- San Diego, California, United States
Adriano Aguzzi
Universitätsspital Zürich, Pathology, Faculty Member
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Recombinant immune interferon (IFN-gamma) induced a dose-related increase in the synthesis and expression of HLA class II antigens by the cultured melanoma cells COLO 38. Although IFN-gamma-treated melanoma cells COLO 38 continue to... more
Recombinant immune interferon (IFN-gamma) induced a dose-related increase in the synthesis and expression of HLA class II antigens by the cultured melanoma cells COLO 38. Although IFN-gamma-treated melanoma cells COLO 38 continue to express higher levels of HLA-DR antigens than of HLA-DQ antigens, the effect of IFN-gamma was more marked on HLA-DQ antigens than on HLA-DR antigens, as indicated by the dose and incubation time required to induce the changes and by the extent and duration of the increase. The effect of IFN-gamma on HLA class II antigens is significantly higher than that of leukocyte and fibroblast interferons. Analysis by one- and two-dimensional gel electrophoresis of antigens synthesized by melanoma cells COLO 38 in the presence of IFN-gamma did not detect any significant change in the structural profile of the subunits of HLA-DR and -DQ antigens.
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Research Interests: Biochemistry, Genetics, Neuroscience, Immunology, Structural Biology, and 22 moreStructure, RNA, Electronics, Plant Biology, Cell Cycle, Immunohistochemistry, Cell Biology, Signal Transduction, Biological Sciences, Brain, Mice, Animals, Cell Death, Cell Signalling, Proteins, Prions, Time Factors, Purkinje Cells, Ataxia, Knockout Mice, Full Length Movies, and Purkinje cell
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Research Interests: Protein Folding, Prion Diseases, Humans, Mice, Animals, and 4 morePrion, Phenotype, Prions, and Prion Protein
The cellular prion protein (PrP(c)), tissue-type plasminogen activator (t-PA) and plasminogen are expressed in synaptic membranes in vivo. In the central nervous system the fibrinolytic system is associated with excitotoxin-mediated... more
The cellular prion protein (PrP(c)), tissue-type plasminogen activator (t-PA) and plasminogen are expressed in synaptic membranes in vivo. In the central nervous system the fibrinolytic system is associated with excitotoxin-mediated neurotoxicity and Alzheimer's disease. Recently binding of the disease associated isoform of the prion protein (PrP(Sc)) to plasminogen and stimulation of t-PA activity have been reported. In this study the interaction of PrP(c) and plasminogen was investigated using chromogenic assays in vitro. We found that plasmin is able to cleave recombinant PrP(c) at lysine residue 110 generating an NH(2)-terminal truncated molecule that has previously been described as a major product of PrP(c) metabolism. We further characterized the proteolytic fragments with respect to their ability to stimulate plasminogen activation in vitro. Our results show that the NH(2)-terminal part of PrP(c) spanning amino acids 23-110 (PrP23-110) together with low molecular weight ...
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Spongiform encephalopathies are infectious neurodegenerative diseases caused by pathogens that seem to be devoid of any informational nucleic acids. Histopathologically, these diseases are characterized by spongiform degeneration of the... more
Spongiform encephalopathies are infectious neurodegenerative diseases caused by pathogens that seem to be devoid of any informational nucleic acids. Histopathologically, these diseases are characterized by spongiform degeneration of the central nervous system. Although the main pathological changes during the course of the disease occur in the brain, the infectious agent accumulates early in lymphoid tissue. The consecutive development of clinical disease depends on the presence of an intact immune system including mature B-cells and follicular dendritic cells. In this article we review the state of knowledge on the routes of neuroinvasion used by the infectious agent in order to gain access to the central nervous system upon entry into extracerebral sites.
