title: 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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Elizabeth M H
authors.initials: EM
authors.lastname: Tank
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
authors.forename: Amar A
authors.initials: AA
authors.lastname: Desai
authors.forename: Heather L
authors.initials: HL
authors.lastname: True
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D006360:Heat-Shock Proteins / Q000378:metabolism; D040582:Inheritance Patterns; D008540:Meiosis; D051379:Mice; D008938:Mitosis; D010454:Peptide Termination Factors; D010641:Phenotype; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D012441:Saccharomyces cerevisiae / Q000166:cytology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D006360:Heat-Shock Proteins; D010454:Peptide Termination Factors; D011328:Prions; D011994:Recombinant Proteins; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae