Huntington’s disease (HD) is a fatal late onset neurodegenerative disorder that is caused by an expansion of a polyglutamine encoding tract in the huntingtin gene. This expansion in mutant huntingtin (mHtt) causes the protein to misfold, aggregate and leads to widespread cellular dysfunction principally through a toxic gain of function mechanism. The expression of mHtt in baker’s yeast recapitulates many of the cellular phenotypes observed in mammalian models. Here I have exploited a yeast HD model to perform genetic screens for mammalian cDNAs whose overexpression suppresses mHtt toxicity. We identified 102 protective genes, which are significantly enriched for components of the translational machinery. Further investigations revealed that translational efficiency but not fidelity is decreased in yeast expressing mHtt. Interestingly, overexpression of a subset of these genetic modifiers further decreases the efficiency of translation in yeast. I have validated a subset of the translation related suppressors in a neuronal model of HD and observed that their overexpression significantly reduces mHtt-dependent caspase activation. In yeast mHtt aggregation and toxicity are dependent on the presence of the Rnq1 prion. Previous genetic screens in our laboratory have identified a number of other putative yeast prions as modifiers of mHtt toxicity. I have further investigated their ability to alter mHtt aggregation and to substitute for the Rnq1 prion. I have observed that overexpression of the aggregation prone Ybr016w and the Sup35 prion partially restores aggregation of mHtt in a dose-dependent manner in a rnq1Δ strain. My studies have revealed new information about the role of genetic modifiers in mHtt toxicity and aggregation, and may help inform novel therapeutic strategies for HD.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:572580 |
| Date | January 2013 |
| Creators | Kantcheva, Ralitsa Boyanova |
| Contributors | Giorgini, Flaviano |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/27915 |
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