Yeast Model For Seeding and Cross-seeding Of Protein Aggregation In Proteopathies

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Deckner, Zachery Jordan
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A variety of human diseases, including Alzheimer’s disease (AD) and tauopathies, are associated with the accumulation of misfolded protein aggregates. These protein aggregates are composed of amyloids, fibrous highly ordered protein polymers that contain intermolecular -sheet structures, are very stable and insoluble. In yeast, amyloids manifest themselves as infectious proteins, termed yeast “prions” that are heritable via the cytoplasm. Deciphering how and why yeast prions form and propagate have led to insights that have translated to better understanding of proteins associated with human diseases. The objective of this work was to employ yeast as a model system for understanding specific sequence elements and conditions that contribute to misfolding of proteins associated with AD in humans, including A42, MAPT, and U1-70k. Here we have shown that the Aβ-based prion can propagate in yeast and is controlled by the A42 of a chimeric protein. Using this prion system, termed [ABE+], we were also able to demonstrate that A42 isolated from AD patients is capable of forming distinct prion variants in yeast. We also demonstrated that MAPT (tau) protein, as well as the repeat domain of MAPT containing pro-aggregation disease-associated mutations, and the C-terminal low-complexity domain of U1-70k protein are capable of forming detergent-resistant aggregates in yeast, a characteristic of amyloids. Lastly, we used a novel yeast assay to study the nucleation capabilities of various mammalian proteins (some of them associated with diseases), as well as use it as a high-throughput screening platform for testing the newly synthesized compounds in order to determine if they can prevent the initial nucleation of A, the triggering event in AD. Overall, this work provides new information on the molecular mechanisms that drive pathogenic protein aggregation.
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