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-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.
Manning-Bog
Amy B
AB
The Parkinson's Institute, Sunnyvale, California 94089-1605, USA.
McCormack
Alison L
AL
Purisai
Maya G
MG
Bolin
Laurel M
LM
Di Monte
Donato A
DA
D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010269:Paraquat; D020734:Parkinsonian Disorders / Q000235:genetics; D011401:Promoter Regions, Genetic; D016622:Silver Staining; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051843:Synucleins; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics; D051844:alpha-Synuclein
D018840:HSP70 Heat-Shock Proteins; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat