Prion Protein Repeat Expansion Results in Increased Aggregation and Reveals Phenotypic Variability

Abstract

Mammalian prion diseases are fatal neurodegenerative disorders dependent on the prion protein PrP. Expansion of the oligopeptide repeats (ORE) found in PrP is associated with inherited prion diseases. Patients with ORE frequently harbor PrP aggregates, but other factors may contribute to pathology, as they often present with unexplained phenotypic variability. We created chimeric yeast-mammalian prion proteins to examine the influence of the PrP ORE on prion properties in yeast. Remarkably, all chimeric proteins maintained prion characteristics. The largest repeat expansion chimera displayed a higher propensity to maintain a self-propagating aggregated state. Strikingly, the repeat expansion conferred increased conformational flexibility, as observed by enhanced phenotypic variation. Furthermore, the repeat expansion chimera displayed an increased rate of prion conversion, but only in the presence of another aggregate, the [RNQ⁺] prion. We suggest that the PrP ORE increases the conformational flexibility of the prion protein, thereby enhancing the formation of multiple distinct aggregate structures and allowing more frequent prion conversion. Both of these characteristics may contribute to the phenotypic variability associated with PrP repeat expansion diseases.

We thank members of the True lab for helpful discussions and J. Weber and S. Stewart for comments on the manuscript. We thank K. Blumer and J. Cooper for the use of equipment and A. Li for advice. We thank M. Tuite, S. Liebman, and S. Lindquist for plasmids, strains, and antibodies. We thank S. Liebman for assistance with the transformation protocol.

This research was supported by National Institutes of Health grants F31 NS054513 (E.M.H.T.) and GM072228 (H.L.T.), the Ellison Medical Foundation (H.L.T.), and the Edward Mallinckrodt, Jr., Foundation (H.L.T.).