Proc Natl Acad Sci U S A. 2002 May 28;99(11):7402-7. Amyloid aggregates of the HET-s prion protein are infectious.
Maddelein ML, Dos Reis S, Duvezin-Caubet S, Coulary-Salin B, Saupe SJ.
Laboratoire de Genetique Moleculaire des Champignons, Institut de Biochimie et de Genetique Cellulaires, Unite Mixte de Recherche 5095, Centre National de la Recherche Scientifique, Universite de Bordeaux 2, France. ML.Maddeleibgc.u-bordeaux2.fr
The [Het-s] infectious element of the filamentous fungus Podospora anserina is a prion. We have recently reported that recombinant HET-s protein aggregates in vitro into amyloid fibers. In vivo, the protein aggregates specifically in the [Het-s] prion strains. Here, we show that biolistic introduction of aggregated recombinant HET-s protein into fungal cells induces emergence of the [Het-s] prion with a high frequency. Thus, we demonstrate that prion infectivity can be created de novo, in vitro from recombinant protein in this system. Although the amyloid filaments formed from HET-s could transmit [Het-s] efficiently, neither the soluble form of the protein nor amorphous aggregates would do so. In addition, we have found that (i) [Het-s] infectivity correlates with the ability to convert HET-s to amyloids in vitro, (ii) [Het-s] infectivity is resistant to proteinase K digestion, and (iii) HET-s aggregates formed in vivo in [Het-s] strains have the ability to convert the recombinant protein to aggregates. Together, our data designate the HET-s amyloids as the molecular basis of [Het-s] prion propagation.
PMID:_12032295
Eye. 2002 May;16(3):281-4. Debris on processed ophthalmic instruments: a cause for concern.
Dinakaran S, Kayarkar VV.
Department of Ophthalmology, Royal Hallamshire Hospital, Sheffield, UK. sdinakaraahoo.com
PURPOSE: To assess the quality of processed ophthalmic instruments and look for the presence of foreign material on the surface of these instruments. METHODS: Data were prospectively collected on the presence of debris on processed instruments in the trays used for phacoemulsification surgery. All instruments were examined under an operating microscope before use and details of the types of debris on the various instruments were noted. If debris was found, a new tray was opened to obtain a clean instrument. RESULTS: Forty-seven trays were opened for use during the study period. Deposits on instruments were found in 29 (62%) trays. These were mainly present on the intraocular lens introducers. Loose fibres were found on instruments from eight (17%) trays. Debris was found in the aspiration channels of three (6%) hand pieces. CONCLUSIONS: A significant number of processed ophthalmic instruments had debris on their surfaces. To reduce the risk of intraocular inflammation and of transmission of prion diseases the instruments should go through a thorough decontamination process before sterilization. Routine mechanical cleaning at the end of surgery and ultrasonic cleaning before sterilization should reduce the occurrence of debris on the instruments. Instruments should also be inspected under the operating microscope before use.
PMID:_12032718
Biochemistry. 2002 Jun 4;41(22):6891-6. Plasminogen activation is stimulated by prion protein and regulated in a copper-dependent manner.
Ellis V, Daniels M, Misra R, Brown DR.
School of Biological Sciences, University of East Anglia, Norwich, UK. v.elliea.ac.uk
Prion diseases are associated with the conversion of the normal prion protein, PrP(C), to the infectious disease form PrP(Sc). Discrimination between these isoforms would significantly enhance diagnosis of these diseases, and it has recently been reported that PrP(Sc) is specifically recognized by the serine protease zymogen plasminogen (Fischer et al. (2000) Nature 408, 479). Here we have tested the hypothesis that PrP is a regulator of the plasminogen activation system. The effect of recombinant PrP, either containing copper (holo-PrP) or devoid of it (apo-PrP), on plasminogen activation by both uPA and tPA was determined. PrP had no effect on plasminogen activation by uPA. By contrast, the activity of tPA was stimulated by up to 280-fold. This was observed only with the apo-PrP isoforms. The copper-binding octapeptide repeat region of PrP was involved in the effects, as a mutant lacking this region failed to stimulate plasminogen activation, although a synthetic peptide corresponding to this region was unable to stimulate tPA activity. Competition experiments demonstrated that, in addition to plasminogen binding, the stimulation required a high-affinity interaction between tPA and PrP (K(d) < 2.5 nM). Kinetic analysis revealed a template mechanism for the stimulation, suggesting independent binding sites for tPA and plasminogen. Lack of copper-binding may be an early event in the conversion of PrP(C) to PrP(Sc), and our data therefore suggest that tPA-catalyzed plasminogen activation may provide the basis for a sensitive detection system for the early stages of prion diseases and also play a role in the pathogenesis of these diseases.
PMID:_12033920
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16285-90. Epub 2002 Nov 21. Prion and doppel proteins bind to granule cells of the cerebellum.
Institute for Neurodegenerative Diseases and Departments of Neurology, University of California, San Francisco, CA 94143, USA.
We reported that expression of the cellular prion protein (PrPC) rescues doppel (Dpl)-induced cerebellar degeneration in mice. To search for protein(s) that mediate this process, we fused the C-termini of mouse (Mo) PrP and Dpl to the Fc portion of an IgG. Although both MoPrP-Fc and MoDpl-Fc bound to many regions of the brain, we observed restricted binding to granule cells in the cerebellum, suggesting a scenario in which granule cells express a protein that mediates Dpl-induced neurodegeneration. Because granule cells do not express PrPC, it seems unlikely that MoPrP-Fc binding reflects a ligand that is involved in the conversion of PrPC into PrPSc, the disease-causing isoform. In contrast, the dominant-negative MoPrP(Q218K)-Fc not only binds to granule cells but also binds to neurons of the molecular layer where PrPC is expressed. These findings raise the possibility that the cells of the molecular layer express an auxiliary protein, provisionally designated protein X, which is involved in prion formation and is likely to be distinct from the protein that mediates Dpl-induced degeneration. Although the binding of the dominant-negative MoPrP(Q218K)-Fc to cells in the molecular layer expressing PrPC is consistent with a scenario for the binding of MoPrP(Q218K)-Fc to protein X, the absence of PrPSc deposition in the molecular layer requires that PrP(Sc), once formed there, be readily transported to the cerebellar white matter where PrPSc is found. Identifying the ligands to which PrP-Fc, Dpl-Fc, and dominant-negative PrP bind may provide new insights into the functions of PrPC and Dpl as well as the mechanism of PrPSc formation.
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