Polyglutamine (polyQ) diseases are a group of progressive neurodegenerative disorders, which are caused by the expansion of an existing glutamine-coding CAG repeat in the coding region of disease genes. The cell nucleus is a major site of polyQ toxicity, and gene transcription is compromised in polyQ-induced neurodegeneration. Understanding the nuclear translocation of mutant polyQ proteins is therefore crucial to unfold the complex pathogenic mechanisms that underlie the neuronal toxicity of polyQ disease. The polyQ domain is the only common sequence found among different mutant disease proteins. Nuclear transport signals have been identified in some, but not all, polyQ disease proteins. The detection of those mutant polyQ proteins that carry no classical nuclear transport signal, but not their normal counterparts, in the cell nucleus suggests the existence of uncharacterized nuclear transport signals in mutant polyQ proteins. Thus, the objective of the present study is to elucidate the nuclear transport pathway(s) adopted by an expanded polyQ domain and determine its correlation with polyQ toxicity. / Through a series of genetic and biochemical studies in cell culture, mouse and transgenic Drosophila models, exportin-1 was found to modulate the nucleocytoplasmic localization of mutant polyQ protein and its toxicity. Further, mutant polyQ protein was also demonstrated to be a novel transport substrate of exportin-1. By promoting the nuclear export of mutant polyQ protein, exportin-1 suppressed polyQ toxicity by reducing the interference of mutant polyQ protein on gene transcription. It was found that the protein level of exportin-1 diminished in the normal ageing process, which would result in an exaggeration of nuclear mutant polyQ toxicity. Thus, the age-dependent decline of exportin-1 level, at least in part, accounts for the progressive degeneration observed in polyQ patients. Results obtained from this project first demonstrated that expanded polyQ domain is a nuclear export signal, and further provided mechanistic explanation of how protein nuclear transport receptors modulate polyQ toxicity. / Chan, Wing Man. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0113. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 189-203). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344375 |
| Date | January 2009 |
| Contributors | Chan, Wing Man, Chinese University of Hong Kong Graduate School. Division of Molecular Biotechnology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xvi, 207 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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