Neuropathol Appl Neurobiol. 1999 Feb;25(1):20-8. The acute inflammatory response in CNS following injection of prion brain homogenate or normal brain homogenate.
Betmouni S, Perry VH.
School of Biological Sciences, University of Southampton, UK.
The neuropathological hallmarks of end-stage prion disease are vacuolation, neuronal loss, astrocytosis and deposition of PrPSc amyloid. We have also shown that there is an inflammatory response in the brains of scrapie-affected mice from 8 weeks post-injection. In this study we have investigated the acute CNS response to the intracerebral injection of scrapie-affected brain homogenate. The ME7 strain of scrapie (Neuropathogenesis Unit, Edinburgh) was used, and control mice were injected with brain homogenate derived from normal C57BL/6 J mice. One microlitre of 10% w/v ME7 (n = 33) and normal brain homogenate (n = 28) was injected stereotaxically into the right dorsal hippocampus. Cryostat sections of brains taken at 1, 2, 5, 7, 14 and 28 days post-injection were examined histologically for neuronal loss, and immunocytochemically to study the inflammatory response. This study shows that ME7 is not acutely neurotoxic in vivo. There is also no difference (ANOVA) in the inflammatory response, which peaked between 2 and 5 days and resolved by 4 weeks after intracerebral injection of either ME7 or normal brain homogenate. The well circumscribed inflammatory response seen previously at 8 weeks is therefore a consequence of a disease process rather than a surgical artefact. This disease process may be related to a localized accumulation of PrPSc sufficient to stimulate an inflammatory response which in turn may contribute to neuronal loss. The role of the inflammatory response in chronic neurodegeneration can be usefully studied using this mouse model of prion disease, and this will undoubtedly shed light on the pathogenic mechanisms underlying other chronic neurodegenerative diseases.
PMID:_10194772
J Biol Chem. 2003 Aug 1;278(31):28944-9. Epub 2003 May 19. Deletion of N-terminal residues 23-88 from prion protein (PrP) abrogates the potential to rescue PrP-deficient mice from PrP-like protein/doppel-induced Neurodegeneration.
Atarashi R, Nishida N, Shigematsu K, Goto S, Kondo T, Sakaguchi S, Katamine S.
Department of Molecular Microbiology and Immunology, Institute of Atomic Bomb Disease, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Accumulating evidence has suggested that prion protein (PrP) is neuroprotective and that a PrP-like protein/Doppel (PrPLP/Dpl) is neurotoxic. A line of PrP-deficient mice, Ngsk Prnp0/0, ectopically expressing PrPLP/Dpl in neurons, exhibits late-onset ataxia because of Purkinje cell death that is prevented by a transgene encoding wild-type mouse PrP. To elucidate the mechanisms of neurodegeneration in these mice, we introduced five types of PrP transgene, namely one heterologous hamster, two mouse/hamster chimeric genes, and two mutants, each of which encoded PrP lacking residues 23-88 (MHM2.del23-88) or with E199K substitution (Mo.E199K), into Ngsk Prnp0/0 mice. Only MHM2.del23-88 failed to rescue the mice from the Purkinje cell death. The transgenic mice, MHM2.del23-88/Ngsk Prnp0/0, expressed several times more PrP than did wild-type (Prnp+/+) mice and PrPLP/Dpl at an equivalent level to Ngsk Prnp0/0 mice. Little difference was observed in the pathology and onset of ataxia between Ngsk Prnp0/0 and MHM2.del23-88/Ngsk Prnp0/0. No detergent-insoluble PrPLP/Dpl was detectable in the central nervous system of Ngsk Prnp0/0 mice even after the onset of ataxia. Our findings provide evidence that the N-terminal residues 23-88 of PrP containing the unique octapeptide-repeat region is crucial for preventing Purkinje cell death in Prnp0/0 mice expressing PrPLP/Dpl in the neuron.
PMID:_12759361
J Cell Sci. 2003 Jul 1;116(Pt 13):2775-9. Epub 2003 May 20. Specific inhibition of pathological prion protein accumulation by small interfering RNAs.
Daude N, Marella M, Chabry J.
Institut de Pharmacologie Moleculaire et Cellulaire, Unite Mixte de Recherche 6097, Centre National de la Recherche Scientifique. 660, route des lucioles, 06560 Valbonne, France.
Development of transmissible spongiform encephalopathies (TSEs) pathogenesis requires the presence of both the normal host prion protein (PrP-sen) and the abnormal pathological proteinase-K resistant isoform (PrP-res). PrP-res forms highly insoluble aggregates, with self-perpetuating properties, by binding and converting PrP-sen molecules into a likeness of themselves. In the present report, we show that small interfering RNA (siRNA) duplexes trigger specific Prnp gene silencing in scrapie-infected neuroblastoma cells. A non-passaged, scrapie-infected culture transfected with siRNA duplexes is depleted of PrP-sen and rapidly loses its PrP-res content. The use of different murine-adapted scrapie strains and host cells did not influence the siRNA-induced gene silencing efficiency. More than 80% of transfected cells were positive for the presence of fluorescein-labeled siRNA duplexes. No cytotoxicity associated with the use of siRNA was observed during the time course of these experiments. Despite a transient abrogation of PrP-res accumulation, our results suggest that the use of siRNA may provide a new and promising therapeutic approach against prion diseases.
PMID:_12759373 [PubMed - in process]
J Protein Chem. 2003 Feb;22(2):115-26. Reversible aggregation of mouse prion protein derivatives with PrPSC-like structural properties.
Lu BY, Atanasov I, Zhou ZH, Chang JY.
Research Center for Protein Chemistry, Institute of Molecular Medicine, Department of Biochemistry and Molecular Biology, The University of Texas, Houston, Texas 77030, USA.
Three carbamylated derivatives of reduced mouse prion protein (mPrP) were isolated during the aborted oxidative folding in the presence of urea. These three prion protein derivatives (mPrP-a, mPrP-b, and mPrP-c) exist as monomer in the acidic solution (pH < 2.0) and exhibit prevalent random coil structure. However, they undergo rapid aggregation and transformation to a predominant beta-sheet structure upon exposure to ionic buffer with pH greater than 3.0. The stability of aggregates of mPrP conformers is in part dependent upon the time that they were allowed to develop. The nascent aggregates comprise a significant fraction of loosely packed mPrP monomers that can be dissociated by treatment with strong acidic solution. Matured aggregates acquired through prolonged sample incubation contain more tightly packed mPrP monomers that cannot be dissociated by strong acid but can be disaggregated by denaturant. The properties of reversible aggregation of mPrP-a, mPrP-b, and mPrP-c bear a striking resemblance to that observed with aggregates of hamster PrPSC.
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