J Epidemiol Biostat. 2000;5(4):209-19. Prevalence of detectable abnormal prion protein in persons incubating vCJD: plausible incubation periods and cautious inference.
Cooper JD, Bird SM, de Angelis D.
Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge, UK.
BACKGROUND: Both small and large variant Creutzfeldt Jakob disease (vCJD) epidemics are consistent with the current observed incidence. Uncertainty in vCJD projections could potentially be reduced by incorporating information on the prevalence of the infectious agent in persons incubating vCJD. The prospect of vCJD prevalence studies has been raised by detection of abnormal prion protein, thought to be the infectious agent, in appendices and tonsils removed from vCJD patients. Although unlinked anonymous testing of stored operative tissues for abnormal prion protein is very appealing, the design and interpretation of such prevalence studies is complicated by the lack of information on how early in the incubation period of vCJD the abnormal prion protein becomes detectable. METHODS: We simulate a range of vCJD epidemics, consistent with the limited available information on the incidence of vCJD, to illustrate some of the potential problems encountered when interpreting the results from prevalence studies of detectable abnormal prion protein. We assume plausible incubation period distributions and dietary exposure patterns. RESULTS: We demonstrate, in the context of our simulated epidemics, that prevalence studies of detectable abnormal prion protein would require the testing of tens of thousands of operative specimens and, even then, that unlinked anonymous testing positives would be unexpected.
PMID:_11055271
Biochem Biophys Res Commun. 2002 Nov 22;299(1):85-90. Cell membrane translocation of the N-terminal (1-28) part of the prion protein.
Lundberg P, Magzoub M, Lindberg M, Hallbrink M, Jarvet J, Eriksson LE, Langel U, Graslund A.
Department of Neurochemistry and Neurotoxicology, Stockholm University, SE-106 91, Stockholm, Sweden.
The N-terminal (1-28) part of the mouse prion protein (PrP) is a cell penetrating peptide, capable of transporting large hydrophilic cargoes through a cell membrane. Confocal fluorescence microscopy shows that it transports the protein avidin (67kDa) into several cell lines. The (1-28) peptide has a strong tendency for aggregation and beta-structure formation, particularly in interaction with negatively charged phospholipid membranes. The findings have implications for how prion proteins with uncleaved signal peptides in the N-termini may enter into cells, which is important for infection. The secondary structure conversion into beta-structure may be relevant as a seed for the conversion into the scrapie (PrP(Sc)) form of the protein and its amyloidic transformation.
PMID:_12435392
J Biol Chem. 2001 Jan 19;276(3):2286-91. Epub 2000 Nov 01. Cleavage of the amino terminus of the prion protein by reactive oxygen species.
McMahon HE, Mange A, Nishida N, Creminon C, Casanova D, Lehmann S.
Institut de Genetique Humaine, CNRS U.P.R. 1142, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France.
Relatively limited information is available on the processing and function of the normal cellular prion protein, PrP(C). Here it is reported for the first time that PrP(C) undergoes a site-specific cleavage of the octapeptide repeat region of the amino terminus on exposure to reactive oxygen species. This cleavage was both copper- and pH-dependent and was retarded by the presence of other divalent metal ions. The oxidative state of the cell also decreased detection of full-length PrP(C) and increased detection of amino-terminally fragmented PrP(C) within cells. Such a post-translational modification has vast implications for PrP(C), in its processing, because such cleavage could alter further proteolysis, and in the formation of the scrapie isoform of the prion protein, PrP(Sc), because abnormal cleavage of PrP(Sc) occurs into the octapeptide repeat region.
PMID:_11060296
Biochemistry. 2000 Nov 7;39(44):13575-83. Expression and structural characterization of the recombinant human doppel protein.
Lu K, Wang W, Xie Z, Wong BS, Li R, Petersen RB, Sy MS, Chen SG.
Institute of Pathology and Mass Spectrometry Core Facility, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA.
The doppel protein (Dpl) is a newly recognized prion protein (PrP)-like molecule encoded by a novel gene locus, prnd, located on the same chromosome as the PrP gene. To study the structural features of Dpl, we have expressed recombinant human Dpl corresponding to the putative mature protein domain (residues 24-152) in Escherichia coli. The primary structure of the recombinant Dpl 24-152 was characterized using gel electrophoresis, N-terminal Edman sequencing, matrix-assisted laser desorption ionization mass spectrometry, and electrospray ionization mass spectrometry. Dpl 24-152 was shown to contain two disulfide bonds (Cys94-Cys145 and Cys108-Cys140). The secondary structure of Dpl was analyzed using far-UV circular dichroism spectroscopy. Dpl 24-152 was found to be an alpha-helical protein having a high helical content (40%). Dpl 24-152 exhibited characteristics of a thermodynamically stable protein that undergoes reversible and cooperative thermal denaturation. In addition, Dpl was found to be soluble and sensitive to proteinase K digestion. Therefore, Dpl 24-152 possesses biochemical properties similar to those of recombinant PrP. This study provides knowledge about the molecular features of human Dpl that will be useful in further investigation into its normal function and the role it may play in neurodegenerative diseases.
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