20 results on '"Glatzel M"'
Search Results
2. Myositis facilitates preclinical accumulation of pathological prion protein in muscle.
- Author
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Neumann M, Krasemann S, Schröck K, Steinbach K, and Glatzel M
- Subjects
- Animals, Blotting, Western, Disease Progression, Immunohistochemistry, Mice, Inbred C57BL, Mice, Knockout, Prion Proteins, Prions genetics, Prions metabolism, Radiation Chimera, Time Factors, Muscles metabolism, Nervous System Autoimmune Disease, Experimental metabolism, PrPSc Proteins metabolism
- Abstract
Background: In human and animal prion diseases, pathological prion protein, PrPSc, as well as prion infectivity is mainly found in the central nervous system, but also in lymphoid organs and muscle. Pathophysiology of prion colonization of lymphoid organs has been studied intensively, yet how myositis influences prion accumulation in muscle is unknown., Result: We have investigated the influence of myositis on PrPSc accumulation and prion infectivity in two distinct mouse models of experimental autoimmune myositis. Furthermore, we have addressed the relevance of PrPC expression in the lymphoreticular system in myositis by generating bone marrow chimeras.Here we show that myositis positively influences muscular PrPSc accumulation at preclinical time points and that PrPC-expression in the lymphoid system is critical for this. In muscle, PrPSc and prion infectivity are uncoupled with detectable PrPSc but no prion infectivity at preclinical time points. Muscle has an intrinsically high ability to clear PrPSc once myositis has ceased, possibly involving autophagy., Conclusion: Our findings provide new insights into the pathophysiology of prion colonization in muscle pointing out that myositis leads to enhanced prion colonization of muscle in subclinical prion disease.
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- 2013
- Full Text
- View/download PDF
3. Roles of endoproteolytic α-cleavage and shedding of the prion protein in neurodegeneration.
- Author
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Altmeppen HC, Prox J, Puig B, Dohler F, Falker C, Krasemann S, and Glatzel M
- Subjects
- ADAM Proteins genetics, ADAM10 Protein, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid Precursor Protein Secretases genetics, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Cell Line, Humans, Membrane Proteins genetics, PrPC Proteins genetics, PrPSc Proteins genetics, Prion Diseases genetics, Prion Diseases pathology, Protein Conformation, Protein Folding, Proteolysis, Signal Transduction, ADAM Proteins metabolism, Alzheimer Disease enzymology, Amyloid Precursor Protein Secretases metabolism, Membrane Proteins metabolism, PrPC Proteins metabolism, PrPSc Proteins metabolism, Prion Diseases enzymology, Protein Processing, Post-Translational
- Abstract
The cellular prion protein (PrP(C)) plays important roles in neurodegenerative diseases. First, it is the well-established substrate for the conformational conversion into its pathogenic isoform (PrP(Sc)) giving rise to progressive and fatal prion diseases. Moreover, several recent reports highlight important roles of PrP(C) in other neurodegenerative conditions such as Alzheimer's disease. Since PrP(C) is subject to proteolytic processing, here we discuss the two main cleavage events under physiological conditions, α-cleavage and shedding. We focus on how these cleavages and the resulting fragments may impact prion diseases as well as other neurodegenerative proteinopathies. Finally, we discuss the recently identified sheddase of PrP(C), namely the metalloprotease ADAM10, with regard to therapeutic potential against neurodegenerative diseases., (© 2013 The Authors Journal compilation © 2013 FEBS.)
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- 2013
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4. Preclinical deposition of pathological prion protein in muscle of experimentally infected primates.
- Author
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Krasemann S, Neumann M, Geissen M, Bodemer W, Kaup FJ, Schulz-Schaeffer W, Morel N, Aguzzi A, and Glatzel M
- Subjects
- Animals, Blotting, Western, Brain metabolism, Macaca mulatta, Myocardium metabolism, Prion Diseases pathology, Tongue metabolism, Muscles metabolism, PrPSc Proteins metabolism, Prion Diseases metabolism
- Abstract
Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc)) of the host encoded prion protein (PrP(C)) in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc) in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc) in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD), variant CJD (vCJD) and bovine spongiform encephalopathy (BSE) in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc) in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.
- Published
- 2010
- Full Text
- View/download PDF
5. Association between deposition of beta-amyloid and pathological prion protein in sporadic Creutzfeldt-Jakob disease.
- Author
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Debatin L, Streffer J, Geissen M, Matschke J, Aguzzi A, and Glatzel M
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Protein Precursor analysis, Amyloid beta-Protein Precursor genetics, Blotting, Western, Creutzfeldt-Jakob Syndrome genetics, Enzyme-Linked Immunosorbent Assay, Female, Frontal Lobe chemistry, Frontal Lobe pathology, Humans, Immunohistochemistry, Male, Middle Aged, Polymerase Chain Reaction, Presenilin-1 analysis, Presenilin-1 genetics, Presenilin-2 analysis, Presenilin-2 genetics, Prion Proteins, Prions analysis, Prions genetics, Protease Nexins, Receptors, Cell Surface analysis, Receptors, Cell Surface genetics, Amyloid beta-Peptides analysis, Brain Chemistry, Creutzfeldt-Jakob Syndrome metabolism, Creutzfeldt-Jakob Syndrome pathology, Peptide Fragments analysis, PrPSc Proteins analysis
- Abstract
Background: Alzheimer's disease (AD) and prion diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) share common features concerning their molecular pathogenesis and neuropathological presentation and the coexistence of AD and CJD in patients suggest an association between the deposition of the proteolytically processed form of the amyloid precursor protein, beta-amyloid (Abeta), which deposits in AD, and the abnormal form of the prion protein, PrP(Sc), which deposits in sCJD., Methods: We have characterized sCJD patients (n = 14), AD patients (n = 5) and nondemented controls (n = 5) with respect to the deposition of PrP(Sc) and Abeta morphologically, biochemically and genetically and correlated these findings to clinical data., Results: sCJD-diseased individuals with abundant deposits of Abeta present with a specific clinicopathological profile, defined by higher age at disease onset, long disease duration, a genetic profile and only minimal amounts of PrP(Sc) in the cerebellum., Conclusion: The co-occurrence of pathological changes typical for sCJD and AD in combination with the inverse association between accumulation of Abeta and PrP(Sc) in a subgroup of sCJD patients is indicative of common pathways involved in the generation or clearance of Abeta and PrP(Sc) in a subgroup of sCJD patients., (Copyright 2008 S. Karger AG, Basel.)
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- 2008
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6. Analysis of prion strains by PrPSc profiling in sporadic Creutzfeldt-Jakob disease.
- Author
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Schoch G, Seeger H, Bogousslavsky J, Tolnay M, Janzer RC, Aguzzi A, and Glatzel M
- Subjects
- Aged, Amino Acid Substitution, Biopsy, Blotting, Western, Brain pathology, Cohort Studies, Creutzfeldt-Jakob Syndrome diagnosis, Creutzfeldt-Jakob Syndrome pathology, Diagnosis, Differential, Electrophoresis, Polyacrylamide Gel, Female, Humans, Male, Middle Aged, Polymorphism, Genetic, PrPC Proteins, PrPSc Proteins genetics, Reference Values, Reproducibility of Results, Sensitivity and Specificity, Creutzfeldt-Jakob Syndrome genetics, PrPSc Proteins analysis
- Abstract
Background: Prion diseases are a group of invariably fatal neurodegenerative disorders affecting humans and a wide range of mammals. An essential part of the infectious agent, termed the prion, is composed of an abnormal isoform (PrPSc) of a host-encoded normal cellular protein (PrPC). The conversion of PrPC to PrPSc is thought to play a crucial role in the development of prion diseases and leads to PrPSc deposition, mainly in the central nervous system. Sporadic Creutzfeldt-Jakob disease (sCJD), the most common form of human prion disease, presents with a marked clinical heterogeneity. This diversity is accompanied by a molecular signature which can be defined by histological, biochemical, and genetic means. The molecular classification of sCJD is an important tool to aid in the understanding of underlying disease mechanisms and the development of therapy protocols. Comparability of classifications is hampered by disparity of applied methods and inter-observer variability., Methods and Findings: To overcome these difficulties, we developed a new quantification protocol for PrPSc by using internal standards on each Western blot, which allows for generation and direct comparison of individual PrPSc profiles. By studying PrPSc profiles and PrPSc type expression within nine defined central nervous system areas of 50 patients with sCJD, we were able to show distinct PrPSc distribution patterns in diverse subtypes of sCJD. Furthermore, we were able to demonstrate the co-existence of more than one PrPSc type in individuals with sCJD in about 20% of all patients and in more than 50% of patients heterozygous for a polymorphism on codon 129 of the gene encoding the prion protein (PRNP)., Conclusion: PrPSc profiling represents a valuable tool for the molecular classification of human prion diseases and has important implications for their diagnosis by brain biopsy. Our results show that the co-existence of more than one PrPSc type might be influenced by genetic and brain region-specific determinants. These findings provide valuable insights into the generation of distinct PrPSc types.