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Research Interests: Biological Chemistry, Molecular Genetics, STEROIDS, Gene expression, Signal Transduction, and 23 moreCell Differentiation, Humans, Mutagenesis, Mutation, Mice, Aldosterone, Renin Angiotensin Aldosterone System, Animals, Biological, HPA axis, Lung, Transcription Factor, Gene Structure, Enzyme, Clinical Sciences, Lung Development, Adrenal cortex, Genetic Recombination, Homologous Recombination, Binding Site, Glucocorticoids, Biochemistry and cell biology, and Adrenal Medulla
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Recent data on the immunolocalization of regulatory peptides and related propeptide sequences in endocrine cells and tumors of the gastrointestinal tract, pancreas, lung, thyroid, pituitary (ACTH and opioids), adrenals and paraganglia... more
Recent data on the immunolocalization of regulatory peptides and related propeptide sequences in endocrine cells and tumors of the gastrointestinal tract, pancreas, lung, thyroid, pituitary (ACTH and opioids), adrenals and paraganglia have been revised and discussed. Gastrin, xenopsin, cholecystokinin (CCK), somatostatin, motilin, secretin, GIP (gastric inhibitory polypeptide), neurotensin, glicentin/glucagon-37 and PYY (peptide tyrosine tyrosine) are the main products of gastrointestinal endocrine cells; glucagon, CRF (corticotropin releasing factor), somatostatin, PP (pancreatic polypeptide) and GRF (growth hormone releasing factor), in addition to insulin, are produced in pancreatic islet cells; bombesin-related peptides are the main markers of pulmonary endocrine cells; calcitonin and CGRP (calcitonin gene-related peptide) occur in thyroid and extrathyroid C cells; ACTH and endorphins in anterior and intermediate lobe pituitary cells, alpha-MSH and CLIP (corticotropin-like intermediate lobe peptide) in intermediate lobe cells; met- and leu-enkephalins and related peptides in adrenal medullary and paraganglionic cells as well as in some gut (enterochromaffin) cells; NPY (neuropeptide Y) in adrenaline-type adrenal medullary cells, etc.. Both tissue-appropriate and tissue-inappropriate regulatory peptides are produced by endocrine tumours, with inappropriate peptides mostly produced by malignant tumours.
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Oligomers of the amyloid-β peptide (Aβ) play a central role in the pathogenesis of Alzheimer's disease and have been suggested to... more
Oligomers of the amyloid-β peptide (Aβ) play a central role in the pathogenesis of Alzheimer's disease and have been suggested to induce neurotoxicity by binding to a plethora of cell-surface receptors. However, the heterogeneous mixtures of oligomers of varying sizes and conformations formed by Aβ42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single-molecule imaging to characterize Aβ42 oligomers (oAβ42) and to confirm the controversial interaction of oAβ42 with the cellular prion protein (PrP(C)) on live neuronal cells. Our results show that, at nanomolar concentrations, oAβ42 interacts with PrP(C) and that the species bound to PrP(C) are predominantly small oligomers (dimers and trimers). Single-molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor-mediated oAβ-induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways.
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Prions cause neurodegeneration in vivo, yet prion-infected cultured cells do not show cytotoxicity. This has hampered mechanistic studies of prion-induced neurodegeneration. Here we report that prion-infected cultured organotypic... more
Prions cause neurodegeneration in vivo, yet prion-infected cultured cells do not show cytotoxicity. This has hampered mechanistic studies of prion-induced neurodegeneration. Here we report that prion-infected cultured organotypic cerebellar slices (COCS) experienced progressive spongiform neurodegeneration closely reproducing prion disease, with three different prion strains giving rise to three distinct patterns of prion protein deposition. Neurodegeneration did not occur when PrP was genetically removed from neurons, and a comprehensive pharmacological screen indicated that neurodegeneration was abrogated by compounds known to antagonize prion replication. Prion infection of COCS and mice led to enhanced fodrin cleavage, suggesting the involvement of calpains or caspases in pathogenesis. Accordingly, neurotoxicity and fodrin cleavage were prevented by calpain inhibitors but not by caspase inhibitors, whereas prion replication proceeded unimpeded. Hence calpain inhibition can uncouple prion replication from its neurotoxic sequelae. These data validate COCS as a powerful model system that faithfully reproduces most morphological hallmarks of prion infections. The exquisite accessibility of COCS to pharmacological manipulations was instrumental in recognizing the role of calpains in neurotoxicity, and significantly extends the collection of tools necessary for rigorously dissecting prion pathogenesis.
