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The Journal of Neuroscience, April 15, 2003, 23(8):3095
BRIEF COMMUNICATION
 -Synuclein Overexpression Protects against Paraquat-Induced
Neurodegeneration
Amy B.
Manning-Bo ,
Alison L.
McCormack,
Maya G.
Purisai,
Laurel M.
Bolin, and
Donato A.
Di
Monte
The Parkinson's Institute, Sunnyvale, California 94089
 -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 -synuclein remain relatively unknown. Here, the relationship between -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 -synuclein driven by the tyrosine hydroxylase (TH) promoter. In control mice, paraquat caused both the
formation of -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 -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 -synuclein transgenic
mice. The results indicate a dissociation between toxicant-induced -synuclein deposition and neurodegeneration. They support a role of
-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.
Key words:
Parkinson; pesticide; inclusion; substantia nigra; HSP70; chaperone
Copyright © 2003 Society for Neuroscience 0270-6474/03/2383095-05$05.00/0
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