Clinical and radiological mimicry of vCJD in a valine homozygous PrP(Sc) type 1 sCJD patient.
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Age of Onset↗
Biomedical subjects
Adriano Aguzzi
Publications and source records attributed to Adriano Aguzzi.
Oral prion infection requires normal numbers of Peyer's patches but not of enteric lymphocytes.
Prion pathogenesis following oral exposure is thought to involve gut-associated lymphatic tissue, which includes Peyer's patches (PPs) and M cells. Recruitment of activated B lymphocytes to PPs requires alpha(4)beta(7) integrin; PPs of beta 7(-/-) mice are normal in number but are atrophic and almost entirely devoid of B cells. Here we report that minimal infectious dose and disease incubation after oral exposure to logarithmic dilutions of prion inoculum were similar in beta 7(-/-) and wild-type mice, and PPs of both beta 7(-/-) and wild-type mice contained 3-4 log LD(50)/g prion infectivity > or =125 days after challenge. Despite marked reduction of B cells, M cells were present in beta 7(-/-) mice. In contrast, mice deficient in both tumor necrosis factor and lymphotoxin-alpha (TNF alpha(-/-) x LT alpha(-/-)) or in lymphocytes (RAG-1(-/-), mu MT), in which numbers of PPs are reduced in number, were highly resistant to oral challenge, and their intestines were virtually devoid of prion infectivity at all times after challenge. Therefore, lymphoreticular requirements for enteric and for intraperitoneal uptake of prions differ from each other. Although susceptibility to prion infection following oral challenge correlates with the number of PPs, it is remarkably independent of the number of PP-associated lymphocytes.
Animals↗
Prions and the immune system: a journey through gut, spleen, and nerves.
For more than two decades it has been contended that prion infection does not elicit immune responses: transmissible spongiform encephalopathies do not go along with conspicuous inflammatory infiltrates, and antibodies to the prion protein are typically undetectable. Why is it, then, that prions accumulate in lymphoid organs, and that various states of immune deficiency prevent peripheral prion infection? This review revisits the current evidence of the involvement of the immune system in prion diseases, while attempting to trace the elaborate mechanisms by which peripherally administered prions invade the brain and ultimately cause damage. The investigation of these questions leads to unexpected detours, including the neurophysiology of lymphoid organs, and even the function of a prion protein homolog in male fertility.
Animals↗
Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs.
Patients suffering from multiple endocrine neoplasia type 1 (MEN1) are predisposed to multiple endocrine tumors. The MEN1 gene product, menin, is expressed in many embryonic, as well as adult tissues, and interacts with several proteins in vitro and in vivo. However, the biological function of menin remains largely unknown. Here we show that disruption of the Men1 gene in mice causes embryonic lethality at E11.5-E13.5. The Men1 null mutant embryos appeared smaller in size, frequently with body haemorrhages and oedemas, and a substantial proportion of them showed disclosure of the neural tube. Histological analysis revealed an abnormal development of the nervous system and heart hypotrophy in some Men1 null embryos. Furthermore, Men1 null livers generally displayed an altered organization of the epithelial and hematopoietic compartments associated with enhanced apoptosis. Chimerism analysis of embryos generated by injection of Men1 null ES cells, showed that cells lacking menin do not seem to have a general cell-autonomous defect. However, primary Men1 null embryonic fibroblasts entered senescence earlier than their wild-type counterparts. Despite normal proliferation ability, Men1 null ES cells exhibited a deficiency to form embryoid bodies, suggesting an impaired differentiation capacity in these cells. The present study demonstrates that menin plays an important role in the embryonic development of multiple organs in addition to its proposed role in tumor suppression.
Alleles↗
Human prion diseases: epidemiology and integrated risk assessment.
Human prion diseases are devastating and incurable, but are very rare. Fears that the bovine spongiform encephalopathy epizootic would lead to a large epidemic of its presumed human counterpart, variant Creutzfeldt-Jakob disease (vCJD), have not been realised. Yet a feeling of uncertainty prevails in the general public and in the biomedical world. The lack of data on the prevalence of asymptomatic carriers of vCJD compounds this uncertainty. In addition to this problem, Switzerland is currently faced with another issue of major public concern: a recent rise in the incidence of CJD. Here we examine the plausibility of several scenarios that may account for the increase in CJD incidence, including ascertainment bias due to improved reporting of CJD, iatrogenic transmission, and transmission of a prion zoonosis. In addition, we present the design and current status of a Swiss population-wide study of subclinical vCJD prevalence.
Creutzfeldt-Jakob Syndrome↗
Prion pathogenesis in the absence of Toll-like receptor signalling.
