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AAV9 vector-mediated production of animal models of spinocerebellar ataxia type 3

  • P3-306
  • 今野 歩 / Ayumu Konno:1 平井 宏和 / Hirokazu Hirai:1 
  • 1:群馬大院医神経生理 / Dept NeuroPhysiol, Gunma Univ, Gunma, Japan  

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.

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