Promoting Prion Propagation

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Science  14 Dec 2001:
Vol. 294, Issue 5550, pp. 2251-2253
DOI: 10.1126/science.294.5550.2251d

The prion diseases, including transmissible spongiform encephalopathies, result from the aberrant folding and aggregation of proteins. The deleterious consequences of producing protease-resistant complexes of prions cannot be overstated.

One approach to understanding the precise mechanisms of pathological prion formation and propagation involves the study of prion-based phenotypes in yeast. Borchsenius et al. examined the propagation of the [PSI+] prion phenotype, which involves the aberrant folding and aggregation of the Sup35 protein. Deleting a portion of Sup35 generated a protein that was defective in propagating itself because it could not efficiently produce “seeds” of aggregated Sup35 to pass on to new generations of yeast. The defect could be corrected by the overproduction of chaperone Hsp104, which disaggregated Sup35.

Priola and Lawson examined the importance of posttranslational modification for prion propagation. In culture, mammalian prion protein can be released from cells, and different species produce prion proteins that are distinctive in amino acid sequence and in glycosylation patterns. When examining the ability of secreted prion protein to form aggregates with prions from different species, they discovered that glycosylation could affect the binding of soluble, protease-sensitive prion protein to insoluble, protease-resistant prion protein. These findings may help to explain aspects of the barriers to transmission of prion diseases between a variety of host species.—SMH

EMBO J.20, 6683; 6692 (2001).

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