Knockdown of Acid-Sensing Ion Channel 1a (ASIC1a) Suppresses Disease Phenotype in SCA1 Mouse Model

摘要: The mutated ataxin-1 protein in spinocerebellar ataxia 1 (SCA1) targets Purkinje cells (PCs) of the cerebellum and causes progressive due to loss PCs neurons brainstem. exact mechanism this cellular is still not clear. Currently, there are no treatments for SCA1; however, understanding mechanisms that regulate SCA1 pathology essential devising new therapies patients. We previously established a connection between intracellular calcium-buffering calcium-signalling proteins with initiation neurodegeneration transgenic (Tg) mice. Recently, acid-sensing ion channel 1a (ASIC1a) have been implicated calcium-mediated toxicity many brain disorders. Here, we report generating Tg mice ASIC1a knockout (KO) background demonstrate deletion gene expression suppression disease phenotype. Loss SCA1/ASIC1a KO resulted improvement motor deficit decreased PC degeneration. Interestingly, ASIC1 variant, ASIC1b, was upregulated both animals as compared wild-type (WT) Further, these exhibited translocation calcium-binding calbindin-D28k from nucleus cytosol young animals, which otherwise cytosolic nuclear localization. Furthermore, addition higher parvalbumin, older showed decrease morphologic abnormalities age-matched animals. Our data suggest may be mediator pathogenesis targeting could novel approach treat SCA1.