Continuum of Prion Protein Structures Enciphers a Multitude of Prion Isolate-specified Phenotypes

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Dec 5

PMID 17142317

Citations 135

Authors

Giuseppe Legname

Hoang-Oanh B Nguyen

David Peretz

Fred E Cohen

Stephen J DeArmond

Stanley B Prusiner

Affiliations

Soon will be listed here.

Abstract

On passaging synthetic prions, two isolates emerged with incubation times differing by nearly 100 days. Using conformational-stability assays, we determined the guanidine hydrochloride (Gdn.HCl) concentration required to denature 50% of disease-causing prion protein (PrP(Sc)) molecules, denoted as the [Gdn.HCl](1/2) value. For the two prion isolates enciphering shorter and longer incubation times, [Gdn.HCl](1/2) values of 2.9 and 3.7 M, respectively, were found. Intrigued by this result, we measured the conformational stabilities of 30 prion isolates from synthetic and naturally occurring sources that had been passaged in mice. When the incubation times were plotted as a function of the [Gdn.HCl](1/2) values, a linear relationship was found with a correlation coefficient of 0.93. These findings demonstrate that (i) less stable prions replicate more rapidly than do stable prions, and (ii) a continuum of PrP(Sc) structural states enciphers a multitude of incubation-time phenotypes. Our data argue that cellular machinery must exist for propagating a large number of different PrP(Sc) conformers, each of which enciphers a distinct biological phenotype as reflected by a specific incubation time. The biophysical explanation for the unprecedented plasticity of PrP(Sc) remains to be determined.

Citing Articles

SENP2-based N-terminal truncation of α-synuclein in Lewy pathology propagation.

Taguchi K, Watanabe Y, Tanaka M iScience. 2025; 28(2):111935.

PMID: 40028275 PMC: 11869972. DOI: 10.1016/j.isci.2025.111935.

Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.

Perez-Castro M, Perez-Castro M, Erana H, Vidal E, Charco J, Lorenzo N PLoS Pathog. 2025; 21(1):e1012890.

PMID: 39841704 PMC: 11774496. DOI: 10.1371/journal.ppat.1012890.

The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics.

Fornara B, Igel A, Beringue V, Martin D, Sibille P, Pujo-Menjouet L iScience. 2024; 27(12):111381.

PMID: 39717079 PMC: 11664133. DOI: 10.1016/j.isci.2024.111381.

Chaperone-mediated disaggregation of infectious prions releases particles that seed new prion formation in a strain-specific manner.

Shoup D, Priola S J Biol Chem. 2024; 301(1):108062.

PMID: 39662829 PMC: 11758957. DOI: 10.1016/j.jbc.2024.108062.

Brain-derived and in vitro-seeded alpha-synuclein fibrils exhibit distinct biophysical profiles.

Lee S, Civitelli L, Parkkinen L Elife. 2024; 13.

PMID: 39584804 PMC: 11588339. DOI: 10.7554/eLife.92775.

References

Supattapone S, Nguyen H, Cohen F, Prusiner S, Scott M . Elimination of prions by branched polyamines and implications for therapeutics. Proc Natl Acad Sci U S A. 1999; 96(25):14529-34. PMC: 24470. DOI: 10.1073/pnas.96.25.14529. View

Criado J, Sanchez-Alavez M, Conti B, Giacchino J, Wills D, Henriksen S . Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol Dis. 2005; 19(1-2):255-65. DOI: 10.1016/j.nbd.2005.01.001. View

Peretz D, Scott M, Groth D, Williamson R, Burton D, Cohen F . Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci. 2001; 10(4):854-63. PMC: 2373967. DOI: 10.1110/ps.39201. View

Prusiner S . Shattuck lecture--neurodegenerative diseases and prions. N Engl J Med. 2001; 344(20):1516-26. DOI: 10.1056/NEJM200105173442006. View

Peretz D, Williamson R, Kaneko K, Vergara J, Leclerc E, Schmitt-Ulms G . Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. 2001; 412(6848):739-43. DOI: 10.1038/35089090. View

Peretz D, Williamson R, Legname G, Matsunaga Y, Vergara J, Burton D . A change in the conformation of prions accompanies the emergence of a new prion strain. Neuron. 2002; 34(6):921-32. DOI: 10.1016/s0896-6273(02)00726-2. View

Si K, Lindquist S, Kandel E . A neuronal isoform of the aplysia CPEB has prion-like properties. Cell. 2003; 115(7):879-91. DOI: 10.1016/s0092-8674(03)01020-1. View

Si K, Giustetto M, Etkin A, Hsu R, Janisiewicz A, Miniaci M . A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell. 2003; 115(7):893-904. DOI: 10.1016/s0092-8674(03)01021-3. View

Zou W, Zheng J, Gray D, Gambetti P, Chen S . Antibody to DNA detects scrapie but not normal prion protein. Proc Natl Acad Sci U S A. 2004; 101(5):1380-5. PMC: 337061. DOI: 10.1073/pnas.0307825100. View

10.

Tanaka M, Chien P, Naber N, Cooke R, Weissman J . Conformational variations in an infectious protein determine prion strain differences. Nature. 2004; 428(6980):323-8. DOI: 10.1038/nature02392. View

11.

Legname G, Baskakov I, Nguyen H, Riesner D, Cohen F, DeArmond S . Synthetic mammalian prions. Science. 2004; 305(5684):673-6. DOI: 10.1126/science.1100195. View

12.

Chesebro B . Biomedicine. A fresh look at BSE. Science. 2004; 305(5692):1918-21. DOI: 10.1126/science.1103581. View

13.

Dickinson A, Meikle V . A comparison of some biological characteristics of the mouse-passaged scrapie agents, 22A and ME7. Genet Res. 1969; 13(2):213-25. DOI: 10.1017/s0016672300002895. View

14.

Dickinson A . Host-pathogen interactions in scrapie. Genetics. 1975; 79 Suppl:387-95. View

15.

Masters C, Richardson Jr E . Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease). The nature and progression of spongiform change. Brain. 1978; 101(2):333-44. DOI: 10.1093/brain/101.2.333. View

16.

Prusiner S, Cochran S, Groth D, Downey D, Bowman K, Martinez H . Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol. 1982; 11(4):353-8. DOI: 10.1002/ana.410110406. View

17.

Prusiner S, McKinley M, Bowman K, Bolton D, Bendheim P, Groth D . Scrapie prions aggregate to form amyloid-like birefringent rods. Cell. 1983; 35(2 Pt 1):349-58. DOI: 10.1016/0092-8674(83)90168-x. View

18.

Prusiner S, Groth D, Bolton D, Kent S, HOOD L . Purification and structural studies of a major scrapie prion protein. Cell. 1984; 38(1):127-34. DOI: 10.1016/0092-8674(84)90533-6. View

19.

McKinley M, Braunfeld M, Bellinger C, Prusiner S . Molecular characteristics of prion rods purified from scrapie-infected hamster brains. J Infect Dis. 1986; 154(1):110-20. DOI: 10.1093/infdis/154.1.110. View

20.

Carlson G, Kingsbury D, Goodman P, Coleman S, Marshall S, DeArmond S . Linkage of prion protein and scrapie incubation time genes. Cell. 1986; 46(4):503-11. DOI: 10.1016/0092-8674(86)90875-5. View