Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity

The fundamental event in prion diseases seems to be a conformational change in cellular prion protein (PrPC) whereby it is converted into the pathologic isoform PrPSc. In fatal familial insomnia (FFI), the protease-resistant fragment of PrPSc after deglycosylation has a size of 19 kilodaltons, whereas that from other inherited and sporadic prion diseases is 21 kilodaltons. Extracts from the brains of FFI patients transmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation and induced formation of the 19-kilodalton PrPSc fragment, whereas extracts from the brains of familial and sporadic Creutzfeldt-Jakob disease patients produced the 21-kilodalton PrPSc fragment in these mice. The results presented indicate that the conformation of PrPSc functions as a template in directing the formation of nascent PrPSc and suggest a mechanism to explain strains of prions where diversity is encrypted in the conformation of PrPSc.

[1]  AC Tose.  Cell , 1993, Cell.

[2]  P. Pergami,et al.  Semipreparative chromatographic method to purify the normal cellular isoform of the prion protein in nondenatured form. , 1996, Analytical biochemistry.

[3]  H. Fraser,et al.  Identification of a gene which controls the incubation period of some strains of scrapie agent in mice. , 1968, Journal of comparative pathology.

[4]  A. Dickinson,et al.  Biological evidence that scrapie agent has an independent genome. , 1987, The Journal of general virology.

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

[6]  P. Lantos,et al.  Transmission of fatal familial insomnia to laboratory animals , 1995, The Lancet.

[7]  L. Hood,et al.  Structural studies of the scrapie prion protein using mass spectrometry and amino acid sequencing. , 1993, Biochemistry.

[8]  P. Roller,et al.  Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. , 1993, The Journal of biological chemistry.

[9]  C. Donnelly,et al.  Transmission dynamics and epidemiology of BSE in British cattle , 1996, Nature.

[10]  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.

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

[12]  C. Anfinsen.  Principles that govern the folding of protein chains. , 1973, Science.

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

[14]  R. Castellani,et al.  Regional distribution of protease‐resistant prion protein in fatal familial insomnia , 1995, Annals of neurology.

[15]  C. Bouras,et al.  Fatal familial insomnia , 1992, Neurology.

[16]  C. Masters,et al.  Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Sträussler syndrome with an analysis of the various forms of amyloid plaque deposition in the virus-induced spongiform encephalopathies. , 1981, Brain : a journal of neurology.

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

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

[19]  H. Wiśniewski,et al.  Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins , 1987, Journal of virology.

[20]  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.

[21]  R J Fletterick,et al.  Structural clues to prion replication. , 1994, Science.

[22]  S. Prusiner,et al.  Scrapie and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells , 1990, The Journal of cell biology.

[23]  J Q Trojanowski,et al.  Molecular basis of phenotypic variability in sporadc creudeldt‐jakob disease , 1996, Annals of neurology.

[24]  E. Broussolle,et al.  New variant of Creutzfeldt-Jakob disease in a 26-year-old French man , 1996, The Lancet.

[25]  H. Fraser,et al.  Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. , 1973, Journal of comparative pathology.

[26]  R. Petersen,et al.  Fatal Familial Insomnia and Familial Creutzfeldt‐Jakob Disease: Clinical, Pathological and Molecular Features , 1995, Brain pathology.

[27]  De Armond.  Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform. , 1993 .

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

[29]  S. Prusiner,et al.  Replication of distinct scrapie prion isolates is region specific in brains of transgenic mice and hamsters. , 1992, Genes & development.

[30]  R. Bowler,et al.  Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

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

[32]  D. Gajdusek.  Unconventional viruses and the origin and disappearance of kuru. , 1977, Science.

[33]  P Brown,et al.  Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. , 1992, Science.

[34]  F. Meggendorfer.  Klinische und genealogische Beobachtungen bei einem Fall von spastischer Pseudosklerose Jakobs , 1930 .

[35]  H. Y. Chen,et al.  Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. , 1992, The New England journal of medicine.

[36]  R. Marsh,et al.  Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy , 1994, Journal of virology.

[37]  R. Marsh,et al.  Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. , 1992, The Journal of general virology.

[38]  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.

[39]  T. Kitamoto,et al.  The sequential development of abnormal prion protein accumulation in mice with Creutzfeldt-Jakob disease. , 1992, The American journal of pathology.

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

[41]  B. Ghetti,et al.  Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  F. Hofmann,et al.  Intestinal Secretory Defects and Dwarfism in Mice Lacking cGMP-Dependent Protein Kinase II , 1996, Science.

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

[44]  P. Brown,et al.  First experimental transmission of fatal familial insomnia , 1995, Nature.

[45]  S. Prusiner,et al.  Regional mapping of prion proteins in brain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.