Prion-mediated protein aggregation/co-aggregation and cellular consequence

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Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), belong to a subgroup of mammalian protein-misfolding neurodegenerative disorders. The pathogens responsible for TSEs are a collection of misfolded conformers (PrPSc) of an otherwise normal cellular protein (PrPC). The mechanism underlying such a conformational switch is yet ambiguous, and TSEs currently remain devastating and incurable. Intriguingly, prion or prion-like proteins have been identified in a broad range of eukaryotic and prokaryotic organisms, playing important roles in not only disease pathologies but also normal biological functions. These aggregation-prone proteins are common in forming self-sustaining conformations (usually amyloids) that can be transmitted from cell to cell, or tissue to tissue. However, we are still in an early stage in elucidating the amyloid-mediated mechanisms that contribute to diverse cellular phenotypes and pathologies. In the budding yeast Saccharomyces cerevisiae, at least eight prion proteins have been verified, which have been proven valuable models for studying prion biology. For example, the Swi1 prion ([SWI+]) discovered in our laboratory is normally a subunit of the ATP-dependent chromatin-remodeling complex SWI/SNF, and is the first prion shown to involve in massive transcriptional regulation of yeast. Upon the conformational switch, cells carrying the [SWI+] prion show a compromised capacity in using non-glucose carbon sources and a complete loss of multicellular features. However, the structural determinants of [SWI+] and their roles in prion-mediated cellular behaviors are still elusive. Moreover, accumulated evidence suggests that distinct yeast prions may interact and act in concert to regulate important cellular traits such as yeast dimorphism – switching between a unicellular form and multicellular forms, involving abundant protein interaction events such as co-aggregation. Thus, in this project, we propose to characterize the sequence features (residues) of Swi1 that are essential for Swi1 amyloid formation, [SWI+] formation and propagation. We also plan to investigate how the Swi1 prion interacts with other prions, such as Mot3 ([MOT3+]) and/or Cyc8 ([OCT+]) prions to regulate yeast multicellularity and global gene transcription in response to cellular and environmental conditions. Finally, we plan to identify prion-interacting proteins and cellular machineries, and examine the significance of such interactions in amyloidogenesis and prion transmission. The success of this project will shed light on the structure of amyloid-forming proteins, and the mechanism governing protein amyloidogenesis, prion transmission, and protein interactions, which are tightly linked to prion- mediated cellular phenotypes and human protein misfolding diseases such as Alzheimer's diseases (AD).