Prion fragment released by human platelets
A cellular form of prion protein in non-neuronal tissues of sheep
The cellular isoform of the prion and caveolae in mouse neuroblastoma cells.
Localization of cellular prion in synaptic boutons of hamster hippocampus.
Muscle macrophage express beta-amyloid precursor, prions and mRNAs.
Developmental expression of the prion protein gene in glial cells
Role of microglia and host prion protein in neurotoxicity of a prion fragment

Prion infection increases the levels of dolichyl phosphate and ubiquinone.
Cholesterol depletion and terminal targeting sequence of prion inhibit scrapie

Neuronal cell death in scrapie-infected mice is due to apoptosis
Detection of apoptosis in murine scrapi

Altered circadian activity in mice devoid of prion protein
Identification of cellular proteins binding to the scrapie prion protein
Detection of prion proteins by anti-peptide antibodies.
Creutzfeldt-Jakob disease after liver transplantation

Italian kindred with CADSIL
Creutzfeldt-Jakob disease after liver transplantation
Die Creutzfeldt-Jakob-Erkrankung
Le prion, des vaches folles au Creutzfeld-Jakob iatrogËne
EncČphalopathies spongiformes humaines

PrP27-30 is a normal soluble prion protein fragment released by human platelets.

Perini F; Vidal R; Ghetti B; Tagliavini F; Frangione B; Prelli F 
Department of Pathology, New York University Medical Center, New York 10016, USA. 
Biochem Biophys Res Commun 223: 572-7 (1996) 
Amyloid proteins are thought to derive from soluble precursors or fragments thereof, present in biological fluids, which in the disease state undergo conformational change leading to aggregation and deposition in target tissues. We report here that platelets carry PrP mRNA and release PrPC, a sialoglycoprotein bound to the cell surface by a glycosylphosphatidylinositol (GPI) anchor.

Soluble PrPC, and a N-terminal truncated PrPC isoform starting at position 90 are secreted by resting and agonist-stimulated platelets and are detectable after partial deglycosylation of releasates. N-terminal sequence analysis of the soluble 27-30 kDa isoform, GQGGGTHSQ(W)NKP, revealed homology to scrapie PrP27-30, the protease resistant core derived from PrPSc. These findings indicate that in addition to PrPC, platelets process a soluble PrP27-30 isoform. Whether this isoform can be converted in scrapie PrP27-30 remains to be determined.

The cellular isoform of the prion and caveolae in mouse neuroblastoma cells.

Harmey JH; Doyle D; Brown V; Rogers MS 
Department of Zoology, University College Dublin, Belfield, Ireland. 

Biochem Biophys Res Commun, 210: 3, 1995 May 25, 753-9 
A major component of the infectious particle causing spongiform encephalopathies or prion diseases is an aberrant isoform (PrPSc) of a glycosyl-phosphatidylinositol (GPI)-anchored cell surface protein, PrPC. The cellular processes involved in the formation of PrPSc are unclear but involve the internalization of PrPC prior to conversion. Here, we demonstrate that PrPC is associated with caveolin, a structural protein component of caveolae. We show that PrPC and caveolin share similar detergent characteristics and copurify in linear sucrose gradients. PrPC was protected from proteinase K digestion in the caveolin fraction but solubilizing the caveolae prior to proteinase K digestion rendered PrPC susceptible to proteinase K digestion. Our results indicate a physical association between PrPC and caveolin in N2a cells. The implication of these results in relation to prion biogenesis is discussed. Language of Publication English Unique Identifier 95283535

Localization of cellular prion in synaptic boutons of hamster hippocampus.

