells have increased Bcl-2 and Bcl-XL, and decreased Bax and cleaved caspase 9 expression levels compared to the untransfected, mock-transfected and the mutants. Flow cytometric analysis with Propidium Iodide staining also revealed that the proliferative index was significantly reduced in cells expressing -Syn PD mutants. Taken together, our results tend to favor the neuroprotective property of wild-type -Syn against the toxicity of Parkinsonian environmental toxins rotenone and maneb, and apoptotic inducer staurosporine. However, this neuroprotection is diminished by -Syn familial PD mutations A30P, A53T and E46K – by causing neuronal cells to become more prone to oxidative and mitochondrial damage. Thus, this ‘loss-of-function’ toxicant-mutant -Syn interaction could have deleterious consequences and may be involved in the pathogenesis of PD.