To reach the brain from peripheral sites, prions must colonize various cell types within the lymphoreticular compartment. However, no prion entry receptors are yet known. Toll-like receptors (TLRs) are pattern-recognition receptors that bind a multitude of pathogens and are therefore candidates as effectors of prion entry. Moreover, injection of unmethylated CpG oligodinucleotides, which stimulate TLR9, has been reported to delay peripherally initiated scrapie. We therefore studied prion infection in MyD88(-/-) mice, which are defective in TLR signalling. Despite subtle defects in splenic microarchitecture, MyD88(-/-) mice challenged intraperitoneally or intracerebrally were fully susceptible to disease and died of scrapie after similar incubation times to those of wild-type mice. Splenic infectivity titres rose to similar levels with the same kinetics, and brains showed similar histopathological changes. TLR signalling therefore does not have any major role in prion pathogenesis, and the protective effect of TLR stimulation is unlikely to result from direct interactions with prions.
Adaptor Proteins, Signal Transducing↗
Immune system and peripheral nerves in propagation of prions to CNS.
Prions are not only unique in the way they replicate. Also the sequence of events triggered by peripheral prion infection, generically termed 'peripheral pathogenesis', sets prions aside from all other known pathogens. Whereas most bacteria, parasites, and viruses trigger innate and adaptive immune responses, the mammalian immune system appears to be remarkably oblivious to prions. Transmissible spongiform encephalopathies (TSEs) do not go along with inflammatory infiltrates, and antibodies to the prion protein are not typically raised during the course of the disease. On the other hand, there is conspicuous involvement of lymphoid organs, which accumulate sizeable concentrations of the infectious agent early during disease. Moreover, various states of immune deficiency can abolish peripheral pathogenesis and prevent 'take' of infection when prions are administered to peripheral sites. Here, we critically re-visit the current evidence for an involvement of the immune system in prion diseases, and will attempt to trace the elaborate mechanisms by which prions, upon entry into the body from peripheral sites, reach the brain.
Amyloid↗
No superoxide dismutase activity of cellular prion protein in vivo.
Prion diseases are characterized by the deposition of PrP(Sc), an abnormal form of the cellular prion protein PrP(C), which is encoded by the Prnp gene. PrP(C) is highly expressed on neurons and its function is unknown. Recombinant PrP(C) was claimed to possess superoxide dismutase (SOD) activity, and it was hypothesized that abrogation of this function may contribute to neurodegeneration in prion diseases. We tested this hypothesis in vivo by studying copper/zinc and manganese SOD activity in genetically defined crosses of mice lacking the Sod1 gene with mice lacking PrP(C), and with hemizygous or homozygous tga20 transgenic mice overexpressing various levels of PrP(C). We failed to detect any influence of the Prnp genotype and gene dosage on SOD1 or SOD2 activity in heart, spleen, brain, and synaptosome-enriched brain fractions. Control experiments included crosses of mice lacking or overexpressing PrPc with mice overexpressing human Cu2+/Zn2+-superoxide dismutase, and confirmed that SOD enzymatic activity correlated exclusively with the gene dosage of bona fide human or murine SOD. We conclude that PrP(C) in vivo does not discernibly contribute to total SOD activity and does not possess an intrinsic dismutase activity.
Animals↗
Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110.
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 heparin stimulates t-PA mediated plasminogen activation in vitro. The apparent rate constant was increased 57 fold in the presence of 800 nM PrP23-110. Furthermore, we compared the stimulation of t-PA activity by PrP(c) and beta-amyloid peptide (1-42). While the activity of the beta-amyloid was independent of low molecular weight heparin, PrP23-110 was approximately 4- and 37 fold more active than beta-amyloid in the absence or presence of low molecular weight heparin. In summary, plasmin cleaves PrP(c) in vitro and the liberated NH(2)-terminal fragment accelerates plasminogen activation. Cleavage of PrP c has previously been reported. Thus cleavage of PrP(c) enhancing plasminogen activation at the cell surface could constitute a regulatory mechanism of pericellular proteolysis.
Amino Acid Sequence↗
Unhampered prion neuroinvasion despite impaired fast axonal transport in transgenic mice overexpressing four-repeat tau.
Transmissible spongiform encephalopathies often are caused by peripheral uptake of infectious prions, and the peripheral nervous system is involved in prion spread to the brain. Although the cellular prion protein is subjected to fast axonal transport, the mechanism of intranerval transport of infectious prions is unclear. Here we administered prions intranervally to transgenic mice overexpressing the four-repeat human tau protein, which exhibit defective fast axonal transport. These mice showed unaltered neuroinvasion, suggesting that transport mechanisms distinct from fast axonal transport effect prion neuroinvasion along peripheral nerves. Surprisingly, scrapie-sick tau transgenic mice accumulated intraneuronal deposits of hyperphosphorylated tau protein. The coincidence of tau and prion pathology resembled Gerstmann-Sträussler-Scheinker syndrome. These findings identify tau pathology as a possible end stretch of prion-induced neurodegeneration.
Animals↗
Absence of the prion protein homologue Doppel causes male sterility.
