About this item:

252 Views | 326 Downloads

Author Notes:

Correspondence: Email: sli@emory.edu (S.H.L.), Email: xjli@genetics.ac.cn (X.J.L.)

S.H., S.Y., S.L. and X.J.L. designed research.

S.H. and S.Y. performed experiments.

S.H., S.Y., S.L. and X.J.L. analyzed the data and wrote the manuscript.

J.G. and Sen Yan assisted with generating reagents.

M.A.G. assisted with mouse breeding.

We thank Heju Zhang at the Transgenic Mouse and Gene Targeting core at Emory for generating the TBP floxed mouse line, Duc M. Duong and Nicholas T. Seyfried at ENNCF Proteomics Core at Emory University for mass spectrometry analysis, Yi Hong at Robert P. Apkarian Integrated Electron Microscopy Core for electron microscopy analysis, Lin Mei at Georgia Health Sciences University for providing C2C12 cells and the human ACT1 promoter, Grace K. Pavlath for advice, Benjamine J. Redpath and Naureen Mith for technical assistance, and Cheryl Strauss for critical reading of this manuscript.


Research Funding:

This work was supported by NIH grants (AG19206 and NS041449 to XJL, NS095279 and NS0405016 to SHL).

This research project was supported in part by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities grant, P30NS055077.


  • Animals
  • Binding Sites
  • CCAAT-Binding Factor
  • Cerebellum
  • Corpus Striatum
  • Crosses, Genetic
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Hippocampus
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle Cells
  • Muscle, Skeletal
  • MyoD Protein
  • Neurons
  • Peptides
  • Promoter Regions, Genetic
  • Protein Binding
  • Signal Transduction
  • Spinocerebellar Ataxias
  • TATA-Box Binding Protein
  • Trinucleotide Repeat Expansion

Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice


Journal Title:

Cell Reports


Volume 13, Number 1


, Pages 196-208

Type of Work:

Article | Final Publisher PDF


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 information:

© 2015 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote