Science. 1999 Mar 19;283(5409):1935-7. Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations.
Jackson GS, Hosszu LL, Power A, Hill AF, Kenney J, Saibil H, Craven CJ, Waltho JP, Clarke AR, Collinge J.
Prion Disease Group, Department of Neurogenetics, Imperial College School of Medicine at St. Mary's, London W2 1NY, UK.
Prion propagation involves the conversion of cellular prion protein (PrPC) into a disease-specific isomer, PrPSc, shifting from a predominantly alpha-helical to beta-sheet structure. Here, conditions were established in which recombinant human PrP could switch between the native alpha conformation, characteristic of PrPC, and a compact, highly soluble, monomeric form rich in beta structure. The soluble beta form (beta-PrP) exhibited partial resistance to proteinase K digestion, characteristic of PrPSc, and was a direct precursor of fibrillar structures closely similar to those isolated from diseased brains. The conversion of PrPC to beta-PrP in suitable cellular compartments, and its subsequent stabilization by intermolecular association, provide a molecular mechanism for prion propagation.
PMID:_10082469
Arch Virol. 1999;144(1):177-84. Detection methods of possible prion contaminants in collagen and gelatin.
Nemoto T, Horiuchi M, Ishiguro N, Shinagawa M.
Department of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan.
We describe methods for the preparation of collagen and gelatin samples to detect possible prion contaminants using Western blotting of a major component of prions, PrPSc. A commercially available collagen solution containing 2% athero-collagen was spiked with rodent adapted scrapie prion and used as the prion-contaminating collagen. The methods developed center on the enzymatic reduction of the collagen solution viscosity with protease treatments and on the concentration of the prion from the protease-digests with polyethylene glycol-#6000 and NaCl. Recovery of the spiked prion as a partially protease-resistant core fragment of PrPSc fluctuated from 30% to 46% of the input amount.
PMID:_10076518
Biochemistry. 1999 Mar 16;38(11):3280-4. Familial prion disease mutation alters the secondary structure of recombinant mouse prion protein: implications for the mechanism of prion formation.
Cappai R, Stewart L, Jobling MF, Thyer JM, White AR, Beyreuther K, Collins SJ, Masters CL, Barrow CJ.
Department of Pathology, The Mental Health Research Institute, The University of Melbourne, Parkville, Victoria, Australia. r.cappaathology.unimelb.edu.au
A considerable body of data supports the model that the infectious agent (called a prion) which causes the transmissible spongiform encephalopathies is a replicating polypeptide devoid of nucleic acid. Prions are believed to propagate by changing the conformation of the normal cellular prion protein (PrPc) into an infectious isoform without altering the primary sequence. Proteins equivalent to the mature form of the wild-type mouse prion protein (residues 23-231) or with a mutation equivalent to that associated with Gerstmann-Straussler-Scheinker disease (proline to leucine at codon 102 in human; 101 in mouse) were expressed in E. coli. The mutation did not alter the relative proteinase K susceptibility properties of the mouse prion proteins. The wild-type and mutant proteins were analyzed by circular dichroism under different pH and temperature conditions. The mutation was associated with a decrease in alpha-helical content, while the beta-sheet content of the two proteins was unchanged. This suggests the mutation, while altering the secondary structure of PrP, is not sufficient to induce proteinase K resistance and could therefore represent an intermediate isoform along the pathway toward prion formation.
PMID:_10079070
Am J Hum Genet. 1999 Apr;64(4):1063-70. Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease.
Lee HS, Sambuughin N, Cervenakova L, Chapman J, Pocchiari M, Litvak S, Qi HY, Budka H, del Ser T, Furukawa H, Brown P, Gajdusek DC, Long JC, Korczyn AD, Goldfarb LG.
Clinical Neurogenetics Unit, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be infectious, sporadic, or hereditary. The 200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation-associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the basis of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation.
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