Fournier JG; Escaig-Haye F; Billette de Villemeur T; Robain O 
INSERM U. 153, hŮpital Saint-Vincent-de-Paul, Paris, France. 
C R Acad Sci III, 318: 3, 1995 Mar, 339-44 
The cellular prion protein (PrPc) is a membrane sialoglycoprotein synthesized in the central nervous system and extraneural tissues. Its post-translational modification produces an accumulation of abnormal isoform PrPsc found in brains of transmissible neurodegenerative disorders in animals (scrapie and bovine spongiform encephalopathy) and humans (Kuru, Creutzfeldt-Jakob disease, Gerstmann-Str”ussler-Scheinker syndrome). One major unanswered question relative to PrPc concerns its physiological role in brain neurons, depending largely on the limited knowledge of its subcellular localization. Using a highly-sensitive immunogold electron microscopy technique, we reported that in the hamster dentate gyrus, the synaptic boutons constituted the submicroscopic site where PrPc was observed. This detection was obtained with 2 highly-specific polyclonal antibodies for prion protein. PrPc localization was assigned, both on structural basis and on its co-localization with synaptophysin. The presence of PrPc in synaptic terminals should provide additional informations on its possible role in neuronal transmission and on the implication of synapses in the pathogenesis of spongiform encephalopathies.

Human muscle macrophages express beta-amyloid precursor, prions and their mRNAs.

Askanas V; Sarkozi E; Bilak M; Alvarez RB; Engel WK 
Department of Neurology, University of Southern California School of Medicine, Los Angeles 90017, USA. 
Neuroreport, 6: 7, 1995 May 9, 1045-9 
Well-characterized antibodies against beta-amyloid precursor protein (beta APP) and prion protein (PrP), and specific cRNA probes, were used to localize beta APP and PrP and their mRNAs in human muscle macrophages. Macrophages present in muscle biopsies of 51 patients with various neuromuscular disorders showed accumulation of beta APP and PrP, and strongly expressed beta APP and PrP mRNAs. These were present in all muscle macrophages unrelated to their localization within the muscle tissue or diagnosis. Our study provides the first demonstration that human muscle resident macrophages synthesize and accumulate beta APP and PrP. We suggest that those proteins play a role in biology of muscle macrophages, including their participation in inflammatory and immune responses.

Creutzfeldt-Jakob disease after liver transplantation.

CrČange A; Gray F; Cesaro P; Adle-Biassette H; Duvoux C; Cherqui D; Bell J; Parchi P; Gambetti P; Degos JD 
Departement de Neurosciences, Centre Hospitalier Universitaire Henri Mondor, CrČteil, France. 
Ann Neurol, 38: 2, 1995 Aug, 269-72 
We report a 57-year-old woman who died from Creutzfeldt-Jakob disease 2 years after a liver transplantation. The liver donor had no history of neurological disease. In one albumin donor, possible Creutzfeldt-Jakob disease developed 3 years later. The patient initially had cerebellar symptoms. Neuropathology included "Kuru-type" plaques and prion protein (PrP) deposits involving the cerebellum predominantly. The patient was homozygote valine at codon 129 of the PrP gene while the liver was homozygote methionine. This observation raises the possibility of transmission of Creutzfeldt-Jakob disease by the graft itself or the associated albumin transfusions and, on a wider extent, by nonneural tissue.

Prion infection increases the levels of dolichyl phosphate and ubiquinone.

Guan Z; S–derberg M; Sindelar P; Prusiner SB; Kristensson K; Dallner G 
Division of Medical Cell Biology, Karolinska Institutet, Stockholm, Sweden. 
J Neurochem, 66: 1, 1996 Jan, 277-85 
The neutral and phospholipid composition of mouse brain infected with scrapie prions was investigated. During the later stages of this disease, the level of dolichol decreased by 30% whereas the level of dolichyl phosphate increased by 30%. In terminally ill mice, there was also a 2.5-fold increase in both total ubiquinone and its reduced form. Furthermore, alpha-tocopherol was elevated at this stage by 50%. In contrast, no changes were observed in phospholipid amount, in phospholipid composition, and in phosphatidylethanolamine plasmalogen content during the entire disease process. The fatty acid and aldehyde composition of individual phospholipids remained unaltered as well. No modifications could be detected in cholesterol content. Thus, the majority of membrane lipids in scrapie-infected mouse brain are modified in neither quantity nor structure, but specific changes occur to a few polyisoprenoid lipids. This specificity indicates that, although prions accumulate in lysosomes, the infection process is not associated with a general membrane destruction caused by lysosomal enzyme leakage. Language of Publication

Altered circadian activity in mice devoid of prion protein

Tobler I; Gaus SE; Deboer T; Achermann P; Fischer M;
Rulicke T; Moser M; Oesch B; McBride PA; Manson JC 
Institute of Pharmacology, University of Zurich, Switzerland. 
Nature 380: 639-42 (1996) 
There is a wealth of data supporting a central role for the prion protein (PrP) in the neurodegenerative prion diseases of both humans and other species, yet the normal function of PrP, which is expressed at the cell surface of neurons and glial cells, is unknown. It has been speculated that neuropathology may be due to loss of normal function of PrP. Here we show that in mice devoid of PrP there is an alteration in both circadian activity rhythms and patterns. To our knowledge, this is the first null mutation that has been shown to affect sleep regulation and our results indicate that at least one of the inherited prion diseases, fatal familial insomnia, where there is a profound alteration in sleep and the daily rhythms of many hormones, may be related to the normal function of the prion protein.

Identification of cellular proteins binding to the scrapie prion protein.

Oesch B; Teplow DB; Stahl N; Serban D; Hood LE; Prusiner SB 
Department of Neurology, University of California, San Francisco 94143. 
Biochemistry 29: 5848-55 (1990)
The scrapie prion protein (PrPSc) is an abnormal isoform of the cellular protein PrPc. PrPSc is found only in animals with scrapie or other prion diseases. The invariable association of PrPSc with infectivity suggests that PrPSc is a component of the infectious particle. In this study, we report the identification of two proteins from hamster brain of 45 and 110 kDa (denoted PrP ligands Pli 45 and Pli 110) which were able to bind to PrP 27-30, the protease-resistant core of PrPSc on ligand blots. Pli 45 and Pli 110 also bound PrPC. Both Pli's had isoelectric points of approximately 5. The dissociation rate constant of the Pli 45/PrP 27-30 complex was 3 x 10(-6) s-1. Amino acid and protein sequence analyses were performed on purified Pli 45. Both the composition and the sequence were almost identical with those predicted for mouse glial fibrillary acidic protein (GFAP). Furthermore, antibodies to Pli 45 reacted with recombinant GFAP. The identification of proteins which interact with the PrP isoforms in normal and diseased brain may provide new insights into the function of PrPC and into the molecular mechanisms underlying prion diseases.

Detection of prion proteins by anti-peptide antibodies.

Yokoyama T; Itohara S; Yuasa N 
National Institute of Animal Health, Ibaraki, Japan. 
Arch Virol 141: 763-9 (1996) 
Antisera to four synthetic peptides containing the substitutions between mouse and hamster prion proteins (PrPs) were produced in rabbits. The synthetic peptides used represent two mouse (Mo-I: residues 100-115 and Mo-V: residues 199-208) and two hamster PrP subregion sequences (Ha-I: 101-116 and Ha-V: 200-209). All antisera reacted strongly with homologous peptides but either not at all or poorly with heterologous peptides in enzymelinked immunosorbent assay (ELISA). Antisera to Mo-I and Mo-V recognized mouse PrPSc but not hamster PrpSc in western blot analysis (WB) and ELISA. Antisera to Ha-I contain antibodies specific to hamster PrPSc. The results indicate that these regions of PrPSc constitute species-specific epitopes. In contrast to these antisera, the antiserum to Ha-V recognized neither hamster nor mouse PrPSc. In this study, we identified mouse subregion-V as a species-specific epitope.

Amyloid fibrils in GSS express only PrP peptides encoded by the mutant allele

Tagliavini F; Prelli F; Porro M; Rossi G; Giaccone G; Farlow MR; Dlouhy SR; Ghetti B; Bugiani O; Frangione B 
Istituto Nazionale Neurologico Carlo Besta, Milano, Italy
 Cell, 79: 4, 1994 Nov 18, 695-703 
Gerstmann-Str”ussler-Scheinker (GSS) disease is a cerebral amyloidosis linked to mutations of the PRNP gene. We previously reported that the amyloid protein in the Indiana kindred of GSS is an internal fragment of prion protein (PrP). To investigate whether this fragment originates only from mutant or from both mutant and wild-type PrP, we have characterized amyloid proteins purified from patients of the Indiana and Swedish GSS families. These patients were heterozygous for the Met-Val polymorphism at PRNP codon 129 and carried a mutation at PRNP codon 198 (Phe-->Ser) and codon 217 (Gln-->Arg), respectively. The smallest amyloid subunit was a 7 kDa peptide spanning residues approximately 81 to approximately 150 in the Indiana patient and approximately 81 to approximately 146 in the Swedish patient. In both patients, only Val was present at position 129. Since Val-129 was in coupling phase with Ser-198 and Arg-217, our findings indicate that only the mutant PrP is involved in amyloid formation in both kindreds.

Developmental expression of the prion protein gene in glial cells

Moser M; Colello RJ; Pott U; Oesch B Brain Research Institute, University of Zurich, Switzerland
Neuron, 14: 3, 1995 Mar, 509-17
Replication of prions is dependent on the presence of the host protein PrPc. During the course of disease, PrPc is converted into an abnormal isoform,PrPSc, which accumulates in the brain. Attempts to identify the cell type(s) in which prion replication and PrP conversion occur have reachedconflicting results. Although PrP mRNA is present in high amounts in neurons throughout the life of the animal, PrPSc initially accumulates in astrocytesand possibly other glial cells and, later in the course of the disease, spreads diffusely in the tissue, often in white matter. We report here that PrP mRNAis expressed not only in neurons but also in astrocytes and oligodendrocytes throughout the brain of postnatal hamsters and rats. The level of glial PrpmRNA expression in neonatal animals was comparable to that of neurons and increased two-fold during postnatal development. A substantial portion ofbrain PrP mRNA is therefore contributed by glial cells. Our results provide an explanation for the accumulation of PrPSc in white matter tissue and inthe cytoplasm of glial cells and argue for a direct involvement of glia in prion propagation.

Cholesterol depletion and terminal targeting sequence of the prion protein inhibit scrapie y

Taraboulos A; Scott M; Semenov A; Avrahami D; Laszlo L; Prusiner SB; Avraham D [corrected to Avrahami D] Department of Neurology, University of California, San Francisco 94143
J Cell Biol, 129: 1, 1995 Apr, 121-32  [publishederratum appears in J Cell Biol 1995 Jul;130(2):501] 
After the cellular prion protein (PrPC) transits to the cell surface where it is bound by a glycophosphatidyl inositol (GPI) anchor, PrPC is eithermetabolized or converted into the scrapie isoform (PrPSc). Because most GPI-anchored proteins are associated with cholesterol-rich membranousmicrodomains, we asked whether such structures participate in the metabolism of PrPC or the formation of PrPSc. The initial degradation of PrPCinvolves removal of the NH2 terminus of PrPC to produce a 17-kD polypeptide which was found in a Triton X-100 insoluble fraction. Both the formationof PrPSc and the initial degradation of PrPC were diminished by lovastatin-mediated depletion of cellular cholesterol but were insensitive to NH4Cl.Further degradation of the 17-kD polypeptide did occur within an NH4Cl-sensitive, acidic compartment. Replacing the GPI addition signal with thetransmembrane and cytoplasmic domains of mouse CD4 rendered chimeric CD4PrPC soluble in cold Triton X-100. Both CD4PrPC and truncated PrPCwithout the GPI addition signal (Rogers, M., F. Yehieley, M. Scott, and S. B. Prusiner. 1993. Proc. Natl. Acad. Sci. USA. 90:3182-3186) were poorsubstrates for PrPSc formation. Thus, it seems likely that both the initial degradation of PrPC to the 17-kD polypeptide and the formation of PrPSc occurwithin a non-acidic compartment bound by cholesterol-rich membranes, possibly glycolipid-rich microdomains, where the metabolic fate of PrPC isdetermined. The pathway remains to be identified by which the 17-kD polypeptide and PrPSc are transported to an acidic compartment, presumablyendosomes, where the 17-kD polypeptide is hydrolyzed and limited proteolysis of PrPSc produces PrP 27-30.

