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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Age Factors
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Animals
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Animals, Newborn
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Brain / cytology
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Cells, Cultured
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Chromatin Immunoprecipitation / methods
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Disease Models, Animal
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Down-Regulation / physiology
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Gene Expression Regulation / genetics
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission / methods
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Molecular Chaperones
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Mutation / physiology
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism*
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Neurodegenerative Diseases / pathology
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Neurodegenerative Diseases / physiopathology
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Neurons / metabolism
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Neurons / ultrastructure
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Polyglutamic Acid / genetics
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Polyglutamic Acid / metabolism*
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Rats
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TATA-Box Binding Protein / genetics
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TATA-Box Binding Protein / metabolism*
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Transcription Factor TFIIB / metabolism*
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Transfection
Substances
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Heat-Shock Proteins
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Hsbp1 protein, mouse
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Molecular Chaperones
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Neoplasm Proteins
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TATA-Box Binding Protein
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Transcription Factor TFIIB
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Polyglutamic Acid