- Published
- 2006
- Full Text
- View/download PDF
7. Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease.
- Author
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Polymenidou M, Stoeck K, Glatzel M, Vey M, Bellon A, and Aguzzi A
- Subjects
- Antibodies, Monoclonal immunology, Antibodies, Monoclonal metabolism, Blotting, Western methods, Brain drug effects, Brain pathology, Creutzfeldt-Jakob Syndrome classification, Densitometry methods, Dose-Response Relationship, Drug, Endopeptidase K pharmacology, Enzyme-Linked Immunosorbent Assay methods, Epitope Mapping methods, Epitopes immunology, Epitopes metabolism, Female, Humans, Hydrogen-Ion Concentration, Immunohistochemistry methods, Male, PrPSc Proteins classification, PrPSc Proteins immunology, Protein Structure, Tertiary physiology, Surface Plasmon Resonance methods, Brain metabolism, Creutzfeldt-Jakob Syndrome metabolism, PrPSc Proteins metabolism
- Abstract
Background: The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrP(Sc)), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrP(Sc) display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively., Methods: We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrP(Sc)., Findings: We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrP(Sc)-rich brain areas, with a typical PrP(Sc) type 1 migration pattern., Interpretation: The regular coexistence of multiple PrP(Sc) types in patients with CJD casts doubts on the validity of electrophoretic PrP(Sc) mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.
- Published
- 2005
- Full Text
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8. Human prion diseases: molecular and clinical aspects.
- Author
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Glatzel M, Stoeck K, Seeger H, Lührs T, and Aguzzi A
- Subjects
- Animals, Brain metabolism, Brain pathology, Cattle, Creutzfeldt-Jakob Syndrome genetics, Creutzfeldt-Jakob Syndrome metabolism, Creutzfeldt-Jakob Syndrome physiopathology, Encephalopathy, Bovine Spongiform genetics, Encephalopathy, Bovine Spongiform metabolism, Encephalopathy, Bovine Spongiform physiopathology, Humans, PrPC Proteins genetics, PrPSc Proteins genetics, Prion Diseases diagnosis, Brain physiopathology, PrPC Proteins metabolism, PrPSc Proteins metabolism, Prion Diseases classification, Prion Diseases genetics
- Abstract
Compared with that of other human pathogens, the proposed replicative cycle of prions is disarmingly simple. It encompasses misfolding of a single protein, the cellular prion protein (PrPC), into a disease-associated form called PrPSc. This is followed by PrPSc aggregation and possibly fragmentation of aggregates, which may augment the number of replicative units. Although there is no formal proof of the correctness of this model, a wealth of evidence indicates that pathogen-encoded informational nucleic acids are dispensable for prion replication. Despite the simplicity of the replicative process, the human phenotypic range of prion diseases is extremely variable and includes the sporadic, inherited, and acquired forms of Creutzfeldt-Jakob disease. In addition, prion diseases occur in a wide range of animals and can be propagated within and between animal species. The present review article discusses current concepts and controversies surrounding the basic biological features of prions.
