Friday, May 3, 2024
5/3/2024
Abstract Formation of toxic protein aggregates is a hallmark of neurodegenerative disorders. In some diseases, including Huntington’s Disease and six subtypes of spinocerebellar ataxia, protein aggregates form due to the expansion of a CAG repeat in the coding region of a specific gene. This CAG repeat encodes for a polyglutamine tract that aggregates when expanded, leading to neuronal death. One potential way to treat these diseases is to suppress polyglutamine aggregation and toxicity. Our laboratory has taken a unique approach to addressing this issue. Instead of studying polyglutamine in organisms where it aggregates and causes toxicity, we have identified the social amoeba Dictyostelium discoideum as a proteostatic outlier that is naturally resistant to polyglutamine aggregation. To investigate this phenomenon, I conducted a proximity labeling screen to identify proteins in Dictyostelium with increased proximity to polyglutamine-expanded huntingtin, the causative protein in Huntington’s Disease. Strikingly, I found that many proteins with increased proximity were highly glutamine-rich and predicted to form prion. This is interesting because prions influence polyglutamine aggregation in a poorly defined manner. Here I propose to help clarify the role of prion-like proteins in Dictyostelium and their potential role in suppressing polyglutamine aggregation. Using parallel investigation in Dictyostelium, human cells, and in vitro experiments, I hope to elucidate the role of prion-like proteins in regulating polyglutamine aggregation. Additionally, I propose to define the roles of prions in Dictyostelium biology. Together these aims begin and define the roles of prion-like proteins in Dictyostelium and determine how they influence the solubility of Dictyostelium’s polyglutamine-rich proteome.
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