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 #
5R01NS045016-10
Application #
8436245
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
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$320,652
Indirect Cost
$113,780
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Xiang, Jianxing; Yang, Hao; Zhao, Ting et al. (2014) Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting. J Clin Invest 124:85-98
Yan, Sen; Wang, Chuan-En; Wei, Wenjie et al. (2014) TDP-43 causes differential pathology in neuronal versus glial cells in the mouse brain. Hum Mol Genet 23:2678-93
Weng, Ling; Lin, Yung-Feng; Li, Alina L et al. (2013) Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation. J Neurosci 33:8172-84
Cape, Austin; Chen, Xingxing; Wang, Chuan-En et al. (2012) Loss of huntingtin-associated protein 1 impairs insulin secretion from pancreatic *-cells. Cell Mol Life Sci 69:1305-17
Huang, Shanshan; Ling, Joseph J; Yang, Su et al. (2011) Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor. Brain 134:1943-58
Li, Xiao-Jiang; Li, Shihua (2011) Proteasomal dysfunction in aging and Huntington disease. Neurobiol Dis 43:4-8
Havel, Lauren S; Wang, Chuan-En; Wade, Brandy et al. (2011) Preferential accumulation of N-terminal mutant huntingtin in the nuclei of striatal neurons is regulated by phosphorylation. Hum Mol Genet 20:1424-37
Li, Xiang; Wang, Chuan-En; Huang, Shanshan et al. (2010) Inhibiting the ubiquitin-proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments. Hum Mol Genet 19:2445-55
Bradford, Jennifer; Shin, Ji-Yeon; Roberts, Meredith et al. (2010) Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. J Biol Chem 285:10653-61
Wang, Chuan-En; Li, Shihua; Li, Xiao-Jiang (2010) Lack of interleukin-1 type 1 receptor enhances the accumulation of mutant huntingtin in the striatum and exacerbates the neurological phenotypes of Huntington's disease mice. Mol Brain 3:33

Showing the most recent 10 out of 26 publications