Abstract
By means of gene delivery with recombinant vectors based on adeno- associated virus (AAV ; serotypes 1 and 2), we developed a simian model of Parkinson disease through overexpression of α-synuclein that induces degeneration/loss of nigral dopamine neurons. Furthermore, we succeeded in protecting against the onset of Parkinson disease by gene delivery of parkin that is considered a functional molecule to reduce α-synuclein accumulation and suppress dopamine neuron death. In parkinsonian monkeys in which intranigral injections of an AAV vector expressing α-synuclein were made, another AAV vector expressing parkin was injected into the substantia nigra. More recently, we have developed a novel parkinsonian model that is subject to α-synuclein overexpression selective to the nigrostriatal dopamine pathway by applying gene manipulation with Cre- loxP site-specific recombination. First, a lentiviral vector pseudotyped with modified glycoprotein of rabies virus that expresses Cre recombinase was injected into the striatum. Then, intranigral injections of an AAV vector that has α-synuclein gene followed by the stop cassette flanked by the loxP sequence were made into the nigra. Then, we observed selective GFP expression in nigral dopamine neurons only on the side ipsilateral to the HIV- 1 and AAV vector injections. These primate models of Parkinson disease will be very useful for analyzing the pathophysiology of the disease and establishing strategies of gene therapy for the disease.
