J Biol Chem. 2001 Apr 6;276(14):11265-71. Epub 2001 Jan 10. In vivo conversion of cellular prion protein to pathogenic isoforms, as monitored by conformation-specific antibodies.
Yokoyama T, Kimura KM, Ushiki Y, Yamada S, Morooka A, Nakashiba T, Sassa T, Itohara S.
National Institute of Animal Health, Tsukuba, Ibaraki 305-0856, Japan, Nippi Research Institute of Biomatrix, Adachi, Tokyo 120-8601, Japan.
The central event in prion disease is thought to be conformational conversion of the cellular isoform of prion protein (PrP(C)) to the insoluble isoform PrP(Sc). We generated polyclonal and monoclonal antibodies by immunizing PrP(C)-null mice with native PrP(C). All seven monoclonal antibodies (mAbs) immunoprecipitated PrP(C), but they immunoprecipitated PrP(Sc) weakly or not at all, thereby indicating preferential reactivities to PrP(C) in solution. Immunoprecipitation using these mAbs revealed a marked loss of PrP(C) in brains at the terminal stage of illness. Histoblot analyses using these polyclonal antibodies in combination of pretreatment of blots dissociated PrP(C) and PrP(Sc) in situ and consistently demonstrated the decrease of PrP(C) at regions where PrP(Sc) accumulated. Interestingly, same mAbs showed immunohistochemical reactivities to abnormal isoforms. One group of mAbs showed reactivity to materials that accumulated in astrocytes, while the other group did so to amorphous plaques in neuropil. Epitope mapping indicated that single mAbs have reactivities to multiple epitopes, thus implying dual specificities. This suggests the importance of octarepeats as a part of PrP(C)-specific conformation. Our observations support the notion that loss of function of PrP(C) may partly underlie the pathogenesis of prion diseases. The conversion of PrP(C) to PrP(Sc) may involve multiple steps at different sites.
PMID:_11152682
Neurosci Lett. 2001 Jan 26;298(1):53-6. The spatial patterns of prion protein deposits in Creutzfeldt-Jakob disease: comparison with beta-amyloid deposits in Alzheimer's disease.
Armstrong RA, Lantos PL, Cairns NJ.
Vision Sciences, Aston University, B4 7ET, Birmingham, UK. r.a.armstronston.ac.uk
Similar pathological processes may be involved in the deposition of extracellular proteins in the brains of patients with Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). Hence, this study compared the spatial patterns of prion protein (PrP) deposits in the cerebral cortex and hippocampus in cases of sporadic CJD with those of beta-amyloid (Abeta) deposits in sporadic AD. PrP and Abeta deposits were aggregated into clusters and, in 90% of brain areas in CJD and 57% in AD, the clusters were regularly distributed parallel to the tissue boundary. In a significant proportion of cortical analyses, the mean diameter of the clusters of PrP and Abeta deposits were similar to those of the cells of origin of the cortico-cortical pathways. Abeta deposits in AD were distributed more frequently in larger-sized clusters than PrP deposits in CJD. In addition, in the hippocampus and dentate gyrus, clustering of Abeta deposits was observed in AD but PrP deposits were rare in these regions in CJD. The size, location and distribution of the extracellular protein deposits within the cortex of both disorders was consistent with the degeneration of the cortico-cortical pathways. Furthermore, spread of the pathology along these pathways may be a pathogenic feature common to CJD and AD.
PMID:_11154834
EMBO J. 2001 Feb 1;20(3):377-86. Sulfated glycans and elevated temperature stimulate PrP(Sc)-dependent cell-free formation of protease-resistant prion protein.
Wong C, Xiong LW, Horiuchi M, Raymond L, Wehrly K, Chesebro B, Caughey B.
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories/NIH, 903 South 4th Street, Hamilton, MT 59840, USA.
A conformational conversion of the normal, protease- sensitive prion protein (PrP-sen or PrP(C)) to a protease-resistant form (PrP-res or PrP(Sc)) is commonly thought to be required in transmissible spongiform encephalopathies (TSEs). Endogenous sulfated glycosaminoglycans are associated with PrP-res deposits in vivo, suggesting that they may facilitate PrP-res formation. On the other hand, certain exogenous sulfated glycans can profoundly inhibit PrP-res accumulation and serve as prophylactic anti-TSE compounds in vivo. To investigate the seemingly paradoxical effects of sulfated glycans on PrP-res formation, we have assayed their direct effects on PrP conversion under physiologically compatible cell-free conditions. Heparan sulfate and pentosan polysulfate stimulated PrP-res formation. Conversion was stimulated further by increased temperature. Both elevated temperature and pentosan polysulfate promoted interspecies PrP conversion. Circular dichroism spectropolarimetry measurements showed that pentosan polysulfate induced a conformational change in PrP-sen that may potentiate its PrP-res-induced conversion. These results show that certain sulfated glycosaminoglycans can directly affect the PrP conversion reaction. Therefore, depending upon the circumstances, sulfated glycans may be either cofactors or inhibitors of this apparently pathogenic process.
PMID:_11157745
J Immunol. 2001 Feb 1;166(3):1448-51. The neurotoxic prion peptide fragment PrP(106-126) is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1.
Le Y, Yazawa H, Gong W, Yu Z, Ferrans VJ, Murphy PM, Wang JM.
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute-Frederick, Science Applications International Corporation-Frederick, Frederick, MD 21702, USA.
Prion diseases are transmissible and fatal neurodegenerative disorders which involve infiltration and activation of mononuclear phagocytes at the brain lesions. A 20-aa acid fragment of the human cellular prion protein, PrP(106-126), was reported to mimic the biological activity of the pathologic isoform of prion and activates mononuclear phagocytes. The cell surface receptor(s) mediating the activity of PrP(106-126) is unknown. In this study, we show that PrP(106-126) is chemotactic for human monocytes through the use of a G protein-coupled receptor formyl peptide receptor-like 1 (FPRL1), which has been reported to interact with a diverse array of exogenous or endogenous ligands. Upon stimulation by PrP(106-126), FPRL1 underwent a rapid internalization and, furthermore, PrP(106-126) enhanced monocyte production of proinflammatory cytokines, which was inhibited by pertussis toxin. Thus, FPRL1 may act as a "pattern recognition" receptor that interacts with multiple pathologic agents and may be involved in the proinflammatory process of prion diseases.
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