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Type: Thesis
Title: ‘Non-self’ mutation in a Drosophila model of expanded CAG repeat neurodegenerative disease
Author: Scott, Andrew William
Issue Date: 2019
School/Discipline: School of Biological Sciences
Abstract: Copy number expansion of tandem repeat sequences beyond a pathogenic threshold causes more than twenty neurodegenerative diseases known as dominantly-inherited expanded repeat diseases. The repeat expansions arise in a diverse range of genomic locations within unrelated genes. Repeat-containing RNA represents a product derived from all affected loci and has thus been hypothesised to constitute a plausible common pathogenic agent. Evidence for bi-directional transcription of repeat RNA, the products of which are predicted to form complementary double-stranded RNA (dsRNA), has been observed across all tested expanded repeat disease loci. Previous work has demonstrated that expression of repeat CAG.CUG dsRNA causes eye-specific and neuronal pathology in a Drosophila model of expanded repeat disease. Additional work revealed that repeat dsRNA not only induces an inflammatory response, but is dependent upon several components of the innate inflammatory system for the resultant pathology. This thesis uses this established Drosophila model of expanded repeat disease to further define the innate inflammatory mechanisms underlying expanded repeat dsRNA pathology at both the cellular and molecular level. Co-expression of repeat dsRNA and a viral protein that inhibits antiviral pathway activation led to complete suppression of the resultant eye pathology. This suggests that the repeat dsRNA is recognized by the host antiviral machinery as a ‘non-self’ threat, thus inducing a damaging inflammatory response that causes the subsequent eye pathology. The reduction of key mitophagy components led to an enhancement of the repeat dsRNA eye pathology, indicating that mitochondrial quality control is protective in response to the expression of repeat dsRNA. The tissue-specific expression of the repeat dsRNA in glial cells responsible for the development and maintenance of the Drosophila blood-brain barrier led to neurodegeneration and mortality, highlighting these glial cell subtypes as key non-cell autonomous determinants of dsRNA-mediated neuronal dysfunction. The characterisation of pathways and cell types that underlie expanded repeat pathogenesis are critical for defining the molecular and cellular determinants of this novel ‘non-self’ RNA pathogenesis. The validation of this model as replicating the corresponding human diseases will enable the development of effective therapeutic interventions for this group of diseases.
Advisor: Richards, Robert
O'Keefe, Louise
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2019
Keywords: Neurodegenerative disease
expanded repeat
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