Prion protein strain differences

Caughey B, Raymond GJ, Bessen RA. Strain-dependent differences in beta-sheet conformations of abnormal prion protein. J Biol Chem 1998 273 32230-32235. 

Tanaka, M., Chien, P., Naber, N., Cooke, R., and Weissman,J. S. (2004). Conformational variations in an infectious protein determine prion strain differences. Nature 428, 323-328. 

A hard-to-understand aspect of the "protein-only" theory of prion diseases is the existence of various "strains" of prion proteins. These do not involve differences in amino acid sequence but differences in the conformations of the PrPSc forms and in the glycosylation patterns. dmw How can there be several different conformations of the same protein, all of which seed the conversion of normal PrP into differing insoluble forms In spite of this puzzle, support for the explanation of strain differences comes from a yeast prion system, which involves transcription termination factor eRF3.x z In this system, which involves a prion whose insoluble form can be redissolved by guanidine hydrochloride,aa differing strains have also been described.ybb cc Nevertheless, the presence of the various strains of animal prions, as well as observed vaccination of inbred mice against specific strains,dd may be more readily understood if the disease is transmitted by an unidentified virus rather than by a pure protein.1/U ee/ff In fact, the diseases have not been successfully transmitted by truly virus-free proteins synthesized from recombinant DNA.ee... 

One remarkable property of yeast prions and their mammalian counterparts is the ability to take up several different yet stable [PRION+] forms that reflect different but stable conformational states of the prion protein. In the case of mammalian prions these are referred to as prion strains and can result in very distinct neuropathologies [94]. In yeast, however, to avoid confusion with the use of the term strain, which is typically used to describe different lineages of this organism, they are referred to as yeast prion variants . Like mammalian prion strains, yeast prion variants can give rise to variant-specific differences in the [PRION+] phenotypes. 

Prion diseases occur through different strains, as evidenced by different progression patterns and clinical features of the disease that seem to be associated with different genetic and/or post-translational polymorphisms in the prion protein, yet how these differences translate into different disease outcomes remains unknown. 

A straightforward approach to in vivo hypothesis testing is to generate a knockout mouse for the gene of interest, inoculate with prions and look at the effect on incubation time as compared to wild type controls. Experiments of this nature have been carried out for the anti-inflammatory cytokines interleukin-4 (114), 1110 and 1113 and the chemokine, monocyte chemoattractant protein-1 (Mcpl) [82, 83]. Following intracerebral inoculation with the RML strain of mouse adapted scrapie, no significant differences were seen for mice deficient in either 114,1113 or both. However, for mice... 

The notion that prion strains are encoded by different conformations of the same protein is supported by a wealth of data showing structural polymorphisms (or strains ) in amyloid fibrils formed by a number of unrelated proteins such as insulin [160], Alzheimer s A(3 peptide [161], and Sup35 [107, 108]. Importantly, the conformational traits defining individual polymorphic forms are often heritable upon seeding, with daughter fibrils adopting the conformation of parent seeds, even if the reaction is performed under conditions that would normally favor... 

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