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

Nature Neuroscience volume 10, pages 1519–1528 (2007)Cite this article

Abstract

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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Figure 1: Expression of mutant TBPs in cultured cells and transgenic mice.
Figure 2: Neuronal distribution of mutant TBP in transgenic SCA17 mice.
Figure 3: Neurological phenotype of transgenic SCA17 mice.
Figure 4: Neurodegeneration in transgenic SCA17 mice.
Figure 5: Influence of polyQ tract length on TBP dimerization.
Figure 6: Effect of polyQ-expanded TBP on gene transcription.
Figure 7: Aberrant interaction of mutant TBP with TFIIB.
Figure 8: Overexpression of HSPB1 suppressed mutant TBP-induced neuritic defects.

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Acknowledgements

We thank C.-E. Wang and H.H. Nguyen for technical assistance, K. Smith for instruction on chromatin immunoprecipitation, A.R. La Spada (University of Washington Medical Center) and D.R. Borchelt (University of Florida College of Medicine) for the prion promoter plasmid, and A. Michalik (University of Antwerp) for the CAA/CAG repeat oligonucleotide. This work was supported by US National Institutes of Health grants (NS045016, NS41669, AG19206, NS36232).

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Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, 30322, Georgia, USA

    Meyer J Friedman, Anjali G Shah, Zhi-Hui Fang, Elizabeth G Ward, Stephen T Warren, Shihua Li & Xiao-Jiang Li

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Contributions

M.J.F. characterized transgenic mice, examined transgene expression as well as biochemical, transcriptional, and pathological changes in animal and cell models, and wrote the manuscript; A.G.S. characterized stably transfected PC12 cells; Z.-H.F. performed immunohistochemical and electron microscopic studies; E.G.W. and S.T.W. conducted and analyzed microarray experiments; S.H.L. and X.-J.L. established transgenic mice and stably transfected cell lines, supervised the project, analyzed data and wrote the manuscript.

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Correspondence to Shihua Li or Xiao-Jiang Li.

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Friedman, M., Shah, A., Fang, ZH. et al. Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration. Nat Neurosci 10, 1519–1528 (2007). https://doi.org/10.1038/nn2011

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