title: Evidence for synergism between cell death mechanisms in a cellular model of neurodegeneration in Parkinson's disease.
abstract: Delineation of how cell death mechanisms associated with Parkinson's disease (PD) interact and whether they converge would help identify targets for neuroprotective therapies. The purpose of this study was to use a cellular model to address these issues. Catecholaminergic SH-SY5Y neuroblastoma cells were exposed to a range of compounds (dopamine, rotenone, 5,8-dihydroxy-1,4-naphtho-107 quinone [naphthazarin], and Z-Ile-Glu(OBut)-Ala-Leu-al [PSI]) that are neurotoxic when applied to these cells for extended periods of times at specific concentrations. At the concentrations used, these compounds cause cellular stress via mechanisms that mimic those associated with causing neurodegeneration in PD, namely oxidative stress (dopamine), mitochondrial dysfunction (rotenone), lysosomal dysfunction (naphthazarin), and proteasomal dysfunction (PSI). The compounds were applied to the SH-SY5Y cells either alone or in pairs. When applied separately, the compounds produced a significant decrease in cell viability confirming that oxidative stress, mitochondrial, proteosomal, or lysosomal dysfunction can individually result in catecholaminergic cell death. When the compounds were applied in pairs, some of the combinations produced synergistic effects. Analysis of these interactions indicates that proteasomal, lysosomal, and mitochondrial dysfunction is exacerbated by dopamine-induced oxidative stress. Furthermore, inhibition of the proteasome or lysosome or increasing oxidative stress has a synergistic effect on cell viability when combined with mitochondrial dysfunction, suggesting that all cell death mechanisms impair mitochondrial function. Finally, we show that there are reciprocal relationships between oxidative stress, proteasomal dysfunction, and mitochondrial dysfunction, whereas lysosome dysfunction appears to mediate cell death via an independent pathway. Given the highly interactive nature of the various cell death mechanisms linked with PD, we predict that effective neuroprotective strategies should target multiple sites in these pathways, for example oxidative stress and mitochondria.
authors.affiliation: Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Yong-Kee
authors.forename: R
authors.initials: R
authors.lastname: Warre
authors.forename: P P
authors.initials: PP
authors.lastname: Monnier
authors.forename: A M
authors.initials: AM
authors.lastname: Lozano
authors.forename: J E
authors.initials: JE
authors.lastname: Nash
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009285:Naphthoquinones / Q000633:toxicity; D009447:Neuroblastoma / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D009498:Neurotoxins; D012402:Rotenone; C005503:naphthazarin; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine