J Biol Chem. 2002 Dec 6;277(49):47671-8. Epub 2002 Sep 30. Intercellular transfer of the cellular prion protein.
Liu T, Li R, Pan T, Liu D, Petersen RB, Wong BS, Gambetti P, Sy MS.
Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
The cellular prion protein (PrP(C)) is a glycosylphosphatidylinositol (GPI)-anchored protein. We investigated whether PrP(C) can move from one cell to another cell in a cell model. Little PrP(C) transfer was detected when a PrP(C) expressing human neuroblastoma cell line was cultured with the human erythroleukemia cells IA lacking PrP(C). Efficient transfer of PrP(C) was detected with the presence of phorbol 12-myristate 13-acetate, an activator of protein kinase C. Maximum PrP(C) transfer was observed when both donor and recipient cells were activated. Furthermore, PrP(C) transfer required the GPI anchor and direct cell to cell contact. However, intercellular protein transfer is not limited to PrP(C), another GPI-anchored protein, CD90, also transfers from the donor cells to acceptor cells after cellular activation. Therefore, this transfer process is GPI-anchor and cellular activation dependent. These findings suggest that the intercellular transfer of GPI-anchored proteins is a regulated process, and may have implications for the pathogenesis of prion disease.
PMID:_12359724
Cell Mol Life Sci. 2002 Aug;59(8):1366-76. Structural features of prions explored by sequence analysis I. Sequence data.
Mornon JP, Prat K, Dupuis F, Callebaut I.
Systemes Moleculaires & Biologie Structurale, LMCP, CNRS UMR 7590, Universites Paris 6 et Paris 7, France. mornomcp.jussieu.fr
Animal prion proteins (PrPs) form at the sequence level a very homogenous and 'closed' family. Therefore, few of their structural and functional features can be gleaned from sequence comparison as is now possible on a wide scale for other protein families. To detect putatively related proteins (at the structural and/or functional level), we used a battery of sequence analysis tools. This analysis resulted in (i) the identification of a putative 'prion-like' domain within the envelope of foamy retroviruses, (ii) the detection of putative similarities between prions and an interferon-inducible membrane protein, and (iii) the proposal that of the TATA-box-binding protein is a structural scaffold, which might allow understanding of a key event leading to the structural conversion from PrP(C) (normal cellular prion structure) towards PrP(Sc) (pathogenic structure).
PMID:_12363039
Phys Rev E Stat Nonlin Soft Matter Phys. 2002 Sep;66(3 Pt 1):031909. Epub 2002 Sep 24. Structural and folding properties of a lattice prion model.
Wind AF, Kemp JP, Ermoshkin AV, Chen JZ.
Department of Physics, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.
Searching through and conducting Monte Carlo folding simulations on 10(6) different 27 mer sequences, we have selected a prionlike lattice model whose energy spectrum and folding properties demonstrate characteristic prion behavior. The energetic competition and structural partition between two closely spaced energy minima yield unique kinetic and thermodynamic properties that can be qualitatively compared with experimental results. Folding simulations indicate that the probability of reaching the first excited state from a denatured random conformation is much higher than the probability of reaching the global energy-minimum state.
PMID:_12366154
J Virol. 2002 Nov;76(21):10905-13. Microglia from Creutzfeldt-Jakob disease-infected brains are infectious and show specific mRNA activation profiles.
Baker CA, Martin D, Manuelidis L.
Section of Neuropathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Neurons are often assumed to be the principal sites for replication of the infectious agents causing Creutzfeldt-Jakob disease (CJD), scrapie, and bovine spongiform encephalopathy because they express high levels of normal and pathological prion protein (PrP). However, isolated brain cell types have not been evaluated for either infection or gene expression. Microglia purified from CJD-infected mice showed infectivity comparable to that of starting brain homogenate but expressed approximately 50-fold less PrP. CJD-infected microglia also displayed morphological changes indicative of cellular activation. To determine the molecular pathways of activation, we evaluated pertinent transcripts, including those linked to inflammation. Semiquantitative reverse transcription-PCR showed a >4-fold increase in cathepsin S, an enzyme important in antigen presentation, the cytokine interleukin-1beta, and the chemokine B-lymphocyte chemoattractant. The profile of microglial changes induced by the CJD agent differed substantially from activation induced by bacterial lipopolysaccharide or by beta-amyloid, a structure comparable to pathological PrP. These microglial studies emphasize migratory hematopoietic cells in the dispersion, and possibly replication, of the CJD agent. The low PrP levels in these highly infectious and activated cells further support the concept that pathological PrP is the result of infection rather than the infectious agent itself. Because microglia develop a specific pattern of responses to the CJD agent, microglial markers may be exploited in the diagnosis of these spongiform encephalopathies.
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