The agent that causes prion diseases is thought to be identical with PrP(Sc), a conformer of the normal prion protein PrP(C). PrP(C)-deficient mice do not exhibit major pathologies, perhaps because they express a protein termed Dpl, which shares significant biochemical and structural homology with PrP(C). To investigate the physiological function of Dpl, we generated mice harbouring a homozygous disruption of the Prnd gene that encodes Dpl. Dpl deficiency did not interfere with embryonic and postnatal development, but resulted in male sterility. Dpl protein was expressed at late stages of spermiogenesis, and spermatids of Dpl mutants were reduced in numbers, immobile, malformed and unable to fertilize oocytes in vitro. Mechanical dissection of the zona pellucida partially restored in vitro fertilization. We conclude that Dpl regulates male fertility by controlling several aspects of male gametogenesis and sperm-egg interaction.
Animals↗
Incidence of Creutzfeldt-Jakob disease in Switzerland.
The incidence of Creutzfeldt-Jakob disease (CJD) in Switzerland increased two-fold in 2001, and figures from the first quarter of 2002 indicate that it continues to rise. Neither age at onset nor duration of disease were different from previous years. Genetic analysis of the 27 reported cases revealed only one disease-associated mutation in the prion gene. None of the recognised risk factors for acquired CJD were reported on the official notification forms. Glycotype profiling, histopathology, and immunohistochemistry indicate that none of the cases fulfilled the definition of variant CJD, which is thought to be caused by bovine prions. Several scenarios could account for the increase in CJD, including improved reporting, iatrogenic transmission, and transmission of a prion zoonosis.
Aged↗
Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma.
Interactions of CD70, a tumor necrosis factor-related cell surface ligand and its receptor, CD27, are thought to play an important role for T-, B-, and natural killer-cell activation. However, ligation of CD27 can also induce apoptosis. Human glioblastoma is paradigmatic for cancer-associated immunosuppression. We identified CD70 as a radioinducible gene in U87 MG glioma cells. A screening of a panel of human glioma cell lines revealed that 11 of 12 cell lines expressed CD70 mRNA and protein. Two human neuroblastoma cell lines did not express CD70. CD70 mRNA expression was enhanced by irradiation in 8 of 12 glioma cell lines in a p53-independent manner. No alteration in CD70 expression was observed after glioma cell exposure to cytotoxic drugs such as lomustine. CD70 protein was also detected by immunocytochemistry in 5 of 12 glioblastomas and 3 of 4 anaplastic astrocytomas in vivo. CD27 expression was not detected in any glioma cell line, and there was no evidence for autocrine or backward signaling of the CD70 system in human glioma cells. Unexpectedly, CD70 expressed on glioma cells did not increase the immunogenicity of glioma cells in vitro. In contrast, CD70-positive glioma cells induced apoptosis in peripheral blood mononuclear cells (PBMCs) in a CD70-dependent manner. Neutralization of CD70 expressed on glioma cells prevented apoptosis and enhanced the release of tumor necrosis factor-alpha in cocultures of glioma cells and PBMCs. The effects of CD70-expressing glioma cells on PBMCs were mimicked by agonistic CD27 antibodies. Conversely, the shedding of CD27 by PBMCs was identified as a possible escape mechanism from glioma cell-induced CD70-dependent apoptosis. Thus, induction of B-cell and T-cell apoptosis via interactions of CD70 expressed on glioma cells and CD27 expressed on B and T cells may be a novel way for the immune escape of malignant gliomas.
Antigens, CD↗
Prions--role of the peripheral nervous system.
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Animals↗
Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells.
Variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to prions, and exhibit early prion accumulation in germinal centers. Follicular dendritic cells (FDCs), whose development and maintenance in germinal centers depends on tumor necrosis factor (TNF) and lymphotoxin (LT) signaling, are thought to be indispensable for extraneural prion pathogenesis. Here, we administered prions intraperitoneally to mice deficient for TNF and LT signaling components. LT alpha(-/-), LT beta(-/-), LT betaR(-/-), and LT alpha(-/-) x TNFalpha(-/-) mice resisted infection and contained no infectivity in spleens and lymph nodes (when present). However, TNFR1(-/-), TNFR2(-/-), and some TNFalpha(-/-) mice developed scrapie similarly to wild-type mice. High prion titers were detected in lymph nodes, but not spleens, of TNFR1(-/-) and TNF alpha(-/-) mice despite absence of FDCs and germinal centers. Transfer of TNFR1(-/-) fetal liver cells into lethally irradiated Prnp(0/0) mice restored infectivity mainly in lymph nodes. Prion protein (PrP) colocalized with a minority of macrophages in tumor necrosis factor receptor (TNFR) 1(-/-) lymph nodes. Therefore, prion pathogenesis can be restricted to lymphoreticular subcompartments, and mature follicular dendritic cells are dispensable for this process. Macrophage subsets are plausible candidates for lymphoreticular prion pathogenesis and neuroinvasion in the absence of FDCs, and may represent a novel target for postexposure prophylaxis.
Animals↗
p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases.
Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation.
Adaptor Proteins, