A synthetic peptide initiates Gerstmann-Sträussler-Scheinker (GSS) disease in transgenic mice.

The molecular basis of the infectious, inherited and sporadic forms of prion diseases is best explained by a conformationally dimorphic protein that can exist in distinct normal and disease-causing isoforms. We identified a 55-residue peptide of a mutant prion protein that can be refolded into at least two distinct conformations. When inoculated intracerebrally into the appropriate transgenic mouse host, 20 of 20 mice receiving the beta-form of this peptide developed signs of central nervous system dysfunction at approximately 360 days, with neurohistologic changes that are pathognomonic of Gerstmann-Sträussler-Scheinker disease. By contrast, eight of eight mice receiving a non-beta-form of the peptide failed to develop any neuropathologic changes more than 600 days after the peptide injections. We conclude that a chemically synthesized peptide refolded into the appropriate conformation can accelerate or possibly initiate prion disease.

[1]  S. Prusiner,et al.  Measurement of the scrapie agent using an incubation time interval assay , 1982, Annals of neurology.

[2]  S. Prusiner.  Novel proteinaceous infectious particles cause scrapie. , 1982, Science.

[3]  S. Prusiner,et al.  Spontaneous neurodegeneration in transgenic mice with mutant prion protein , 1990, Science.

[4]  R. Kimberlin,et al.  Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. , 1987, The Journal of general virology.

[5]  F. Cohen,et al.  Prion Protein Biology , 1998, Cell.

[6]  F. Cohen,et al.  Predicted alpha-helical regions of the prion protein when synthesized as peptides form amyloid. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Fred E. Cohen,et al.  Conformational Transformations in Peptides Containing Two Putative α-Helices of the Prion Protein , 1995 .

[8]  S. Prusiner,et al.  Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. , 1996, Genes & development.

[9]  S. Prusiner,et al.  Linkage of prion protein and scrapie incubation time genes , 1986, Cell.

[10]  A. Aguzzi,et al.  Mice devoid of PrP are resistant to scrapie , 1993, Cell.

[11]  L. Hood,et al.  Purification and structural studies of a major scrapie prion protein , 1984, Cell.

[12]  F E Cohen,et al.  Prion protein peptides induce alpha-helix to beta-sheet conformational transitions. , 1995, Biochemistry.

[13]  H. Fraser,et al.  Transmission of bovine spongiform encephalopathy and scrapie to mice , 2007 .

[14]  Stephen J. DeArmond,et al.  Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques , 1989, Cell.

[15]  S. Prusiner,et al.  Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Dickinson Ag.  Scrapie in sheep and goats. , 1976 .

[17]  F. Cohen,et al.  Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. L. Chandler.  Encephalopathy in mice produced by inoculation with scrapie brain material. , 1961, Lancet.

[19]  S. Prusiner,et al.  A transmembrane form of the prion protein in neurodegenerative disease. , 1998, Science.

[20]  R. Fletterick,et al.  Perturbation of the secondary structure of the scrapie prion protein under conditions that alter infectivity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Prusiner,et al.  Scrapie prions aggregate to form amyloid-like birefringent rods , 1983, Cell.

[22]  F. Cohen,et al.  Molecular properties of complexes formed between the prion protein and synthetic peptides. , 1997, Journal of molecular biology.

[23]  S. Prusiner,et al.  Attempts to restore scrapie prion infectivity after exposure to protein denaturants. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[24]  G. Forloni,et al.  Neurotoxicity of a prion protein fragment , 1993, Nature.

[25]  F E Cohen,et al.  A conformational transition at the N terminus of the prion protein features in formation of the scrapie isoform. , 1997, Journal of molecular biology.

[26]  TIKVAH ALPER,et al.  Does the Agent of Scrapie Replicate without Nucleic Acid ? , 1967, Nature.

[27]  Jurg Ott,et al.  Linkage of a prion protein missense variant to Gerstmann–Sträussler syndrome , 1989, Nature.

[28]  S. Prusiner,et al.  Scrapie prion liposomes and rods exhibit target sizes of 55,000 Da. , 1988, Virology.

[29]  A. Akowitz,et al.  Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Martín,et al.  Analysis of the prion protein gene in thalamic dementia , 1992, Neurology.

[31]  P E Fraser,et al.  A kinetic model for amyloid formation in the prion diseases: importance of seeding. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. Fraser,et al.  CEREBRAL AMYLOIDOSIS IN SCRAPIE IN THE MOUSE: EFFECT OF AGENT STRAIN AND MOUSE GENOTYPE , 1976 .

