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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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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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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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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DOI: https://doi.org/10.1038/nn2011
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