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- 2005
- Full Text
- View/download PDF
9. Intrinsic resistance of oligodendrocytes to prion infection.
- Author
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Prinz M, Montrasio F, Furukawa H, van der Haar ME, Schwarz P, Rülicke T, Giger OT, Häusler KG, Perez D, Glatzel M, and Aguzzi A
- Subjects
- Animals, Astrocytes metabolism, Female, Glycosylation, Immunity, Innate, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myelin Basic Protein genetics, Neurons metabolism, Organ Specificity, PrPC Proteins deficiency, PrPC Proteins genetics, Protein Processing, Post-Translational, Recombinant Fusion Proteins metabolism, Schwann Cells metabolism, Scrapie etiology, Tissue Extracts adverse effects, Virulence, Visual Pathways metabolism, Oligodendroglia cytology, PrPC Proteins metabolism, PrPSc Proteins pathogenicity
- Abstract
Within the CNS, the normal form of cellular prion protein (PrP(C)) is expressed on neurons, oligodendrocytes, and astrocytes. The contribution of these cell types to prion replication and pathogenesis is unclear. To assess the role of oligodendrocytes, we expressed PrP(C) under the control of the myelin basic protein (MBP) promoter in mice lacking endogenous PrP(C). PrP(C) was detected in oligodendrocytes and Schwann cells but not in neurons and astrocytes. MBP-PrP mice never developed scrapie after intracerebral, intraperitoneal, or intraocular challenge with scrapie prions. Transgenic brains did not contain protease-resistant prion protein and did not transmit scrapie when inoculated into PrP(C)-overexpressing indicator mice. To investigate whether prion spread within the CNS depends on oligodendrocytic PrP(C), we implanted PrP(C)-overexpressing neuroectodermal grafts into MBP-PrP brains. After intraocular prion inoculation, none of the grafts showed spongiform encephalopathy or prion infectivity. Hence oligodendrocytes do not support cell-autonomous prion replication, establishment of subclinical disease, and neural spread of prions. Prion resistance sets oligodendrocytes aside from both neurons and astrocytes.
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- 2004
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10. Creutzfeldt-Jakob disease and inclusion body myositis: abundant disease-associated prion protein in muscle.
- Author
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Kovacs GG, Lindeck-Pozza E, Chimelli L, Araújo AQ, Gabbai AA, Ströbel T, Glatzel M, Aguzzi A, and Budka H
- Subjects
- Aged, Blotting, Western, Brain metabolism, Creutzfeldt-Jakob Syndrome complications, Creutzfeldt-Jakob Syndrome metabolism, Humans, Immunohistochemistry, Male, Muscle, Skeletal metabolism, Myositis, Inclusion Body complications, Myositis, Inclusion Body metabolism, Polymerase Chain Reaction, PrPC Proteins metabolism, Brain pathology, Creutzfeldt-Jakob Syndrome pathology, Muscle, Skeletal pathology, Myositis, Inclusion Body pathology, PrPSc Proteins metabolism
- Abstract
Pathologicalprion protein (PrP(Sc)) is the hallmark of prion diseases affecting primarily the central nervous system. Using immunohistochemistry, paraffin-embedded tissue blot, and Western blot, we demonstrated abundant PrP(Sc) in the muscle of a patient with sporadic Creutzfeldt-Jakob disease and inclusion body myositis. Extraneural PrP(C)-PrP(Sc) conversion in Creutzfeldt-Jakob disease appears to become prominent when PrP(C) is abundantly available as substrate, as in inclusion body myositis muscle.
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- 2004
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11. Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease.
- Author
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Glatzel M, Abela E, Maissen M, and Aguzzi A
- Subjects
- Blotting, Western, Brain metabolism, Brain pathology, Creutzfeldt-Jakob Syndrome pathology, Humans, Muscle, Skeletal pathology, Prions genetics, Spleen pathology, Creutzfeldt-Jakob Syndrome metabolism, Muscle, Skeletal metabolism, PrPSc Proteins metabolism, Spleen metabolism
- Abstract
Background: In patients with sporadic Creutzfeldt-Jakob disease, pathologic disease-associated prion protein (PrPSc) has been identified only in the central nervous system and olfactory-nerve tissue. Understanding the distribution of PrPSc in Creutzfeldt-Jakob disease is important for classification and diagnosis and perhaps even for prevention., Methods: We used a highly sensitive method of detection--involving the concentration of PrPSc by differential precipitation with sodium phosphotungstic acid, which increased the sensitivity of Western blot analysis by up to three orders of magnitude--to search for PrPSc in extraneural organs of 36 patients with sporadic Creutzfeldt-Jakob disease who died between 1996 and 2002., Results: PrPSc was present in the brain tissue of all patients. In addition, we found PrPSc in 10 of 28 spleen specimens and in 8 of 32 skeletal-muscle samples. Three patients had PrPSc in both spleen and muscle specimens. Patients with extraneural PrPSc had a significantly longer duration of disease and were more likely to have uncommon molecular variants of sporadic Creutzfeldt-Jakob disease than were patients without extraneural PrPSc., Conclusions: Using sensitive techniques, we identified extraneural deposition of PrPSc in spleen and muscle samples from approximately one third of patients who died with sporadic Creutzfeldt-Jakob disease. Extraneural PrPSc appears to correlate with a long duration of disease., (Copyright 2003 Massachusetts Medical Society)
- Published
- 2003
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12. Clinical and radiological mimicry of vCJD in a valine homozygous PrP(Sc) type 1 sCJD patient.
- Author
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Rossetti AO, Glatzel M, Aguzzi A, Janzer R, and Bogousslavsky J
- Subjects
- Age of Onset, Autopsy, Brain pathology, Codon, Creutzfeldt-Jakob Syndrome complications, Creutzfeldt-Jakob Syndrome diagnosis, Diagnosis, Differential, Female, Humans, Magnetic Resonance Imaging, Mental Disorders etiology, Middle Aged, Creutzfeldt-Jakob Syndrome pathology, PrPSc Proteins genetics
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- 2003
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13. Sympathetic prions.
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Glatzel M and Aguzzi A
- Subjects
- Animals, Mice, Peripheral Nerves pathology, Scrapie chemically induced, Scrapie pathology, Sympathetic Nervous System pathology, PrPSc Proteins toxicity, Scrapie etiology, Sympathetic Nervous System physiopathology
- Abstract
Transmissible spongiform encephalopathies are a group of invariably fatal neurodegenerative diseases. The infectious agent is termed prion and is thought to be composed of a modified protein (PrP Sc or Pr PRES ), a protease-resistant conformer of the normal host-encoded membrane glycoprotein, PrP C. Bovine spongiform encephalopathy, scrapie of sheep, and Creutzfeldt-Jakob disease are among the most notable transmissible spongiform encephalopathies. Prions are most efficiently propagated trough intracerebral inoculation, yet the entry point of the infectious agent is often through peripheral sites like the gastrointestinal tract. The process by which prions invade the brain is termed neuroinvasion. We and others have speculated that, depending on the amount of infectious agent injected, the injection site, and the strain of prions employed, neuroinvasion can occur either directly via peripheral nerves or first through the lymphoreticular system and then via peripheral nerves.
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- 2001
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14. Plasminogen binds to disease-associated prion protein of multiple species.
- Author
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Maissen M, Roeckl C, Glatzel M, Goldmann W, and Aguzzi A
- Subjects
- Animals, Cattle, Humans, Immunomagnetic Separation, Mice, Sheep, Brain metabolism, Creutzfeldt-Jakob Syndrome metabolism, Encephalopathy, Bovine Spongiform metabolism, Plasminogen metabolism, PrPSc Proteins metabolism
- Published
- 2001
- Full Text
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15. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells.