[33]  S. Prusiner,et al.  Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[34]  F E Cohen,et al.  Pathologic conformations of prion proteins. , 1998, Annual review of biochemistry.

[35]  J. Ott,et al.  Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD). , 1993, American journal of human genetics.

[36]  G. D. Hunter,et al.  The physico-chemical nature of the scrapie agent. , 1976, Frontiers of biology.

[37]  S. Prusiner,et al.  Linkage of the Indiana kindred of Gerstmann-Sträussler-Scheinker disease to the prion protein gene , 1992, Nature Genetics.

[38]  T. Kitamoto,et al.  An amber mutation of prion protein in Gerstmann-Sträussler syndrome with mutant PrP plaques. , 1993, Biochemical and biophysical research communications.

[39]  Stephen J. DeArmond,et al.  Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication , 1990, Cell.

[40]  S. Prusiner,et al.  Thiocyanate and hydroxyl ions inactivate the scrapie agent. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[41]  F. Cohen,et al.  Prion protein gene variation among primates. , 1995, Journal of molecular biology.

[42]  E Goormaghtigh,et al.  Secondary structure and dosage of soluble and membrane proteins by attenuated total reflection Fourier-transform infrared spectroscopy on hydrated films. , 1990, European journal of biochemistry.

[43]  R J Fletterick,et al.  Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[44]  F. Cohen,et al.  Structures of prion proteins and conformational models for prion diseases. , 1996, Current topics in microbiology and immunology.

[45]  R. Marsh,et al.  Comparison of scrapie and transmissible mink encephalopathy in hamsters. II. Clinical signs, pathology, and pathogenesis. , 1975, The Journal of infectious diseases.

[46]  B. Ghetti,et al.  Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Riek,et al.  NMR structure of the mouse prion protein domain PrP(121–231) , 1996, Nature.

[48]  P. Lansbury,et al.  Species specificity in the cell-free conversion of prion protein to protease-resistant forms: a model for the scrapie species barrier. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Prusiner,et al.  Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[50]  F E Cohen,et al.  Prion protein (PrP) synthetic peptides induce cellular PrP to acquire properties of the scrapie isoform. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[51]  P. Hochstein,et al.  POTENTIAL VARIANTS OF PHENYLKETONURIA , 1975, The Lancet.

[52]  C. Frith,et al.  Inherited prion disease with 144 base pair gene insertion. 1. Genealogical and molecular studies. , 1992, Brain : a journal of neurology.

[53]  P. Lansbury,et al.  Cell-free formation of protease-resistant prion protein , 1994, Nature.

[54]  H. Fraser,et al.  The genomic identity of different strains of mouse scrapie is expressed in hamsters and preserved on reisolation in mice. , 1989, The Journal of general virology.

[55]  P E Wright,et al.  Structure of the recombinant full-length hamster prion protein PrP(29-231): the N terminus is highly flexible. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[56]  T. Alper,et al.  The exceptionally small size of the scrapie agent. , 1966, Biochemical and biophysical research communications.

[57]  R. Kimberlin,et al.  Characteristics of a short incubation model of scrapie in the golden hamster. , 1977, The Journal of general virology.

[58]  F. Cohen,et al.  Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[59]  F. Cohen,et al.  Eight prion strains have PrPSc molecules with different conformations , 1998, Nature Medicine.

[60]  F. Cohen,et al.  Prion Protein of 106 Residues Creates an Artificial Transmission Barrier for Prion Replication in Transgenic Mice , 1999, Cell.

[61]  S. Prusiner,et al.  RAPID DETECTION OF CREUTZFELDT-JAKOB DISEASE AND SCRAPIE PRION PROTEINS: 88 , 1990 .

[62]  F E Cohen,et al.  Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[63]  S. Prusiner,et al.  Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins , 1994, Cell.

[64]  F. Cohen,et al.  Separation of scrapie prion infectivity from PrP amyloid polymers. , 1996, Journal of molecular biology.

[65]  F. Cohen,et al.  Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein , 1995, Cell.

[66]  B. Caughey,et al.  Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy. , 1991, Biochemistry.

[67]  B. Chesebro.  Human TSE disease — viral or protein only? , 1997, Nature Medicine.

[68]  B. Ghetti,et al.  Synthetic peptides homologous to prion protein residues 106-147 form amyloid-like fibrils in vitro. , 1993, Proceedings of the National Academy of Sciences of the United States of America.