ecdysterone and Parkinson-Disease--Secondary

Mutations of the alpha-synuclein gene have been identified in autosomal dominant Parkinson's disease (PD). Transgenic mice overexpressing wild-type human alpha-synuclein develop motor impairments, intraneuronal inclusions and loss of dopaminergic terminals in the striatum. To study the mechanism of action through which mutant alpha-synuclein toxicity is mediated, we have generated stable, inducible cell models expressing wild-type or PD-associated mutant (G209A) alpha-synuclein in human-derived HEK293 cells. Increased expression of either wild-type or mutant alpha-synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant alpha-synuclein induced a significant increase in sensitivity to dopamine toxicity compared with the wild-type protein expression. These results provide an explanation for the preferential dopaminergic neuronal degeneration seen in both the PD G209A mutant alpha-synuclein families and suggest that similar mechanisms may underlie or contribute to cell death in sporadic PD.

Topics: alpha-Synuclein; Blotting, Western; Cell Death; Cell Line; Cell Size; Dopamine; Drug-Related Side Effects and Adverse Reactions; Ecdysterone; Gene Expression; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Male; Mutation; Nerve Tissue Proteins; Neurons; Parkinson Disease; Parkinson Disease, Secondary; Synucleins; Transfection