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α-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway

Citation

Musgrove, REJ and King, AE and Dickson, TC, α-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway, Neurotoxicity Research, 23, (4) pp. 358-369. ISSN 1476-3524 (2013) [Refereed Article]

Copyright Statement

Copyright 2012 Springer Science+Business Media, LLC 2012

DOI: doi:10.1007/s12640-012-9352-5

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.

Item Details

Item Type:Refereed Article
Keywords:alpha-synuclein, oxidative stress, apoptosis, MAPK, mitochondria, Parkinson's disease
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurology and Neuromuscular Diseases
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Musgrove, REJ (Ms Ruth Musgrove)
Author:King, AE (Associate Professor Anna King)
Author:Dickson, TC (Associate Professor Tracey Dickson)
ID Code:81042
Year Published:2013 (online first 2012)
Funding Support:National Health and Medical Research Council (457621)
Web of Science® Times Cited:12
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-11-21
Last Modified:2017-11-06
Downloads:0

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