A 7-kDa Prion Protein (PrP) Fragment, an Integral Component of the PrP Region Required for Infectivity, Is the Major Amyloid Protein in Gerstmann-Sträussler-Scheinker Disease A117V*

Gerstmann-Sträussler-Scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP). The aim of this study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 129, Val129 being in coupling phase with mutant Val117. The major peptide extracted from amyloid fibrils was a ∼7-kDa PrP fragment. Sequence analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly88 and Gly90 and ending with Arg148, Glu152, or Asn153. Only Val was present at positions 117 and 129, indicating that the amyloid protein originated from mutant PrP molecules. In addition to the ∼7-kDa peptides, the amyloid fraction contained N- and C-terminal PrP fragments corresponding to residues 23–41, 191–205, and 217–228. Fibrillogenesis in vitro with synthetic peptides corresponding to PrP fragments extracted from brain tissue showed that peptide PrP-(85–148) readily assembled into amyloid fibrils. Peptide PrP-(191–205) also formed fibrillary structures although with different morphology, whereas peptides PrP-(23–41) and PrP-(217–228) did not. These findings suggest that the processing of mutant PrP isoforms associated with Gerstmann-Sträussler-Scheinker disease may occur extracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracellular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a ∼7-kDa protease-resistant core that is similar in patients with different mutations. Furthermore, the present data suggest that C-terminal fragments of PrP may participate in amyloid formation.

[1]  B. Ghetti,et al.  Neuropathology of Gerstmann‐Sträussler‐Scheinker disease , 2000, Microscopy research and technique.

[2]  F E Cohen,et al.  A synthetic peptide initiates Gerstmann-Sträussler-Scheinker (GSS) disease in transgenic mice. , 2000, Journal of molecular biology.

[3]  K Wüthrich,et al.  NMR solution structure of the human prion protein. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  F. Tagliavini,et al.  Creutzfeldt‐Jakob Disease: Carnoy's Fixative Improves the Immunohistochemistry of the Proteinase K‐ Resistant Prion Protein , 2000, Brain pathology.

[5]  S. Prusiner,et al.  Transmissible and genetic prion diseases share a common pathway of neurodegeneration , 1999, Nature.

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

[7]  B. Ghetti,et al.  Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues. , 1998, The American journal of pathology.

[8]  D. Dickson,et al.  Phenotypic Variability of Gerstmann-Straussler-Scheinker Disease is Associated with Prion Protein Heterogeneity , 1998, Journal of neuropathology and experimental neurology.

[9]  H. Budka,et al.  Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

[11]  E. Cochran,et al.  Allelic origin of the abnormal prion protein isoform in familial prion diseases , 1997, Nature Medicine.

[12]  M. Brunori,et al.  Identification of the prion protein allotypes which accumulate in the brain of sporadic and familial Creutzfeldt-Jakob disease patients , 1997, Nature Medicine.

[13]  F. Cohen,et al.  Recombinant scrapie-like prion protein of 106 amino acids is soluble. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[14]  B. Ghetti,et al.  Proteinase-K-Resistant Prion Protein Isoforms in Gerstmann-Straussler-Scheinker Disease (Indiana Kindred) , 1996, Journal of neuropathology and experimental neurology.

[15]  G. Lenzi,et al.  Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity in a previously unreported family with Gerstmann-Straussler-Scheinker disease (PrP-P102L mutation) , 1996, Neurology.

[16]  B. Ghetti,et al.  Prion Protein Amyloidosis , 1996, Brain pathology.

[17]  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.

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

[19]  B. Ghetti,et al.  Amyloid fibrils in Gerstmann-Sträussler-Scheinker disease (Indiana and Swedish Kindreds) express only PrP peptides encoded by the mutant allele , 1994, Cell.

[20]  G. Forloni,et al.  Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein. , 1994, The Journal of biological chemistry.

[21]  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.

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

[23]  K. Doh-ura,et al.  Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. , 1993, Biochemical and biophysical research communications.

[24]  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.

[25]  S. Prusiner,et al.  Prion protein preamyloid and amyloid deposits in Gerstmann-Sträussler-Scheinker disease, Indiana kindred. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

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

[27]  S. Prusiner,et al.  Mutant prion proteins in Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles , 1992, Nature Genetics.

[28]  S. Prusiner,et al.  Epitope mapping of the Syrian hamster prion protein utilizing chimeric and mutant genes in a vaccinia virus expression system. , 1991, Journal of immunology.

[29]  J. Henion,et al.  Structural characterization of protein tryptic peptides via liquid chromatography/mass spectrometry and collision-induced dissociation of their doubly charged molecular ions. , 1991, Analytical chemistry.

[30]  S. Prusiner,et al.  Molecular biology of prion diseases , 1991, Science.

[31]  G. Schellenberg,et al.  A prion protein variant in a family with the telencephalic form of Gerstmann‐Sträussler‐Scheinker syndrome , 1991, Neurology.

[32]  S. Prusiner,et al.  Amyloid protein of Gerstmann‐Sträussler‐Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N‐terminal glycine at codon 58. , 1991, The EMBO journal.

[33]  K. Doh-ura,et al.  A prion protein missense variant is integrated in kuru plaque cores in patients with Gerstmann‐Sträussler syndrome , 1991, Neurology.

[34]  Y. Sakaki,et al.  Immunochemical, molecular genetic, and transmission studies on a case of Gerstmann‐Straussler‐Scheinker syndrome , 1990, Neurology.

[35]  S. Prusiner,et al.  Unusual topogenic sequence directs prion protein biogenesis. , 1990, Science.

[36]  B. Ghetti,et al.  Gerstmann‐Sträussler‐Scheinker disease II. Neurofibrillary tangles and plaques with PrP‐amyloid coexist in an affected family , 1989, Neurology.

[37]  Y. Sakaki,et al.  Pro----leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Sträussler syndrome. , 1989, Biochemical and biophysical research communications.

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

[39]  T. Kitamoto,et al.  Gerstmann‐Sträussler‐Scheinker disease: Immunohistological and experimental studies , 1988, Annals of neurology.

[40]  S. Prusiner,et al.  Evidence for a secretory form of the cellular prion protein. , 1987, Biochemistry.

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

[42]  S. Prusiner,et al.  Biogenesis and Transmembrane Orientation of the Cellular Isoform of the Scrapie Prion Protein , 1987, Molecular and cellular biology.

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

[44]  J. Gerstmann,et al.  Über eine eigenartige hereditär- familiäre Erkrankung des Zentralnervensystems , 1935 .

[45]  S. Prusiner,et al.  Insoluble wild–type and protease–resistant mutant prion protein in brains of patients with inherited prion disease , 1996, Nature Medicine.