There are nine inherited neurodegenerative disorders caused by the expansion of a polyglutamine (polyQ) domain in proteins associated with various diseases, including Huntington's disease (HD) and several spinocerebellar ataxia (SCA) disorders. Although all polyQ disease proteins are widely expressed in the brain and body, they selectively kill neurons in distinct brain regions depending on the polyQ disease involved. Understanding the mechanism by which expanded polyQ-containing proteins mediate selective neurodegeneration is critical to the development of effective therapeutic strategies for treating these polyQ diseases. It is now clear that protein context modulates the toxicity of polyQ expansion and determines the selective neurodegeneration seen in polyQ diseases;however, the exact mechanism for this selective neurodegeneration remains unknown. It is apparent that before we can uncover this mechanism, we must first understand the function of the polyQ protein. In this application, we will focus on SCA17 to explore the issue of selective neurodegeneration in polyQ diseases. Spinocerebellar ataxia type 17 (SCA17) is caused by polyQ expansion in TBP, a TATA-box binding protein that is essential for gene transcription. Expansion of the polyQ domain in this important transcription factor also induces selective neurodegeneration reminiscent of HD and other polyQ diseases. As the function and structure of TBP are well characterized, SCA17 makes an excellent model for studying how polyQ expansion alters normal protein function and causes neurodegeneration. Our earlier studies have demonstrated that the expanded polyQ domain can alter the binding of TBP to DNA and transcriptional factors. In this application, we will focus on how mutant TBP with an expanded polyQ causes selective neurodegeneration in the brain. We hypothesize that the accumulation of toxic forms of mutant TBP may be different in affected neurons versus other types of cells and that this difference contributes to neuronal vulnerability. To test this hypothesis, we will use conditional SCA17 knock-in mice that express mutant TBP in selected types of cells at the endogenous level. Specifically, in Aim 1 we will examine the neurological phenotypes of conditional SCA17 knock-in mice that selectively express mutant TBP in different types of cells.
In Aim 2 we will investigate whether different forms of mutant TBP accumulate differently in various types of cells.
In Aim 3 we will study the effects of different forms of mutant TBP on nuclear transcription factors and related neuronal function. These studies will give us insight into the pathogenesis of SCA17 and the selective neurodegeneration seen in polyQ diseases.

Public Health Relevance

Nine inherited neurodegenerative disorders are caused by the expansion of a polyglutamine (polyQ) domain in various disease proteins. Although all polyQ disease proteins are widely expressed in the brain and body, they selectively kill neurons in distinct brain regions in each polyQ disease. Understanding the mechanism by which expanded polyQ-containing proteins mediate selective neurodegeneration would greatly help treat these polyQ diseases. In this application, we will focus on spinocerebellar ataxia-17 (SCA17) to address the issue of selective neurodegeneration in polyQ diseases. SCA17 is caused by polyQ expansion in TBP, a TATA-box binding protein that is ubiquitously expressed and essential for gene transcription. Expansion of the polyQ domain in this important transcription factor with well-characterized function also induces selective neurodegeneration. We will investigate conditional knock-in SCA17 mice that express mutant TBP in selective types of cells and the role of mutant TBP in neurodegeneration. These studies aim to provide insight into the selective neurodegeneration in polyQ diseases and help develop effective therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045016-08
Application #
8044755
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Sutherland, Margaret L
Project Start
2002-12-01
Project End
2014-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
8
Fiscal Year
2011
Total Cost
$332,281
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Chen, Yongchang; Zheng, Yinghui; Kang, Yu et al. (2015) Functional disruption of the dystrophin gene in rhesus monkey using CRISPR/Cas9. Hum Mol Genet 24:3764-74

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