Unraveling the Function and Regulation of Circular RNAs in Aging and Age-Related Diseases
Loading...
Authors
Alshareef, Hussam Z.
Issue Date
2024
Type
Dissertation
Language
Keywords
Aging , Alzheimer's Disease , Circular RNA
Alternative Title
Abstract
Aging is a time-related deterioration of the physiological functions necessary for survival and fertility and is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes. Among many factors that might play a role in aging and age-related diseases, circRNAs have been linked to aging and Alzheimer's Disease (AD). circRNAs are non-coding RNAs produced via a back- splicing event and expressed in many organisms, but their function in aging and age- related diseases remains unclear. My work presented in this dissertation is focused on understanding the role of circular RNAs in aging and AD development. I used Caenorhabditis elegans as a model organism to investigate the role of circRNAs in aging and AD. Previous work showed that circRNAs accumulate during aging in several organisms, including C. elegans . We hypothesize that circRNA accumulation during aging is detrimental and might contribute to the progression of age-related diseases such as AD. In Chapter 2 , we used a CRISPR/Cas9 strategy to genetically remove circRNAs (referred to as circ- crh-1 ) derived from the host crh-1 /CREB gene by targeting intronic sequences that are required for circularization. We found that mutations in circ- crh-1 increased the mean lifespan of C. elegans . In Chapter 3 , we showed that loss of this age- accumulated circ- crh-1 ameliorated the amyloid b-induced toxicity in a well-established C. elegans transgenic model for AD. We further show that the collagen gene, col-49 , functions in promoting amyloid b-induced paralysis. Lastly, in Chapter 4 , we investigated the function of the RNA-binding protein NOVA-1 in C. elegans . Its homolog in mice, NOVA-2, is a known regulator of circRNA biogenesis in neural tissues of mice. In C. elegans , we found that mutations in nova-1 extend the mean lifespan and show increased heat resistance. Moreover, we identified both new and existing circRNAs that are differentially expressed in nova-1 mutants, including circ- crh-1 . Together, these results suggest that NOVA-1 might regulate lifespan by controlling the abundance of a sub-group of circRNAs. However, further experiments are required to understand better the role of NOVA-1 in circRNA regulation and the aging process.