A Size Threshold Limits Prion Transmission and Establishes Phenotypic Diversity

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Science  29 Oct 2010:
Vol. 330, Issue 6004, pp. 680-683
DOI: 10.1126/science.1197785

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Processing Prion Phenotype

How misfolding of a prion protein translates into transmissible changes in cellular physiology is unclear. Derdowski et al. (p. 680) integrated a computational model of prion aggregate dynamics with an empirical analysis of the physical and functional dynamics of prion protein in yeast cells. Remarkably, they found that prion phenotypes resulted from fluctuations in the accumulation of aggregates and suggested that it is the process rather than the product of protein misfolding that is crucial in establishing the severity or stability of the resulting phenotype.


According to the prion hypothesis, atypical phenotypes arise when a prion protein adopts an alternative conformation and persist when that form assembles into self-replicating aggregates. Amyloid formation in vitro provides a model for this protein-misfolding pathway, but the mechanism by which this process interacts with the cellular environment to produce transmissible phenotypes is poorly understood. Using the yeast prion Sup35/[PSI+], we found that protein conformation determined the size distribution of aggregates through its interactions with a molecular chaperone. Shifts in this range created variations in aggregate abundance among cells because of a size threshold for transmission, and this heterogeneity, along with aggregate growth and fragmentation, induced age-dependent fluctuations in phenotype. Thus, prion conformations may specify phenotypes as population averages in a dynamic system.

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