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Title: | Ataxin-1 Nuclear Bodies are Subnuclear Sites of Ataxin-1 Function |
Other Titles: | Ataxin-1 Nuclear Bodies |
Authors: | Irwin, Stuart |
Advisor: | Truant, Ray |
Department: | Biochemistry |
Keywords: | Ataxin-1;nuclear |
Publication Date: | Jan-2004 |
Abstract: | Ataxin-1 is the protein affected in Spinocerebellar Ataxia Type 1 (SCA1) polyglutamine neurodegenerative disease. The biological function of ataxin-1 is unknown. By using live cell fluorescence microscopy and cultured human HeLa cells, we have shown that ataxin-1 nuclear inclusions (ataxin-1 NIs) are unique subnuclear sites of ataxin-1 function that do not resemble typical ataxin-1 polyglutamine nuclear aggregates or neuronal intranuclear inclusions (NIIs). Ataxin-1 NIs form independent of polyglutamine expansion in ataxin-1, and we found that ataxin-1 NIs are capable of recruiting the mRNA export factor TAP /NXF1. We propose that ataxin-1 NIs may be more accurately termed ataxin-1 nuclear bodies (ataxin-1 NBs) and suggest that ataxin-1 NBs play a role in mRNA processing and transport. We discovered that the serine to alanine mutation at position 776 of ataxin-1 (S776), known to inhibit spinocerebellar ataxia type 1 (SCA1) pathogenesis, plays a critical role in the frequency and size of ataxin-1 NBs. We found that polyglutamine expansion was not essential for ataxin-1 NB formation, and that serine 776 may be important in turnover regulation of polyglutamine expanded ataxin-1. In addition, we found that serine 776 does not significantly affect nuclear localization of ataxin-1, and that the ataxin-1 associated protein, 14-3-3 zeta, does not have a role in the nucleo-cytoplasmic transport of ataxin-1. These findings reveal that the serine 776-mediated 14-3-3 zeta co-localization with ataxin-1 is likely not important to SCA1 pathogenesis, but that the role of serine phosphorylation of ataxin-1 does have an effect on the formation of ataxin-1 NBs, thereby implicating ataxin-1 NB formation as important for understanding SCA1 disease. |
URI: | http://hdl.handle.net/11375/22693 |
Appears in Collections: | Digitized Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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irwin_stuart_2004Jan_masters.pdf.pdf | 8.13 MB | Adobe PDF | View/Open |
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