Deactivation of TBP contributes to SCA17 pathogenesis.

Abstract

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by the expansion of polyglutamine (polyQ) within the TATA box-binding protein (TBP). Previous studies have shown that polyQ-expanded TBP forms neurotoxic aggregates and alters downstream genes. However, how expanded polyQ tracts affect the function of TBP and the link between dysfunctional TBP and SCA17 is not clearly understood. In this study, we generated novel Drosophila models for SCA17 that recapitulate pathological features such as aggregate formation, mobility defects and premature death. In addition to forming neurotoxic aggregates, we determined that polyQ-expanded TBP reduces its own intrinsic DNA-binding and transcription abilities. Dysfunctional TBP also disrupts normal TBP function. Furthermore, heterozygous dTbp amorph mutant flies exhibited SCA17-like phenotypes and flies expressing polyQ-expanded TBP exhibited enhanced retinal degeneration, suggesting that loss of TBP function may contribute to SCA17 pathogenesis. We further determined that the downregulation of TBP activity enhances retinal degeneration in SCA3 and Huntington's disease fly models, indicating that the deactivation of TBP is likely to play a common role in polyQ-induced neurodegeneration.

• Authors: Tun-Chieh Hsu, Cheng-Kuang Wang, Chun-Yen Yang, Li-Ching Lee, Hsiu-Mei Hsieh-Li, Long-Sun Ro, Chiung-Mei Chen, Guey-Jen Lee-Chen, Ming-Tsan Su
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 25 Pg. 6878-93 (Dec 20 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 25104854 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Peptides
• Protein Aggregates
• TATA-Box Binding Protein
• polyglutamine

Topics

• Animals
• Disease Models, Animal
• Drosophila melanogaster (genetics, metabolism)
• Gene Expression Regulation
• Heterozygote
• Humans
• Huntington Disease (genetics, metabolism, pathology)
• Longevity (genetics)
• Machado-Joseph Disease (genetics, metabolism, pathology)
• Peptides (chemistry)
• Phenotype
• Protein Aggregates
• Protein Binding
• Retinal Degeneration (genetics, metabolism, pathology)
• Signal Transduction
• Spinocerebellar Ataxias (genetics, metabolism, pathology)
• TATA-Box Binding Protein (chemistry, genetics, metabolism)