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Research Interests: Biological Sciences, Dogs, Cell line, Humans, Sequence alignment, and 6 moreMice, Animals, Vaccine, Prions, Amino Acid Sequence, and Scrapie
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Research Interests: Genetics, Infant Toddler Care, Twins, Pregnancy, Humans, and 26 moreMutation, Mice, Sex ratio, Female, Animals, Male, Infant, Etiology, Pedigree, Posture, Clinical Sciences, Newborn Infant, Doxorubicin, Oncogenes, Rats, Adult, Esophagus, Sex Factors, Neurobiology of Aging, Rabbits, Environment, Neurosciences, Brain Neoplasms, Maternal Exposure, ENVIRONMENTAL SCIENCE AND MANAGEMENT, and Acetabulum
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Research Interests: Electron Microscopy, Stem Cells, Cell Biology, In Situ Hybridization, Biological Sciences, and 18 moreBrain, Capillaries, Mice, Animals, Spinal Cord, Polymerase Chain Reaction, Astrocyte, Central Nervous System, Neurons, Molecular cloning, Degeneration, Amino Acid Sequence, Base Sequence, Cerebellar Cortex, Extracellular Matrix Proteins, Motor activity, Brain stem, and Vacuoles
Research Interests: Physiology, Animal Behavior, Neuronal cell death, Cell line, Cerebellum, and 16 moreMice, Animals, Cell Death, Life Expectancy, Medical Physiology, Neurons, Phenotype, Caspase, Prion disease, Oxidative Damage, Degeneration, Protein isoforms, Knockout Mice, Biochemistry and cell biology, Motor activity, and Prion Protein
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Research Interests: Stem Cells, Biological Sciences, Spleen, Brain, Mice, and 7 moreAnimals, T lymphocytes, Prions, B Lymphocytes, Lymphocytes, Leukocytes, and Scrapie
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Conformational transitions of the cellular form of the prion protein, PrP(C), into an infectious isoform, PrP(Sc), are considered to be central events in the progression of fatal neurodegenerative diseases known as transmissible... more
Conformational transitions of the cellular form of the prion protein, PrP(C), into an infectious isoform, PrP(Sc), are considered to be central events in the progression of fatal neurodegenerative diseases known as transmissible spongiform encephalopathies. Tricyclic phenothiazine compounds exhibit antiprion activity; however, the underlying molecular mechanism of PrP(Sc) inhibition remains elusive. We report the molecular structures of two phenothiazine compounds, promazine and chlorpromazine bound to a binding pocket formed at the intersection of the structured and the unstructured domains of the mouse prion protein. Promazine binding induces structural rearrangement of the unstructured region proximal to β1, through the formation of a "hydrophobic anchor." We demonstrate that these molecules, promazine in particular, allosterically stabilize the misfolding initiator-motifs such as the C terminus of α2, the α2-α3 loop, as well as the polymorphic β2-α2 loop. Hence, the stabilization effects of the phenothiazine derivatives on initiator-motifs induce a PrP(C) isoform that potentially resists oligomerization.
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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... more
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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The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to... more
The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the Abeta peptide, whereas PrPC begets the malignant prion protein PrPSc. Both Abeta and PrPSc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa.
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A 46-year-old white female was admitted for decompensated cor pulmonale (CP). It had not interfered with her daily activities and she had not experienced shortness of breath, fatigue or muscle weakness prior to the onset of right heart... more
A 46-year-old white female was admitted for decompensated cor pulmonale (CP). It had not interfered with her daily activities and she had not experienced shortness of breath, fatigue or muscle weakness prior to the onset of right heart failure. A thorough investigation revealed severe generalized muscle weakness with restrictive chest bellows disease and secondary CP (mean pressure in the pulmonary artery 60 mm Hg). After having refused respiratory support the patient died a few days after admission. The muscle biopsy was consistent with adult-onset acid-maltase deficiency. This is a rare case of metabolic myopathy presenting as decompensated CP without previous symptoms of muscle weakness. This condition can easily be treated with nocturnal ventilatory support, improving the quality and length of life.
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Research Interests: Multidisciplinary, Prion Diseases, Mice, Female, Animals, and 3 moreMale, Amyloidosis, and Brain Diseases
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The Prnp gene encodes the cellular prion protein PrP(C). Removal of its ORF does not result in pathological phenotypes, but deletions extending into the upstream intron result in cerebellar degeneration, possibly because of ectopic... more
The Prnp gene encodes the cellular prion protein PrP(C). Removal of its ORF does not result in pathological phenotypes, but deletions extending into the upstream intron result in cerebellar degeneration, possibly because of ectopic cis-activation of the Prnd locus that encodes the PrP(C) homologue Doppel (Dpl). To test this hypothesis, we removed Prnd from Prnp(o/o) mice by transallelic meiotic recombination. Balanced loxP-mediated ablation yielded mice lacking both PrP(C) and Dpl (Prn(o/o)), which developed normally and showed unimpaired immune functions but suffered from male infertility. However, removal of the Prnd locus abolished cerebellar degeneration, proving that this phenotype is caused by Dpl upregulation. The absence of compound pathological phenotypes in Prn(o/o) mice suggests the existence of alternative compensatory mechanisms. Alternatively, Dpl and PrP(C) may exert distinct functions despite having partly overlapping expression profiles.