Die Creutzfeldt-Jakob-Erkrankung

Schnyder H; Aguzzi A Neurologische Klinik, Universit”tsspital Z¸rich
Schweiz Med Wochenschr, 125: 16, 1995 Apr 22, 802-9
Creutzfeldt-Jakob's disease is a transmissible encephalopathy manifesting with dementia and motor disturbances, which usually progresses rapidly and islethal within months. It occurs mainly sporadically, but it can also be transmitted by proteinaceous infective particles called prions. The diagnosis has torely on clinical symptoms, EEG and brain biopsy being the most suitable additional examinations. No therapy is yet known. "Naturally" occurringtransmission has not been observed: all transmitted cases reported so far have been iatrogenic and followed administration of cadaveric hypophysealhormones, transplantation of tissue from CNS or related organs, or brain surgery with contaminated instruments. Remarkable discoveries in the pastdecades with respect to the molecular and genetic characterization of the transmissible pathogen have led to a new understanding of the disease. Theinfective agent appears to be an abnormal isoform of a physiologically occurring protein: the cellular prion (PrPc). The crucial pathogenetic event is theconformational conversion of PrPc into its pathological isoform (PrPsc), an event thought to be triggered autocatalytically by the infectious agent itself.The disease can be elicited in experimental animals by inoculation of PrPsc. In the sporadic cases of Creutzfeldt-Jakob's disease, PrPsc is thought to arisethrough spontaneous conversion of PrPc. A growing body of evidence indicates that specific alleles of the prion gene confer a genetic predisposition toCreutzfeldt-Jakob's disease and to related pathologies.

EncČphalopathies spongiformes humaines

Laplanche JL; Beaudry P; Ripoll L; Launay JM Formation de Recherche AssociČe Claude Bernard, Neurochimie des Communications Cellulaires, HŮpital Saint-Louis, Paris, France
Pathol Biol (Paris), 43: 2, 1995 Feb, 104-13
Transmissible subacute spongiform encephalopathies (TSSE), also known as prion diseases, are rare neurodegenerative disorders of both humans andanimals. The biochemical hallmark of these diseases is an accumulation in the brain of an abnormal form of the host-encoded prion protein (PrP). Thispathological accumulation could result from a protein conformational change under the influence of unknown factors. The normal function of PrP isunknown. The abnormal form is thought to induce neurodegeneration when experimentally or accidentally introduced in recipient hosts. Such a possibilitywould explain the transmissible character of these diseases illustrated in humans by iatrogenic contamination. Considerable attention has been focused onthe host PrP gene and its relation with the genetic susceptibility of humans and animals. Mutations in PRNP, the gene which encodes PrP in humans, arepresent in 16% of the patients and might be causative. In patients without any PRNP mutation, a coding polymorphism (129 Met/Val) defines apredisposing factor. Since few years, important progress in the molecular genetics of TSSE in both humans and animals have been performed and point outthat the development of different forms of these diseases, experimental, iatrogenic or spontaneous, are strongly dependent on the primary structure of thehost PrP.

