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Suppression of Calbindin-D28k Expression Exacerbates SCA1 Phenotype in a Disease Mouse Model

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a polyglutamine tract in the mutant protein ataxin-1. The cerebellar Purkinje cells (PCs) are the major targets of mutant ataxin-1. The mechanism of PC death in SCA1 is not known; however, previous work indicates that downregulation of specific proteins involved in calcium homeostasis and signaling by mutant ataxin-1 is the probable cause of PC degeneration in SCA1. In this study, we explored if targeted deprivation of PC specific calcium-binding protein calbindin-D28k (CaB) exacerbates ataxin-1 mediated toxicity in SCA1 transgenic (Tg) mice. Using behavioral tests, we found that though both SCA1/+ and SCA1/+: CaB null (−/+) double mutants exhibited progressive impaired performance on the rotating rod, a simultaneous enhancement of exploratory activity, and absence of deficits in coordination, the double mutants were more severely impaired than SCA1/+ mice. With increasing age, SCA1/+ mice showed a progressive loss in the expression and localization of CaB and other PC specific calcium-binding and signaling proteins. In double mutants, these changes were more pronounced and had an earlier onset. Gene expression profiling of young mice exhibiting no behavior or biochemical deficits revealed a differential expression of many genes common to SCA1/+ and CaB−/+ lines, and unique to SCA1/+: CaB−/+ phenotype. Our study provides further evidence for a critical role of CaB in SCA1 pathogenesis, which may help identify new therapeutic targets to treat SCA1 or other cerebellar ataxias.

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Acknowledgments

This work was supported by a grant from The National Institutes of Health (RO1 NS41546).

Conflict of Interest (COI) Statement

There is no conflict of interest. The data reported in this manuscript has not been published or submitted for publication elsewhere. All authors have agreed to the contents of this article and there are no ethical issues involved.

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Correspondence to Parminder J.S. Vig.

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Vig, P.J., Wei, J., Shao, Q. et al. Suppression of Calbindin-D28k Expression Exacerbates SCA1 Phenotype in a Disease Mouse Model. Cerebellum 11, 718–732 (2012). https://doi.org/10.1007/s12311-011-0323-9

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