Adeno-associated virus serotype 9 (AAV9) vectors have great potential to transfer a foreign gene into various organs including the CNS. We have succeeded to transduce most neurons in mouse cerebellum by a single injection of AAV9 vectors into the cerebellar cortex. Then, we thought that the AAV9 vector-mediated gene delivery to the cerebellum might be used for generation of animal models of cerebellar diseases. To verify the feasibility of this method, we produce a mouse model of spinocerebellar ataxia type 3 (SCA3), a progressive neurodegenerative disease.
Using AAV9 vectors, we expressed GFP and the full length ataxin-3 having an abnormally expanded polyglutamine (polyQ) tract, a mutant protein responsible for SCA3. AAV9 vectors expressing GFP and the ataxin-3 having a normal length of polyQ tract (15 glutamines) were used as a control. Those AAV9 vectors expressed the transgenes under the control of a neuron-specific synapsin-I promoter. AAV9 vectors harboring mutant ataxin-3 or normal ataxin-3 was injected into the cerebellar cortex and the behavioral phenotype was examined every week by a rotarod. Subsequently, the pathological changes in the cerebellum were immunohistochemically examined. We found that mice that received AAV9 vectors expressing mutant ataxin-3, but not normal ataxin-3, showed poor rotarod performance and immunohistochemical features characteristic to the SCA3. These results suggest that our approach can be used for the generation of mouse models of cerebellar diseases.