- Author
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Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F, Aguzzi A, and Weissmann C
- Subjects
- Animals, Cell Differentiation genetics, Cell Differentiation immunology, Dendritic Cells, Follicular metabolism, Immunoglobulins genetics, Lymphotoxin beta Receptor, Lymphotoxin-alpha antagonists & inhibitors, Lymphotoxin-alpha genetics, Lymphotoxin-alpha immunology, Mice, Mice, Inbred C57BL, Mice, SCID, PrPSc Proteins administration & dosage, Receptors, Tumor Necrosis Factor antagonists & inhibitors, Receptors, Tumor Necrosis Factor genetics, Receptors, Tumor Necrosis Factor immunology, Recombinant Fusion Proteins administration & dosage, Scrapie immunology, Scrapie metabolism, Signal Transduction genetics, Signal Transduction immunology, Spleen immunology, Spleen metabolism, Virus Replication genetics, Dendritic Cells, Follicular pathology, Dendritic Cells, Follicular virology, PrPSc Proteins biosynthesis, Spleen pathology, Spleen virology, Virus Replication immunology
- Abstract
In scrapie-infected mice, prions are found associated with splenic but not circulating B and T lymphocytes and in the stroma, which contains follicular dendritic cells (FDCs). Formation and maintenance of mature FDCs require the presence of B cells expressing membrane-bound lymphotoxin-alpha/beta. Treatment of mice with soluble lymphotoxin-beta receptor results in the disappearance of mature FDCs from the spleen. We show that this treatment abolishes splenic prion accumulation and retards neuroinvasion after intraperitoneal scrapie inoculation. These data provide evidence that FDCs are the principal sites for prion replication in the spleen.
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- 2000
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16. Sympathetic Prions
- Author
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Glatzel, M., Adriano Aguzzi, University of Zurich, and Glatzel, M
- Subjects
sympathetic nervous system ,PrPSc Proteins ,lcsh:T ,animal diseases ,lcsh:R ,10208 Institute of Neuropathology ,lcsh:Medicine ,610 Medicine & health ,General Medicine ,lcsh:Technology ,General Biochemistry, Genetics and Molecular Biology ,neuroinvasion ,nervous system diseases ,2300 General Environmental Science ,peripheral nerves ,Mice ,1300 General Biochemistry, Genetics and Molecular Biology ,570 Life sciences ,biology ,Animals ,lcsh:Q ,prions ,lcsh:Science ,Directions in Science ,General Environmental Science ,Scrapie - Abstract
Transmissible spongiform encephalopathies are a group of invariably fatal neurodegenerative diseases. The infectious agent is termed prion and is thought to be composed of a modified protein (PrPSc or PrPRES), a protease-resistant conformer of the normal host-encoded membrane glycoprotein, PrPC[1]. Bovine spongiform encephalopathy, scrapie of sheep, and Creutzfeldt-Jakob disease are among the most notable transmissible spongiform encephalopathies. Prions are most efficiently propagated trough intracerebral inoculation, yet the entry point of the infectious agent is often through peripheral sites like the gastrointestinal tract[2,3]. The process by which prions invade the brain is termed neuroinvasion[4]. We and others have speculated that, depending on the amount of infectious agent injected, the injection site, and the strain of prions employed, neuroinvasion can occur either directly via peripheral nerves or first through the lymphoreticular system and then via peripheral nerves[5].
