Presenting Author:

Luzivette Robles-Cardona, B.S.

Principal Investigator:

Liming Li, Ph.D.

Department:

Biochemistry and Molecular Genetics

Keywords:

Prions, Protein-misfolding, Amyloid, Saccharomyces cerevisiae, Yeast, [SWI+]

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B7 - Basic Science

Identifying small molecules that antagonize prions and alleviate amyloid toxicity

Prions, proteinaceous infectious particles, are misfolded proteins that can self-propagate by recruiting their isomers to adopt their misfolded conformations. Prions can cause neurodegenerative disorders called transmissible spongiform encephalopathies. It is believed that a similar protein-only mechanism also underlies several other mammalian misfolding diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. These diseases are characterized by the accumulation of aggregates with altered amyloid conformations, and they are incurable. Thus, there is an urgent need for the development of new therapeutics. Saccharomyces cerevisiae, budding yeast, is a good model system for this type of research as it contains several amyloid-based prion elements. In addition, several neurodegenerative disease models have been established in yeast for 𝛂-synuclein, FUS (fused in sarcoma), and Htt103Q (a mutant Huntingtin protein fragment with an expanded glutamine tract). Using these S. cerevisiae disease models, we tested 13 compounds, which were previously shown to eliminate the yeast prion [SWI+] in a high-throughput screen, for their antagonistic activities in the yeast disease models, as well as other yeast prions including [PSI+], [URE3], and [MOT3+]. We specifically measured if these small molecule compounds could suppress the toxicity caused by aggregation of the disease-associated proteins in a cell growth assay. For yeast prions, a colony color change assay combined with fluorescence microscopy was used to determine prion curing. Preliminary results show that some compounds work to eliminate the [PSI+] and [MOT3+] prions, but we have not found clear results for their effect on yeast models of neurodegenerative diseases. The identification of compounds that reduce the toxicity of neurodegenerative proteins and eliminate yeast prions will aid our understanding of the mechanisms that underlie protein misfolding. These compounds may also have potential as probes for prion research or as therapeutic drugs for neurodegenerative diseases.