Le prion, des vaches folles au Creutzfeld-Jakob iatrogËne y

Paul J INSERM ADR 5, Lyon, France
Pathol Biol (Paris), 43: 2, 1995 Feb, 114-20
The long latency time, without any characteristic clinical sign, of transmissible degenerative encephalopathies, the transmissibility of the called "prion"infectious agent, associated with its exceptional resistance to normal inactivation methods, are resulting in accidental transmissions, both human(Creutzfeldt-Jakob disease), and animal (bovine spongiform encephalopathy). Among data about physical and chemical inactivation methods tested, weretain, to avoid professional or iatrogenic transmissions in the laboratory or in hospital, steam autoclaving and sodium hypochlorite or hydroxidetreatment. But inactivation shall not be performed using the current processes as regarding parameters such as temperature, concentration and durationof exposure.

Italian kindred with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Ragno M; Tournier-Lasserve E; Fiori MG; Manca A; Patrosso MC; Ferlini A; Sirocchi G; Trojano L; Chabriat H; Salvi F Division of Neurology, C. & G. Mazzoni Hospital, Ascoli Piceno, Italy
Ann Neurol, 38: 2, 1995 Aug, 231-6
Vascular dementia is usually sporadic and associated with definite risk factors. Several cases also occur in a familial fashion, and may affect middle-agedor even younger subjects. Recently, an autosomal dominant inheritance was demonstrated in two unrelated French families, the members of which wereaffected by stroke-like episodes culminating in progressive dementia. Genetic linkage analysis assigned the disease locus to chromosome 19q12. We reportan additional kindred of Italian origin in which at least 16 subjects presented leukoencephalopathic alterations. Recurrent strokes, psychiatricdisturbances, dementia, and in 2 members, tetraplegia and pseudobulbar palsy were the hallmarks of this syndrome. Notably, 5 asymptomatic individualshad neuroradiological signs of leukoencephalopathy. Pathological examination of 1 subject revealed a widespread vasculopathy of the perforatingarterioles, characterized by deposition of eosinophilic-congophilic material that did not immunostain with antibodies against prion protein,beta-amyloid, cystatin C, transthyretin, or heat-shock protein 70 and was similar to that described in the French families. Based on the maximum lodscore, the most likely location for the disease locus was also mapped to chromosome 19q12, and found to coincide with the CADASIL (cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy) locus. The present results confirm the existence of a nosologically distinct,autosomal dominant cerebrovascular disease, presenting with recurrent subcortical ischemic strokes independent of vascular risk factors.

Creutzfeldt-Jakob disease after liver transplantation

CrČange A; Gray F; Cesaro P; Adle-Biassette H; Duvoux C; Cherqui D; Bell J; Parchi P; Gambetti P; Degos JD Departement de Neurosciences, Centre Hospitalier Universitaire Henri Mondor, CrČteil, France
Ann Neurol, 38: 2, 1995 Aug, 269-72
We report a 57-year-old woman who died from Creutzfeldt-Jakob disease 2 years after a liver transplantation. The liver donor had no history ofneurological disease. In one albumin donor, possible Creutzfeldt-Jakob disease developed 3 years later. The patient initially had cerebellar symptoms.Neuropathology included "Kuru-type" plaques and prion protein (PrP) deposits involving the cerebellum predominantly. The patient was homozygotevaline at codon 129 of the PrP gene while the liver was homozygote methionine. This observation raises the possibility of transmission ofCreutzfeldt-Jakob disease by the graft itself or the associated albumin transfusions and, on a wider extent, by nonneural tissue.

A cellular form of prion protein in non-neuronal tissues of sheep

Horiuchi M; Yamazaki N; Ikeda T; Ishiguro N; Shinagawa M Department of Veterinary Public Health, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan
J Gen Virol, 76 ( Pt 10):1995 Oct, 2583-7
A cellular form of the prion protein (PrPC) is thought to be a substrate for an abnormal isoform of the prion protein (PrPSc) in scrapie. PrPC isabundant in tissues of the central nervous system, but little is known about the distribution of PrPC in non-neuronal tissues of sheep, the natural host ofscrapie. This study investigated the tissue distribution of PrPC in sheep. Although PrPC was abundant in neuronal tissues, it was detected in non-neuronaltissues such as spleen, lymph node, lung, heart, kidney, skeletal muscle, uterus, adrenal gland, parotid gland, intestine, proventriculus, abomasum andmammary gland. Neither PrPC nor PrP mRNA was detected in the liver. The tissue distribution of PrPC appears to be inconsistent with the tissues whichpossess scrapie infectivity, suggesting that factor(s) specific to certain cell types may be required to support multiplication of the scrapie agent.