- Published
- 2001
17. Preclinical deposition of pathological prion protein in muscle of experimentally infected primates
- Author
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Nathalie Morel, Franz-Josef Kaup, Susanne Krasemann, Markus Geissen, Markus Glatzel, Walter Bodemer, Walter J. Schulz-Schaeffer, Adriano Aguzzi, Melanie Neumann, University of Zurich, and Glatzel, M
- Subjects
Pathology ,PrPSc Proteins ,animal diseases ,lcsh:Medicine ,Disease ,Macaque ,Prion Diseases ,0302 clinical medicine ,Primate ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,biology ,Transmission (medicine) ,Muscles ,Brain ,3. Good health ,medicine.anatomical_structure ,Research Article ,medicine.medical_specialty ,Bovine spongiform encephalopathy ,Blotting, Western ,Central nervous system ,10208 Institute of Neuropathology ,610 Medicine & health ,1100 General Agricultural and Biological Sciences ,03 medical and health sciences ,Tongue ,Infectious Diseases/Prion Diseases ,1300 General Biochemistry, Genetics and Molecular Biology ,biology.animal ,mental disorders ,medicine ,Animals ,Pathological ,030304 developmental biology ,1000 Multidisciplinary ,Infectious Diseases/Infectious Diseases of the Nervous System ,Myocardium ,lcsh:R ,medicine.disease ,Macaca mulatta ,Virology ,nervous system diseases ,nervous system ,570 Life sciences ,lcsh:Q ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc)) of the host encoded prion protein (PrP(C)) in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc) in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc) in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD), variant CJD (vCJD) and bovine spongiform encephalopathy (BSE) in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc) in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD. peerReviewed
- Published
- 2010
18. Association between deposition of beta-amyloid and pathological prion protein in sporadic Creutzfeldt-Jakob disease
- Author
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Markus Glatzel, Johannes Streffer, Laura Debatin, Jakob Matschke, Markus Geissen, Adriano Aguzzi, University of Zurich, and Glatzel, M
- Subjects
Male ,Pathology ,medicine.medical_specialty ,PrPSc Proteins ,Amyloid ,Prions ,animal diseases ,Blotting, Western ,10208 Institute of Neuropathology ,Enzyme-Linked Immunosorbent Assay ,Receptors, Cell Surface ,610 Medicine & health ,Disease ,Polymerase Chain Reaction ,Creutzfeldt-Jakob Syndrome ,Prion Proteins ,Amyloid beta-Protein Precursor ,Alzheimer Disease ,Presenilin-2 ,mental disorders ,Presenilin-1 ,Humans ,Medicine ,Prion protein ,Beta (finance) ,Pathological ,Aged ,Aged, 80 and over ,Brain Chemistry ,Amyloid beta-Peptides ,business.industry ,Molecular pathogenesis ,Sporadic Creutzfeldt-Jakob disease ,11359 Institute for Regenerative Medicine (IREM) ,Middle Aged ,Immunohistochemistry ,Peptide Fragments ,Frontal Lobe ,nervous system diseases ,Protease Nexins ,2728 Neurology (clinical) ,Neurology ,2808 Neurology ,570 Life sciences ,biology ,Female ,Neurology (clinical) ,business - Abstract
Background: Alzheimer’s disease (AD) and prion diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) share common features concerning their molecular pathogenesis and neuropathological presentation and the coexistence of AD and CJD in patients suggest an association between the deposition of the proteolytically processed form of the amyloid precursor protein, β-amyloid (Aβ), which deposits in AD, and the abnormal form of the prion protein, PrPSc, which deposits in sCJD. Methods: We have characterized sCJD patients (n = 14), AD patients (n = 5) and nondemented controls (n = 5) with respect to the deposition of PrPSc and Aβ morphologically, biochemically and genetically and correlated these findings to clinical data. Results: sCJD-diseased individuals with abundant deposits of Aβ present with a specific clinicopathological profile, defined by higher age at disease onset, long disease duration, a genetic profile and only minimal amounts of PrPSc in the cerebellum. Conclusion: The co-occurrence of pathological changes typical for sCJD and AD in combination with the inverse association between accumulation of Aβ and PrPSc in a subgroup of sCJD patients is indicative of common pathways involved in the generation or clearance of Aβ and PrPSc in a subgroup of sCJD patients.
