脊髄小脳失調症34型モデルマウスの確立

抄録

Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant neurodegenerative disease characterized by slowly progressive ataxia. It is caused by missense mutations of elongation of very long-chain fatty acids-4 (ELOVL4), which is mainly expressed in neurons in the cerebellum. In this study, we attempted to establish SCA34 model mice via the gene transfer of mutant ELOVL4 to cerebellar neurons and to reveal the pathogenic mechanisms of SCA34. We used adeno-associated viral (AAV) vectors to express wild-type or missense mutant (W246G) FLAG-ELOVL4 in a neuron-specific manner. These AAV vectors were injected into the cerebella of 4-week-old male ICR mice. Motor function was evaluated by beam-walking tests. Mice expressing mutant FLAG-ELOVL4 showed progressive motor impairment from the 2nd week after the AAV vector injection. Immunohistochemical analyses of cerebellar sections revealed that the expression of mutant FLAG-ELOVL4 triggered a slight loss of Purkinje cells and microglial activation at an early phase. The severe degeneration of Purkinje cells, shrinkage of the molecular layer, and activation of both microglia and astrocytes were observed in cerebellar slices of mice expressing mutant FLAG-ELOVL4 at the late phase. Taken together, we succeeded in establishing a mouse model of SCA34.