Cellular Mechanisms and Consequences of Protein Misfolding and Resolution

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8. Project Summary/Abstract Many proteins access, in addition to their native state, an alternative pathway of folding leading to the formation of amyloid aggregates. Amyloidogenesis has been linked not only to more than fifty human diseases but also to functions, which benefit the organism. Once arising, the amyloid state is perpetuated through the incorporation and conformational conversion of native- state protein, fragmentation of growing complexes and transmission both within and to other individuals. These central events are modulated by protein sequence and conformation, protein quality control pathways, and cell biology. Yet, how these contributing factors and processes intersect to impact organismal physiology is poorly understood, despite a growing appreciation of the contributions of amyloid to the biology of systems from yeast to man. This current gap in knowledge is a critical barrier to progress in the field because we are unable to rationally explain, predict, exploit, and reverse the link between amyloidogenesis and its physiological effects. Our long-term goal is to bridge this gap by determining how these inputs are balanced and disrupted to create and cure dynamic phenotypic states. Toward this end, we are exploiting prions of Saccharomyces cerevisiae as an outstanding and robust model. Sharing many characteristics with metazoan amyloids, yeast prions are a naturally evolved system in which the thresholds separating phenotypic states can be accessed, studied, and traversed under physiologically relevant conditions. We will exploit dichotomies in yeast prion biology, where the same event yields distinct outcomes in different contexts, as experimental entryways to elucidate system balance for the most crucial transitions: prion appearance, interference, curing, and toxicity. Together, our studies will elucidate the molecular basis of proteostatic niches that allow amyloid to survive or to be lost and will provide a framework for understanding similar transitions in higher eukaryotes.