- Published
- 2008
19. Analysis of prion strains by PrPSc profiling in sporadic Creutzfeldt-Jakob disease
- Author
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Robert C. Janzer, Gaby Schoch, Markus Tolnay, Julien Bogousslavsky, Adriano Aguzzi, Harald Seeger, Markus Glatzel, University of Zurich, and Glatzel, M
- Subjects
Gene isoform ,Male ,PrPSc Proteins ,Biopsy ,animal diseases ,Blotting, Western ,10208 Institute of Neuropathology ,lcsh:Medicine ,610 Medicine & health ,Disease ,2700 General Medicine ,Biology ,Sensitivity and Specificity ,Creutzfeldt-Jakob Syndrome ,PRNP ,Cohort Studies ,Diagnosis, Differential ,Reference Values ,medicine ,Pathology ,Humans ,PrPC Proteins ,Gene ,Aged ,Genetics ,Polymorphism, Genetic ,medicine.diagnostic_test ,Brain biopsy ,lcsh:R ,Brain ,Reproducibility of Results ,General Medicine ,Sporadic Creutzfeldt-Jakob disease ,Middle Aged ,Virology ,nervous system diseases ,Infectious Diseases ,Amino Acid Substitution ,nervous system ,Geriatrics ,Electrophoresis, Polyacrylamide Gel ,Female ,570 Life sciences ,biology ,Research Article ,Neuroscience - Abstract
Background Prion diseases are a group of invariably fatal neurodegenerative disorders affecting humans and a wide range of mammals. An essential part of the infectious agent, termed the prion, is composed of an abnormal isoform (PrPSc) of a host-encoded normal cellular protein (PrPC). The conversion of PrPC to PrPSc is thought to play a crucial role in the development of prion diseases and leads to PrPSc deposition, mainly in the central nervous system. Sporadic Creutzfeldt–Jakob disease (sCJD), the most common form of human prion disease, presents with a marked clinical heterogeneity. This diversity is accompanied by a molecular signature which can be defined by histological, biochemical, and genetic means. The molecular classification of sCJD is an important tool to aid in the understanding of underlying disease mechanisms and the development of therapy protocols. Comparability of classifications is hampered by disparity of applied methods and inter-observer variability. Methods and Findings To overcome these difficulties, we developed a new quantification protocol for PrPSc by using internal standards on each Western blot, which allows for generation and direct comparison of individual PrPSc profiles. By studying PrPSc profiles and PrPSc type expression within nine defined central nervous system areas of 50 patients with sCJD, we were able to show distinct PrPSc distribution patterns in diverse subtypes of sCJD. Furthermore, we were able to demonstrate the co-existence of more than one PrPSc type in individuals with sCJD in about 20% of all patients and in more than 50% of patients heterozygous for a polymorphism on codon 129 of the gene encoding the prion protein (PRNP). Conclusion PrPSc profiling represents a valuable tool for the molecular classification of human prion diseases and has important implications for their diagnosis by brain biopsy. Our results show that the co-existence of more than one PrPSc type might be influenced by genetic and brain region–specific determinants. These findings provide valuable insights into the generation of distinct PrPSc types., Internal standards allow meaningful comparison of PrPSc profiles from different origins. Applying the new method to 50 postmortem samples from patients with sporadic CJD reveals substantial differences in molecular pathology.
- Published
- 2006
20. Human Prion Diseases
- Author
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Harald Seeger, Thorsten Lührs, Katharina Stoeck, Adriano Aguzzi, Markus Glatzel, University of Zurich, and Glatzel, M
- Subjects
PrPSc Proteins ,animal diseases ,10208 Institute of Neuropathology ,Brain ,610 Medicine & health ,Computational biology ,Disease ,Biology ,Phenotype ,Virology ,Creutzfeldt-Jakob Syndrome ,Prion Diseases ,nervous system diseases ,Encephalopathy, Bovine Spongiform ,2728 Neurology (clinical) ,Arts and Humanities (miscellaneous) ,1201 Arts and Humanities (miscellaneous) ,Animals ,Humans ,570 Life sciences ,biology ,Cattle ,PrPC Proteins ,Neurology (clinical) ,Prion protein ,Animal species - Abstract
Compared with that of other human pathogens, the proposed replicative cycle of prions is disarmingly simple. It encompasses misfolding of a single protein, the cellular prion protein (PrPC), into a disease-associated form called PrPSc. This is followed by PrPSc aggregation and possibly fragmentation of aggregates, which may augment the number of replicative units. Although there is no formal proof of the correctness of this model, a wealth of evidence indicates that pathogen-encoded informational nucleic acids are dispensable for prion replication. Despite the simplicity of the replicative process, the human phenotypic range of prion diseases is extremely variable and includes the sporadic, inherited, and acquired forms of Creutzfeldt-Jakob disease. In addition, prion diseases occur in a wide range of animals and can be propagated within and between animal species. The present review article discusses current concepts and controversies surrounding the basic biological features of prions.
- Published
- 2005
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