Structure and Replication of Yeast Prions

Abstract

By analogy with the yeast model, the fragmentation of prion and amyloid polymers performed by Hsp104p homologs or other factors should influence their propagation and accumulation. The fragmentation might accelerate accumulation of prion and amyloid aggregates, but it might also serve to dissolve these aggregates if the fragmenting activity is high enough. The level of chaperone activity could control the appearance of amyloids and explain their age-dependent onset. The fragmentation of prions would be essential for their transmissibility, but would not be so critical for amyloid polymers, which are not transmissible and can appear by nucleation.The different frequency of fragmentation could explain the different properties of prions in two human diseases. The absence of observable fibrils in some cases of human CJD probably reflects a high level of PrPSc fragmentation. Another human prion disease, Gerstmann-Straussler-Sheinker syndrome, is characterized by filamentous, amyloid-like PrP deposits and a slower disease progression than CJD. These phenotypes could be related: more frequent fragmentation of CJD fibrils could mean higher overall polymerization speed and faster disease progression.In vitro, yeast Hsp104p interacted specifically with Sup35p, PrP and β-amyloid 1–42 peptide (Schirmer and Lindquist 1997xSchirmer, E.C and Lindquist, S. Proc. Natl. Acad. Sci. USA. 1997; 94: 13932–13937Crossref | PubMed | Scopus (75)See all ReferencesSchirmer and Lindquist 1997), and moreover, promoted the prion conversion of PrP (DebBurman et al. 1997xDebBurman, S.K, Raymond, G.J, Caughey, B, and Lindquist, S. Proc. Natl. Acad. Sci. USA. 1997; 94: 13938–13943Crossref | PubMed | Scopus (202)See all ReferencesDebBurman et al. 1997). These results suggest that Hsp104p analogs in mammals could also interact with such proteins and participate in prion and amyloid formation. Hsp104p is likely to occur in animals, since it shows similarity to the Clp/Hsp100 family of bacterial and eukaryotic chaperones and is functionally conserved between yeast and plants. However, in contrast to yeast prions, which propagate inside cells, mammalian prions and most amyloids occur extracellularly. Hsp104p is not secreted in yeast and it is likely to be so in mammals as well. At least one might expect different levels of chaperone fragmenting activity and probably even different factors causing fragmentation in intra- and extracellular compartments.Thus, in terms of the type and levels of fragmenting activity the best analogy with yeast prions may be found in intracellular amyloid diseases, related to the expansion of polyglutamine tracts in some human proteins. These diseases are accompanied by neuronal nuclear inclusions, formed by the respective polyglutamine proteins. The expanded polyglutamine domain of one such protein, huntingtin, was shown to form amyloid fibrils in vitro (Scherzinger et al. 1997xScherzinger, E, Lurz, R, Turmaine, M, Mangiarini, L, Hollenbach, B, Hasenbank, R, Bates, G.P, Davies, S.W, Lehrach, H, and Wanker, E.E. Cell. 1997; 90: 549–558Abstract | Full Text | Full Text PDF | PubMed | Scopus (833)See all ReferencesScherzinger et al. 1997). The abundance of glutamine and the related amino acid asparagine is also a characteristic feature of prion domains of Sup35p and Ure2p of S. cerevisiae. This feature is common for Sup35p from different yeast species and fungi, although not from higher eukaryotes. The importance of these residues was further demonstrated by the finding that the mutations which interfere with the prion properties of Sup35p fall within a short amino-terminal fragment, which is rich in Gln and Asn (DePace et al. 1998xDePace, A.H, Santoso, A, Hillner, P, and Weissman, J.S. Cell. 1998; 93: 1241–1252Abstract | Full Text | Full Text PDF | PubMed | Scopus (276)See all ReferencesDePace et al. 1998). The yeast prions and polyglutamine proteins might be considered as a single structural class, in contrast to other amyloidogenic proteins, which are not abundant in Gln and Asn. These similarities suggest that chaperones like Hsp104p might play an important role in diseases associated with expanded polyglutamine tracts.