Polyglutamine domain modulates the TBP-TFIIB interaction: Implications for its normal function and neurodegeneration

Emory University, Atlanta, Georgia, United States
Nature Neuroscience (Impact Factor: 16.1). 01/2008; 10(12):1519-28. DOI: 10.1038/nn2011
Source: PubMed


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.

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    • "Mutant TBP accumulates in muscle nuclei and becomes misfolded with age, consistent with its late-onset effect on MyoD function in adult muscles. TBP levels are tightly regulated, since floxed SCA17 KI mice, which express one copy of the normal TBP gene, or are equivalent to heterozygous TBP knockout mice, show the same levels of normal TBP as WT TBP mice, which carry two copies of the normal TBP gene (Friedman et al., 2007, 2008; Yang et al., 2014). Similarly, in SCA17 KI mouse brain and muscle, expressing one copy of mutant TBP can downregulate the level of endogenous normal TBP (Figures 1 and S1). "
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    • "Previous studies have shed light on the role of repeat expansions in conferring onset of disease, though the exact mechanism by which the polyQ repeat of TBP affects transcription has largely confounded researchers. However, Friedman and colleagues demonstrate the mechanistic role of the polyQ repeats in the transcriptional regulation of TBP [69]. TBP dimerization has previously been shown to prevent unregulated gene expression and modulate its own degradation [70]. "
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