Overexpression ofα-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation ofα-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson's disease.

To elucidate the role of &aplha;-synuclein in the pathogenesis of Parkinson's disease, both human &aplha;-synuclein transgenic mice and targeted overexpression of human &aplha;-synuclein in rat substantia nigra using viral vector-based methods have been studied, however, little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in brains with Parkinson's disease are recapitulated in these models. Here, we used the recombinant adeno-associated viral (rAAV) vector system for human &aplha;-synuclein gene transfer to rat substantia nigra and observed approximately 50% loss of dopaminergic neurons at 13 weeks after infection, which was comparably slower than the progression of neurodegeneration reported in other studies. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of Parkinson's disease, such as phosphorylation of &aplha;-synuclein at Ser129 and activation of caspase-9. Both findings were also evident in cortical tissues overexpressing &aplha;-synuclein via rAAV. Our results indicate that overexpression of &aplha;-synuclein via rAAV apparently recapitulates several important features of brains with Parkinson's disease and dementia with Lewy bodies, and thus &aplha;-synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of Parkinson's disease and dementia with Lewy bodies. [ABSTRACT FROM AUTHOR]