Neuronal cell death in scrapie-infected mice is due to apoptosis

Giese A; Groschup MH; Hess B; Kretzschmar HA Department of Neuropathology, University of G–ttingen, Germany
Brain Pathol, 5: 3, 1995 Jul, 213-21
Neuronal loss is a salient yet poorly understood feature in the pathology of transmissible spongiform encephalopathies (prion diseases). Cell cultureexperiments with neurotoxic prion protein fragments suggest that neuronal cell death in these diseases may be due to apoptosis. To test this hypothesis invivo we used the in situ end-labeling (ISEL) technique and electron microscopy to study cell death in an experimental scrapie system in the mouse. ISEL,which relies on the incorporation of labeled nucleotides in fragmented DNA by terminal transferase, showed labeled nuclei in the brains and retinae ofmice infected with the 79A strain of scrapie, whereas no labeling was observed in control animals. In the retina the highest numbers of labeled nucleiwere found in the outer nuclear layer 120 days post infection followed by massive cell loss in this layer. In the brain, labeled nuclei were mainly found inthe granular layer of the cerebellum of terminally ill mice. This corresponded to the presence of small dark nuclei with condensed and occasionallyfragmented chromatin at the light and electron microscopical levels. Our results support the hypothesis that neuronal loss in spongiform encephalopathiesis due to apoptosis. This may explain the almost complete absence of inflammatory response in prion diseases in the face of widespread neuronal cell death,and may also have therapeutic implications in the future.

Detection of apoptosis in murine scrapie

Lucassen PJ; Williams A; Chung WC; Fraser H Graduate School of Neurosciences Amsterdam, Netherlands Institute for Brain Research, The Netherlands
Neurosci Lett, 198: 3, 1995 Oct 6, 185-8
In order to determine whether apoptosis contributes to the neuronal loss in scrapie, in situ end labeling was applied on brains of mice showing clinicalsigns of the disease. Positively labeled, apoptotic neurons were observed in the cerebellum, cerebral cortex and hippocampus, areas known to showcharacteristic scrapie-related vacuolation, and were absent in the brains of control mice. We conclude that apoptosis plays a role in the neuronal loss thatoccurs in scrapie. The importance of apoptosis as a predominant cell death mechanism in scrapie, however, remains to be determined.

Role of microglia and host prion protein in neurotoxicity of a prion fragment

Brown DR; Schmidt B; Kretzschmar HA Institut f¸r Neuropathologie, Universit”t G–ttingen, Germany
Nature, 380: 6572, 1996 Mar 28, 345-7
The prion protein PrPc is a glycoprotein of unknown function normally found in neurons and glia. It is involved in diseases such as bovine spongiformencephalopathy (BSE), scrapie and Creutzfeldt-Jakob disease. PrPSc, an altered isoform of PrPC that is associated with disease, shows greater proteaseresistance and is part of the infectious agent, the prion. Prion diseases are characterized by neuronal degeneration, gliosis and accumulation of PrPSc.Mice devoid of PrPC are resistant to scrapie. A fragment of human PrP consisting of amino acids 106-126 that forms fibrils in vitro is toxic to culturedneurons. Here we show that this toxic effect requires the presence of microglia which respond to PrP106-126 by increasing their oxygen radicalproduction. The combined direct and microglia-mediated effects of PrP106-126 are toxic to normal neurons but are insufficient to destroy neurons frommice not expressing PrPC.