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01-05-2013 | Original Article

α-Synuclein Protects Neurons from Apoptosis Downstream of Free-Radical Production Through Modulation of the MAPK Signalling Pathway

Authors: Ruth E. J. Musgrove, Anna E. King, Tracey C. Dickson

Published in: Neurotoxicity Research | Issue 4/2013

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.

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Title: α-Synuclein Protects Neurons from Apoptosis Downstream of Free-Radical Production Through Modulation of the MAPK Signalling Pathway
Authors: Ruth E. J. Musgrove
Anna E. King
Tracey C. Dickson
Publication date: 01-05-2013
Publisher: Springer-Verlag
Published in: Neurotoxicity Research / Issue 4/2013
Print ISSN: 1029-8428
Electronic ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-012-9352-5

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α-Synuclein Protects Neurons from Apoptosis Downstream of Free-Radical Production Through Modulation of the MAPK Signalling Pathway

Abstract

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Abstract

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