Nine inherited neurodegenerative disorders are caused by an expansion of a polyglutamine tract in the associated disease proteins. Increasing evidence indicates that huntingtin containing an expanded polyglutamine tract accumulates in the nucleus and affects gene expression in Huntington disease (HD). Transcriptional dysregulation may also be the major pathological cause in SCA17 in which polyglutamine expansion is present in the TATA binding protein (TBP). HD and SCA17 show similar neurological phenotypes and neuropathology characterized by neurodegeneration in the striatum and cortex, suggesting that both diseases may share a similar pathological mechanism. Although recent studies have shown that mutant huntingtin binds to the transcriptional factors Sp1 and TAF130, the mechanism by which mutant polyglutamine proteins affect gene expression remains to be investigated. Furthermore, it is unclear how the abnormal interactions between mutant polyglutamine proteins and transcription factors contribute to the disease process. We hypothesize that soluble polyglutamine proteins interfere with gene expression by altering the interactions between transcription factors and their DNA targets before the formation of large nuclear inclusions. To test this hypothesis, we will (1) study how mutant N-terminal huntingtin abnormally binds to Sp1 to affect gene expression, (2) investigate whether polyglutamine expansion causes TBP to abnormally bind to the TATA box and its associated factors, and (3) examine whether polyglutamine expansion causes TBP and huntingtin to abnormally bind to the transcriptional factor TAF130, leading to a common transcriptional defect that may contribute to the similar neuropathology in HD and SCA17. These studies aim to provide insights into the mechanism by which polyglutamine expansion affects gene expression. They will also help identify a therapeutic target for the treatment of polyglutamine diseases ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Oliver, Eugene J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
Guo, Jifeng; Cui, Yiting; Liu, Qiong et al. (2018) Piperine ameliorates SCA17 neuropathology by reducing ER stress. Mol Neurodegener 13:4
Yan, Sen; Tu, Zhuchi; Liu, Zhaoming et al. (2018) A Huntingtin Knockin Pig Model Recapitulates Features of Selective Neurodegeneration in Huntington's Disease. Cell 173:989-1002.e13
Yang, Su; Yang, Huiming; Chang, Renbao et al. (2017) MANF regulates hypothalamic control of food intake and body weight. Nat Commun 8:579
Hong, Yan; Zhao, Ting; Li, Xiao-Jiang et al. (2017) Mutant Huntingtin Inhibits ?B-Crystallin Expression and Impairs Exosome Secretion from Astrocytes. J Neurosci 37:9550-9563
Cui, Yiting; Yang, Su; Li, Xiao-Jiang et al. (2017) Genetically modified rodent models of SCA17. J Neurosci Res 95:1540-1547
Yang, Yang; Yang, Su; Guo, Jifeng et al. (2017) Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17. J Neurosci 37:9101-9115
Zhao, Ting; Hong, Yan; Li, Shihua et al. (2016) Compartment-Dependent Degradation of Mutant Huntingtin Accounts for Its Preferential Accumulation in Neuronal Processes. J Neurosci 36:8317-28
Yang, Su; Li, Xiao-Jiang; Li, Shihua (2016) Molecular mechanisms underlying Spinocerebellar Ataxia 17 (SCA17) pathogenesis. Rare Dis 4:e1223580
Hong, Yan; Zhao, Ting; Li, Xiao-Jiang et al. (2016) Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP. J Neurosci 36:8790-801
Huang, Brenda; Wei, WenJie; Wang, Guohao et al. (2015) Mutant huntingtin downregulates myelin regulatory factor-mediated myelin gene expression and affects mature oligodendrocytes. Neuron 85:1212-26

Showing the most recent 10 out of 56 publications