title: α-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway.
abstract: α-Synuclein is a pre-synaptic chaperone and its accumulation contributes to differential cell loss in Parkinson's disease. Cytoplasmic expression of α-synuclein can directly modulate apoptotic pathways and contribute to cell survival, whereas induced over-expression of the protein causes oxidative stress through mitochondrial and cytosolic free-radical production. This study aimed to clarify the contribution of endogenous α-synuclein to oxidative stress and its association with cell death. Primary cortical neurons were derived from α-synuclein knock-out (Snca-/-) and wild-type (C57BL/6; WT) mice and treated with in vitro models of oxidative-stress, complex I inhibition and excitotoxicity. Mitochondrial free radical production was determined in isolated mitochondria derived from each mouse strain. Snca-/- derived cortical cultures were more susceptible (P < 0.05) to oxidative-stress, but not excitotoxicity. This result was determined by significant increases in cell death (Propidium-Iodide staining) after 6 h treatment in Snca-/- (45 % ± 2.7 SEM), relative to WT (33 % ± 3.9 SEM) cultures. α-Synuclein also confers significant (P < 0.05) resistance to low-dose (5 nM) rotenone toxicity, with a twofold reduction in cell death in WT, compared with Snca-/- cortical neurons. The expression of α-synuclein had no effect on cortical glutathione levels, or the production of reactive oxygen intermediates in isolated mitochondria. These data indicate that endogenous levels of α-synuclein confer resistance to oxidative stress downstream of free radical production and scavenging. The current data suggest that α-synuclein prevents cytochrome c release and apoptosis through inhibition of the MAPK signalling pathway.
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Private Bag 23, Hobart, TAS, 7000, Australia.
authors.forename: Ruth E J
authors.initials: RE
authors.lastname: Musgrove
authors.forename: Anna E
authors.initials: AE
authors.lastname: King
authors.forename: Tracey C
authors.initials: TC
authors.lastname: Dickson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000378:metabolism; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
chemical_list: D016166:Free Radical Scavengers; D005609:Free Radicals; D051844:alpha-Synuclein