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A gene signature for Alzheimer’s disease using RNAi in C. elegans


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Type

Thesis

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Authors

Ciryam, Prashanth 

Abstract

Alzheimer’s disease (AD) is a complex multifactorial disorder that is responsible for the large majority of the 50 million cases of dementia worldwide. This disease is still incurable, a situation caused at least in part by the fact that its genetics are incompletely known. In our laboratory, we have developed a novel computational approach—Network-based Transcriptome-Wide Association Studies (nTWAS)—that seeks to identify the genes associated with AD by comparing gene expression patterns across tissues in the brain. nTWAS acts as an in silico pre-screen by providing a list of gene candidates, thus enabling us to pursue investigations into each gene candidate with significantly more depth. To that end, we use RNA interference in an AD model in the nematode worm Caenorhabditis elegans to validate the results of this pre-screen. C. elegans is a well-established research tool in biological and biochemical research for its ease of culture, small size, short generation time, and relative simplicity. Furthermore, the worm’s facility for genetic manipulation and remarkably similar cellular characteristics to those of humans have allowed for numerous advances in the study of cancer, neurodegeneration, and ageing. Our approach takes advantage of an automated worm tracking platform, developed in our laboratory, that can simultaneously track hundreds of worms and make precise measurements of their motility, defects of which has been shown to correlate with neurological and muscular toxicity. While standard approaches typically only take data on dozens of worms, the vastly increased population size of our approach greatly improves the statistical power of our screen. We have leveraged these improvements in screening methods to associate the differences in distributions of these parameters with phenotypic changes across various siRNA conditions. Through both motility screening and validation by imaging, we identified ckr-2, skr-21, and Y92H12A.2 as modulators of amyloid beta aggregation. While skr-21 and Y92H12A.2 are both components of the ubiquitin-proteasome system, ckr-2 is an ortholog of a neuronal cholecystokinin receptor which has been suggested to be a biomarker of AD but for which no mechanism is known. The results of this work thus contribute to extending our understanding of the gene signature of AD.

Description

Date

2020-12-31

Advisors

Vendruscolo, Michele

Keywords

Alzheimer's disease, Caenorhabditis elegans, Genetic screening

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge