Characterization of Pathogenesis of SCA17 Transgenic Mice

TATA binding protein (TBP) is a general transcription factor that plays an important role in initiation of transcription. TBP gene is located in chromosome 6q27 and contains a CAG/CAA trinucleotide repeat region in its 5’ end, which encodes a polyglutamine (polyQ) tract. Spinocerebellar ataxias type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by TBP gene with an expanded polyQ tract correlated to the disease onset and progression. To investigate the TBP trinucleotide expansion effect on neurodegeneration, we have generated transgenic mice expressing the human TBP gene with expanded CAA/CAG tracts under the control of Purkinje cell-specific promoter, Pcp2/L7 promoter. Our previous studies have shown that these hTBP109Q transgenic mice had ataxia and severe Purkinje cell loss in the cerebellum. In the present study, we found Bergmann glia surrounding the Purkinje cells were also increased as astrocytes that was identified in our previous study and suggesting a neurodegeneration occurred in the mouse cerebella. According to the result of cDNA microarray analysis, we found several calcium regulatory protein expression were differentiated expressed in the transgenic mouse cerebella. We further conducted western analysis and confirmed that the expressions of calbindin, inositol 1, 4, 5-triphosphate receptor 1 (IP3R1) and Cacnα1G were downregulated in the SCA17 mouse cerebellum. We suggest that hTBP109Q mutant protein in the mouse brain might result in the impairment of calcium homeostasis.