J Neuroimmunol. 2003 Jul;140(1-2):137-42. Comparison of PrP transcription and translation in two murine myeloma cell lines.
Kim JI, Kuizon S, Rubenstein R.
New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Richard.Rubensteimr.state.ny.us
The generation of monoclonal antibodies (MAbs) to the prion protein, PrP, is important in order to establish a large repertoire of useful reagents for the diagnosis of transmissible spongiform encephalopathies (TSE), or prion diseases. However, the presence of PrP on the surface of all mammalian cells (PrP(C)) causes self-recognition, thereby restricting the ability of mice to produce an immune response to the PrP immunogen. Although this problem has been alleviated with the generation and use of PrP-knockout mice, the production of MAbs has continued to be severely hampered presumably since the fusion partner for spleen-derived lymphocytes was PrP(C)-containing myeloma cell lines. The availability of a mouse myeloma cell line expressing little or no PrP(C) on the surface would therefore be useful for MAb generation. Our data indicate that cells differ in their levels of PrP(C) expression and suggest that not all murine myeloma cell lines are equally useful for obtaining hybridomas secreting anti-PrP MAbs.
PMID:_12864981 [PubMed - in process]
J Biol Chem. 2003 Jul 14 [Epub ahead of print]. The N-terminal region of the prion protein ectodomain contains a lipid raft targeting determinant.
Walmsley AR, Zeng F, Hooper NM.
School of Biochemistry and Molecular Biology, University of Leeds, Leeds, W. Yorks. LS2 9JT.
The association of the prion protein (PrP) with sphingolipid- and cholesterol-rich lipid rafts is instrumental in the pathogenesis of the neurodegenerative prion diseases. Although the glycosyl-phosphatidylinositol (GPI) anchor is an exoplasmic determinant of raft association, PrP remained raft associated in human neuronal cells even when the GPI anchor was deleted or substituted for a transmembrane anchor indicating that the ectodomain contains a raft localisation signal. The raft association of transmembrane-anchored PrP occurred independently of Cu(II) binding as it failed to be abolished by either deletion of the octapeptide repeat region (residues 51-90) or treatment of cells with a Cu(II) chelator. Raft association of transmembrane-anchored PrP was only abolished by the deletion of the N-terminal region (residues 23-90) of the ectodomain. This region was sufficient to confer raft localisation when fused to the N-terminus of a non-raft transmembrane-anchored protein and suppressed the clathrin-coated pit localisation signal in the cytoplasmic domain of the amyloid precursor protein. These data indicate that the N-terminal region of PrP acts as a cellular raft targeting determinant and that residues 23-90 of PrP represent the first proteinaceous raft targeting signal within the ectodomain of a GPI anchored protein.
PMID:_12865430 [PubMed - as supplied by publisher]
Lancet. 2003 Jul 12;362(9378):128-30. Distribution of codon 129 genotype in human growth hormone-treated CJD patients in France and the UK.
Brandel JP, Preece M, Brown P, Croes E, Laplanche JL, Agid Y, Will R, Alperovitch A.
National Reference Centre of Iatrogenic CJD, Salpetriere Hospital, 75651 Cedex 13, Paris, France. jean-philippe.brandesl.ap-hop-paris.fr <jean-philippe.brandesl.ap-hop-paris.fr>
Since homozygosity MM at codon 129 of the prion protein gene is a recognised risk factor in all forms of Creutzfeldt-Jakob disease (CJD), we studied the distribution of codon 129 polymorphism in patients in France and in the UK with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in UK patients was surprisingly low (4%) compared with that in French patients (62%). There is no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone.
PMID:_12867116
J Gen Virol. 2003 Aug;84(Pt 8):2279-83. Up-regulation of cathepsin B and cathepsin L activities in scrapie-infected mouse Neuro2a cells.
Zhang Y, Spiess E, Groschup MH, Burkle A.
Department of Gerontology, Institute for Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
Prion diseases are characterized by the accumulation of an abnormal, proteinase K-resistant isoform of the prion protein, PrP(Sc), which is generated by a post-translational conversion of the protease-sensitive normal cell-surface glycoprotein PrP(c) involving major conformational changes. The conversion is thought to occur at the plasma membrane or along the endocytic pathway towards the lysosome. PrP(Sc) aggregates have been found to accumulate in secondary lysosomes. In our study, the activities of two major lysosomal cysteine proteases, cathepsins B and L, were found to be significantly increased in scrapie-infected Neuro2a cells compared with uninfected cells using biochemical and cytochemical methods. We hypothesize that lysosomal proteases may be involved in a 'second autocatalytic loop' of PrP(Sc) formation, acting in concert with the well-known autocatalytic enhancement of PrP conversion in the presence of PrP(Sc).
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