Prions are infectious proteins that form transmissible, self-propagating amyloids that convert protein from its normal state into the prion state. The accumulation of amyloid is the causative agent of several neurodegenerative diseases, for instance, Huntington’s disease, which is caused by a polyglutamine expansion in the huntingtin (Htt) protein. In this study, a yeast-based Huntington’s disease model was created to investigate the mechanism of amyloid toxicity and how nuclear genes modulate this toxicity. The model amyloid used was Rnq1, a transferable epigenetic modifier which is able to form a prion known as [PIN+]. [PIN+] is known to enhance the formation of polyglutamine aggregates in yeast. In this study, a series of cellular assays were employed to determine the mechanism of Rnq1-mediated cytotoxicity and compared with polyglutamine-rich-protein-mediated cytotoxicity dependent upon the [PIN+] prion. In [PIN+] cells RNQ1 overexpression leads to a significant increase in the production of reactive oxygen species (ROS). Furthermore, overexpression of RNQ1 resulted in a nuclear migration defect in [PIN+] cells. Upf1 (Up-frameshift protein 1), a highly conserved protein that plays an important role in nonsense-mediated mRNA decay, was found to modify amyloid toxicity. In a upf1Δ deletion strain, both Rnq1 and polyglutamine-rich-protein-mediated cytotoxicity were suppressed in a [PIN+] background. To further study the novel role of Upf1 in amyloid toxicity, a combination of cell biological and genetic approaches were being employed.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:684394 |
| Date | January 2016 |
| Creators | Li, Zhiyuan |
| Contributors | Tuite, Mick |
| Publisher | University of Kent |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kar.kent.ac.uk/55116/ |
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