Cell Reports
Volume 13, Issue 1, 6 October 2015, Pages 196-208
Journal home page for Cell Reports

Article
Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice

https://doi.org/10.1016/j.celrep.2015.08.060Get rights and content
Under a Creative Commons license
open access

Highlights

  • A large polyQ repeat in TBP causes primary muscle degeneration

  • The severity of muscle degeneration is polyQ-number dependent

  • Different polyQ numbers differentially affect TBP’s interaction with NF-YA and MyoD

  • Impaired transcriptional activity of MyoD underlies muscle degeneration in SCA17

Summary

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.

Cited by (0)

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

4

Co-first author