949. AAV-Parkin Gene Therapy for Alpha-Synucleinopathy as Parkinson's Diseased Model

Abstract

Top of pageAbstract Parkin gene is likely to be one of the appropriate genes for the therapeutic use for Parkinson's disease because it has been revealed that parkin mitigated the neuronal cell death induced by |[alpha]|-synuclein overexpression. To evaluate the role of parkin in the pathogenesis of PD, we tested whether overexpression of parkin could protect against the toxicity of AAV-|[alpha]|-synuclein in a rat model of PD. In the present study, the recombinant adeno-associated viral (rAAV) vector system was used for human |[alpha]|-synuclein gene transfer to rat SN and induced |[alpha]|-synucleinopathy because this model appeared to be more closely resemble the human disease. And then, the inhibitory effect of parkin was investigated by co-infection of rAAV-parkin with rAAV-|[alpha]|-synuclein into dopaminergic neurons in SN. At 13 weeks after rAAV infection, overexpressed |[alpha]|-synuclein induced dopaminergic neuron loss, however, co-expressed parkin mitigated the |[alpha]|-synuclein toxicity with neither decrease in the amount of |[alpha]|-synuclein protein nor formation of inclusions reminiscent Lewy bodies. These results indicate that the use of parkin gene is a potent therapeutic strategy for |[alpha]|-synucleinopathy such as PD, which means parkin gene therapy for PD.