Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson's disease.
Parkin is known to mitigate alpha-synuclein-induced neuronal cell death in vitro, which suggests that the parkin gene therapy is a candidate for therapeutic strategies for Parkinson's disease (PD). In the present study, the parkin gene therapy was investigated for its ameliorative effects on alpha-synucleinopathy in substantia nigra (SN) of rats. A recombinant adeno-associated viral (rAAV) vector system has frequently been used for the gene transfer to rat SN, and we have previously demonstrated that this technique induced the alpha-synucleinopathy, which closely resembles pathogenetic changes in PD. Therefore, in the present study, the effect of parkin was examined by co-infection of rAAV-parkin with rAAV-alpha-synuclein into dopaminergic neurons in SN. At 13 weeks post-rAAV infection, alpha-synuclein overexpression induced dopaminergic neuron loss, while co-expression of parkin mitigated the alpha-synuclein toxicity. Moreover, alpha-synuclein-induced dopaminergic neuron loss consequently resulted in motor dysfunction, which was also mitigated by parkin. Taken together, our results indicate that the parkin gene therapy is effective against alpha-synucleinopathy, suggesting its potential suitability for patients with PD.
Yamada
Masanori
M
Research Institute for Diseases of Old Age, Juntendo University, Tokyo 113-8421, Japan.
Mizuno
Yoshikuni
Y
Mochizuki
Hideki
H
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018390:Gene Targeting; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000633:toxicity; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine