Genetic modifiers of ALS-associated defects in a C. elegans sod-1 model

Yanagi, Katherine Shizue

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Overview

Year:: 2021
Contributor:: Yanagi, Katherine Shizue (creator); Kaun, Karla (Reader); Hart, Anne (Advisor); Jaworski, Alexander (Reader); Wharton, Kristi (Reader); Pierce-Shimomura, Jonathan (Reader); Brown University. Department of Neuroscience (sponsor)
Genre:: theses
Subject:: Amyotrophic lateral sclerosis; Caenorhabditis elegans
Extent:: 17, 145 p.

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Abstract:: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that results from the loss of glutamatergic and cholinergic motor neurons. Variations in many genes have been genetically linked with ALS, including the superoxide dismutase 1 (SOD1) gene that encodes an enzyme that catalyzes the breakdown of superoxide radicals. Further, multiple cellular processes including oxidative stress response and RNA homeostasis are implicated in ALS pathogenesis. There is a wide range of clinical variability observed in the ALS patient population which poses major complications for the development of treatments. Genetic modifiers, genes that enhance or suppress disease-associated defects, can contribute to the heterogeneity in the patient population and provide valuable insight into pathogenic mechanisms. Here we sought to identify genetic modifiers of ALS using two approaches: (1) a meta-analysis of previously published genetic modifiers of ALS-associated defects in model organisms or genetic modifiers identified through genome-wide association studies and (2) a novel forward genetic screen for suppressors of stress-induced glutamatergic neuron degeneration in a C. elegans sod-1G85R model. From our suppressor screen, we identified loss of an RNA binding protein is a suppressor of stress-induced glutamatergic and cholinergic neuron degeneration. Interestingly, many other ALS-linked genes have RNA binding capabilities, and the disruption of RNA granules are thought to be key mediators of neurodegeneration. These results suggests that RNA-based regulatory mechanisms may underly common pathways leading to degeneration.
Notes:: Thesis (Ph. D.)--Brown University, 2021

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Citation

Yanagi, Katherine Shizue, "Genetic modifiers of ALS-associated defects in a C. elegans sod-1 model" (2021). Neuroscience Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:svn8ssyg/

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Neuroscience Theses and Dissertations

Theses and Dissertations for the Neuroscience department.
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