Knockdown of acid-sensing ion channel 1a (ASIC1a) suppresses disease phenotype in SCA1 mouse model.

Abstract

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

• Authors: Parminder J S Vig, Scoty M Hearst, Qingmei Shao, Maripar E Lopez
• Journal: Cerebellum (London, England) (Cerebellum) Vol. 13 Issue 4 Pg. 479-90 (Aug 2014) ISSN: 1473-4230 [Electronic] United States
• PMID: 24788087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ASIC1 protein, mouse
• Acid Sensing Ion Channels
• Calbindin 1
• Parvalbumins

Topics

• Acid Sensing Ion Channels (deficiency, genetics)
• Animals
• Calbindin 1 (genetics, metabolism)
• Cerebellum (pathology)
• Disease Models, Animal
• Gene Expression Regulation (genetics)
• Mice
• Mice, Transgenic
• Motor Activity (physiology)
• Movement Disorders (etiology, genetics)
• Parvalbumins (genetics, metabolism)
• Phenotype
• Purkinje Cells (metabolism, pathology)
• Rotarod Performance Test
• Spinocerebellar Ataxias (complications, genetics, pathology)
• Time Factors