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Type: Thesis
Title: Investigation of pathways responsible for repeat RNA-mediated cellular perturbation in Drosophila models of dominant expanded repeat disease.
Author: Lawlor, Kynan Thomas
Issue Date: 2012
School/Discipline: School of Molecular and Biomedical Science
Abstract: The expansion of polymorphic repeat sequences within unrelated genes is responsible for pathology in a family of dominant human diseases. Based on clinical and genetic similarities, it is hypothesised that common pathways may contribute to all of these diseases, with evidence for a number of mechanisms mediated by the expanded repeat. Where the repeats are translated, a long polyglutamine protein has been shown to have pathogenic properties. However, the identification of diseases caused by untranslated repeats has led to the discovery of repeat RNA-mediated pathogenic pathways. As expanded repeat-containing transcripts are present in the case of both translated and untranslated repeats, repeat RNA is a candidate common pathogenic agent. Therefore, determining its contributions to pathology will be important in understanding these diseases. Using the model organism Drosophila melanogaster, this study identifies common CUG and CAG repeat RNA-mediated phenotypes, enabling the investigation of common pathways of cellular perturbation. Ubiquitous expression of either repeat sequence led to reduced viability and disruption to the development of the adult dorsal abdominal tergites through a specific effect on histoblast cells. This phenotype provides a biological read-out of common RNA-mediated effects, enabling examination of the pathways involved by quantifying the changes in the phenotype when specific candidate genes are genetically altered. Tergite disruption was not strongly modified by reducing activity of the well-characterised muscleblind mediated pathway. Furthermore, the presence of specific nuclear RNA foci, an indicator of repeat RNA-mediated protein sequestration, was not correlated with the phenotype. Results indicate that tergite disruption is not strongly dependent on muscleblind sequestration and may involve an alternative pathway. Ectopic expression of either repeat did not cause significant phenotypes in the eye, or neurons, except in the case of one fortuitous transgene insertion. In this case, bidirectional transcription of the repeat tract facilitated by an endogenous promoter was necessary for pathology, providing support for a novel pathway of pathology involving the formation of double-stranded RNA. Subsequent comparison of the pathways involved in hairpin-forming single stranded RNA, and bi-directional double-stranded RNA mediated phenotypes in Drosophila supports the existence of multiple distinct pathways that contribute to cellular perturbation.
Advisor: Richards, Robert Ian
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2012
Keywords: expanded repeat disease; Drosophila; repeat RNA
Provenance: Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
Appears in Collections:Research Theses

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