Abstract
In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than those of adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knockin mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA-box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP's interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Binding Sites
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CCAAT-Binding Factor / genetics
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CCAAT-Binding Factor / metabolism
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Cerebellum / metabolism
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Cerebellum / pathology
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Crosses, Genetic
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Disease Models, Animal
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Female
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Gene Expression Regulation
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Gene Knock-In Techniques
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Hippocampus / metabolism
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Hippocampus / pathology
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Humans
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Male
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Mice
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Mice, Transgenic
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Muscle Cells / metabolism*
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Muscle Cells / pathology
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Muscle, Skeletal / metabolism*
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Muscle, Skeletal / pathology
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MyoD Protein / genetics*
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MyoD Protein / metabolism
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Neurons / metabolism
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Neurons / pathology
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Peptides / metabolism*
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Promoter Regions, Genetic
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Protein Binding
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Signal Transduction
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Spinocerebellar Ataxias / genetics*
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Spinocerebellar Ataxias / metabolism
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Spinocerebellar Ataxias / pathology
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TATA-Box Binding Protein / genetics*
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TATA-Box Binding Protein / metabolism
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Trinucleotide Repeat Expansion
Substances
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CCAAT-Binding Factor
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MyoD Protein
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MyoD1 myogenic differentiation protein
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Nfya protein, mouse
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Peptides
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TATA-Box Binding Protein
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polyglutamine
Supplementary concepts
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Spinocerebellar Ataxia 17