Publication Date

2023

Document Type

Thesis

Committee Members

Shulin Ju, Ph.D. (Advisor); Michael Markey, Ph.D. (Committee Member); Andrew Voss, Ph.D. (Committee Member)

Degree Name

Master of Science (MS)

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the degeneration of motor neurons which leads to loss of motor function and eventual death. Over 20 genes have been implicated in ALS’s pathogenesis, one being TARDBP, which codes for TDP-43. TDP-43 mislocalizes from the nucleus, accumulates, and then aggregates in the cytoplasm and is linked to cellular toxicity. We have modeled this aggregation and toxicity of TDP-43 in budding yeast. From genetic screens of human genes and their ability to modulate TDP-43 toxicity, we found 50 human genes that were able to reduce TDP-43 toxicity. 12 of these genes expressed the strongest rescue phenotype. Interestingly, these 12 genes did not lower the protein level or aggregation of TDP-43, nor did they exhibit any protein-protein interactions with TDP-43. We then investigated a possible cellular pathway that could be associated with TDP-43 toxicity and examined how our suppressors were able to reverse its effects. We identified four suppressors that were implicated in the cAMP/PKA pathway, with two of them directly downregulating it. Further analysis revealed that out of these four genes, two led to significantly increased cAMP levels compared to TDP-43 alone. We then studied a downstream target of the cAMP/PKA pathway, stress granule formation. Our observation indicated that TDP-43 not only colocalized with stress granules but also stimulated their formation.

Page Count

74

Department or Program

Department of Biological Sciences

Year Degree Awarded

2023


Included in

Biology Commons

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