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In partial fulfillment of the requirements for the degree of
Doctor of Philosophy in Biology
In the
School of Biological Sciences
Zachery Deckner
Will defend his dissertation
YEast model for seeding and cross-seeding of protein aggregation in proteopathies
Thursday, July 8th, 2021
11:00 AM
https://bluejeans.com/607594679/4139
Meeting ID: 607 594 679
Thesis Advisor:
Yury Chernoff, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Committee Members:
Kirill Lobachev, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Francesca Storici, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Nicholas Seyfried, Ph.D.
Department of Biochemistry
Emory University
Matthew Torres, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
ABSTRACT: 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, protein aggregates that contain highly ordered b-sheet structures that are very stable and quite insoluble. Yeast are also plagued by amyloids. In yeast, amyloids manifest themselves as infectious proteins, termed yeast “prions” that are heritable via the cytoplasm. While not necessarily considered a disease in yeast, our understanding in how and why yeast prions form and propagate have led to insights that have translated to our understanding of proteins associated with human diseases. My thesis work has employed yeast as a model system to understand the specific sequence elements as well as other cellular factors that contribute to protein misfolding of proteins associated with disease in humans, including Ab42, MAPT, and U1-70k, all of which are associated with AD. Firstly, I have shown that the Aβ-based prion in yeast is controlled by the Ab42 peptide. I also used this prion system to study Ab42 isolated from patients suffering from AD to demonstrate that Ab42 is capable of forming prion variants. Secondly, using high expression plasmids I have shown that MAPT, the repeat domain of MAPT, and the C-terminal domain of U1-70k are capable of forming detergent-resistant aggregates in yeast, a characteristic of amyloids. Lastly, I have used a novel yeast assay to study the nucleation capabilities of protein peptides that have recently been associated with diseases, as well as use it as a high-throughput screening platform to test newly synthesized compounds to determine if they can prevent the initial nucleation of Ab, the triggering event in AD. Overall, this work provides new information on the molecular mechanisms that drive protein aggregation.
