Chronic suppression of inositol 1,4,5-triphosphate receptor-mediated calcium signaling in Cerebellar Purkinje cells alleviates pathological phenotype in Spinocerebellar ataxia 2 mice

Spinocerebellar ataxia 2 (SCA2) is a neurodegenerative disorder characterized by progressive ataxia. SCA2 results from a poly(Q) (polyglutamine) expansion in the cytosolic protein ataxin-2 (Atx2). Cerebellar Purkinje cells (PCs) are primarily affected in SCA2, but the cause of PC dysfunction and death in SCA2 is poorly understood. In previous studies, we reported that mutant but not wild-type Atx2 specifically binds the inositol 1,4,5-trisphosphate receptor (InsP₃R) and increases its sensitivity to activation by InsP₃.We further proposed that the resulting supranormal calcium (Ca²⁺) release from the PC endoplasmic reticulum plays a key role in the development of SCA2 pathology. To test this hypothesis, we achieved a chronic suppression of InsP3R-mediated Ca²⁺ signaling by adenoassociated virusmediated expression of the inositol 1,4,5-phosphatase (Inpp5a) enzyme (5PP) in PCs of a SCA2 transgenic mouse model. We determined that recombinant 5PP overexpression alleviated age-dependent dysfunction in the firing pattern of SCA2 PCs.Wefurther discovered that chronic 5PP overexpression also rescued age-dependent motor incoordination and PC death in SCA2 mice. Our findings further support the important role of supranormal Ca²⁺ signaling in SCA2 pathogenesis and suggest that partial inhibition of InsP3-mediated Ca²⁺ signaling could provide therapeutic benefit for the patients afflicted with SCA2 and possibly other SCAs.