alpha -Synuclein Overexpression Protects against Paraquat-Induced Neurodegeneration

Alpha-synuclein is likely to play a role in neurodegenerative processes, including the degeneration of nigrostriatal dopaminergic neurons that underlies Parkinson's disease. However, the toxicological properties of alpha-synuclein remain relatively unknown. Here, the relationship between alpha-...

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Bibliographic Details
Published in:The Journal of neuroscience 2003-04, Vol.23 (8), p.3095-3099
Main Authors: Manning-Bog, Amy B, McCormack, Alison L, Purisai, Maya G, Bolin, Laurel M, Di Monte, Donato A
Format: Article
Language:English
Subjects:
alpha-Synuclein
Animals
Brief Communication
Cell Count
Cell Survival - drug effects
HSP70 Heat-Shock Proteins - metabolism
Humans
Macromolecular Substances
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - pharmacology
Neurodegenerative Diseases - chemically induced
Neurodegenerative Diseases - pathology
Neurodegenerative Diseases - prevention & control
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Paraquat
Parkinsonian Disorders - genetics
Promoter Regions, Genetic
Silver Staining
Substantia Nigra - drug effects
Substantia Nigra - metabolism
Substantia Nigra - pathology
Synucleins
Tyrosine 3-Monooxygenase - biosynthesis
Tyrosine 3-Monooxygenase - genetics
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Summary:Alpha-synuclein is likely to play a role in neurodegenerative processes, including the degeneration of nigrostriatal dopaminergic neurons that underlies Parkinson's disease. However, the toxicological properties of alpha-synuclein remain relatively unknown. Here, the relationship between alpha-synuclein expression and neuronal injury was studied in mice exposed to the herbicide paraquat. Paraquat neurotoxicity was compared in control animals versus mice with transgenic expression of human alpha-synuclein driven by the tyrosine hydroxylase (TH) promoter. In control mice, paraquat caused both the formation of alpha-synuclein-containing intraneuronal deposits and the degeneration of nigrostriatal neurons, as demonstrated by silver staining and a reduction of the counts of TH-positive and Nissl-stained cells. Mice overexpressing alpha-synuclein, either the human wild-type or the Ala53Thr mutant form of the protein, displayed paraquat-induced protein aggregates but were completely protected against neurodegeneration. These resistant animals were also characterized by increased levels of HSP70, a chaperone protein that has been shown to counteract paraquat toxicity in other experimental models and could therefore contribute to neuroprotection in alpha-synuclein transgenic mice. The results indicate a dissociation between toxicant-induced alpha-synuclein deposition and neurodegeneration. They support a role of alpha-synuclein against toxic insults and suggest that its involvement in human neurodegenerative processes may arise not only from a gain of toxic function, as previously proposed, but also from a loss of defensive properties.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.23-08-03095.2003