Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Strong, Michael J.

2nd Supervisor

Rylett, Jane

Co-Supervisor

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder that causes the death of motor neurons. While alterations in the metabolism of RNA, including RNA-binding proteins have been linked to the pathogenesis of ALS, our understanding of the role of non-coding RNAs including circRNAs is less well developed. In this study, using a combination of fluorescence in situ hybridization (FISH) and immunofluorescence (IF) with markers of RNP granules, I investigated the effect of osmotic stress on the localization and expression of a selection of circRNAs whose expression is dysregulated in ALS. Alteration in the number of granules for two circRNAs was observed in HEK293T cells under osmotic stress. I also have observed that circRNAs are present in RNP granules under a stress condition. This finding is consistent with the hypothesis that circRNAs might participate in the biology of ribonucleprotein (RNP) granules under pathological conditions such as those observed in ALS.

Summary for Lay Audience

There is a recently discovered group of RNAs which is circular and more stable than their linear counterparts. Evidence shows that these circular RNAs are abundant in the brain and can have a regulatory function at the cellular level. Some studies have suggested that circular RNAs play a role in neurodegenerative diseases. Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease that leads to a loss of all motor functions and death within 3 to 5 years. It is shown that specific types of proteins that interact with RNA are aggregated in the neurons of ALS patients. There are also changes in the RNA expression in the spinal cord of ALS patients, supporting the idea of ALS as a disorder of altered RNA metabolism. In this study, I examined the effect of cellular stress on the localization of circular RNAs for which the expression is altered in ALS.

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