Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice

• Type of Material: Article
• Authors: Shanshan Huang, Emory University; Su Yang, Emory University; Jifeng Guo, Emory University; Sen Yan, Emory University; Marta A. Gaertig, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2015-09-17
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2015 The Authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2015.08.060
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 13
• Issue: 1
• Start Page: 196
• End Page: 208
• Grant/Funding Information: 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.
• Keywords: Protein Binding; Trinucleotide Repeat Expansion; Mice, Transgenic; Muscle Cells; Spinocerebellar Ataxias; Corpus Striatum; TATA-Box Binding Protein; Female; CCAAT-Binding Factor; Mice; Muscle, Skeletal; Crosses, Genetic; Gene Expression Regulation; Neurons; Disease Models, Animal; MyoD Protein; Signal Transduction; Hippocampus; Humans; Animals; Binding Sites; Male; Gene Knock-In Techniques; Promoter Regions, Genetic; Cerebellum; Peptides
• Research Categories: Biology, Genetics; Biology, Neuroscience

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.