Friedman Meyer J, Shah Anjali G, Fang Zhi-Hui, Ward Elizabeth G, Warren Stephen T, Li Shihua, Li Xiao-Jiang
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
Nat Neurosci. 2007 Dec;10(12):1519-28. doi: 10.1038/nn2011. Epub 2007 Nov 11.
Expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). It remains unclear how the polyQ tract regulates normal protein function and induces selective neuropathology in SCA17. We generated transgenic mice expressing polyQ-expanded TBP. These mice showed weight loss, progressive neurological symptoms and neurodegeneration before early death. Expanded polyQ tracts reduced TBP dimerization but enhanced the interaction of TBP with the general transcription factor IIB (TFIIB). In SCA17 transgenic mice, the small heat shock protein HSPB1, a potent neuroprotective factor, was downregulated, and TFIIB occupancy of the Hspb1 promoter was decreased. Overexpression of HSPB1 or TFIIB alleviated mutant TBP-induced neuritic defects. These findings implicate the polyQ domain of TBP in transcriptional regulation and provide insight into the molecular pathogenesis of SCA17.
人类TATA盒结合蛋白（TBP）中聚谷氨酰胺（polyQ）序列的扩展会导致神经退行性疾病脊髓小脑共济失调17型（SCA17）。目前尚不清楚polyQ序列如何调节正常蛋白质功能并在SCA17中引发选择性神经病理学改变。我们构建了表达polyQ扩展型TBP的转基因小鼠。这些小鼠在早期死亡前出现体重减轻、进行性神经症状和神经退行性变。扩展的polyQ序列减少了TBP二聚化，但增强了TBP与通用转录因子IIB（TFIIB）的相互作用。在SCA17转基因小鼠中，强效神经保护因子小分子热休克蛋白HSPB1被下调，并且TFIIB对Hspb1启动子的占据减少。HSPB1或TFIIB的过表达减轻了突变型TBP诱导的神经突缺陷。这些发现表明TBP的polyQ结构域参与转录调控，并为SCA17的分子发病机制提供了见解。
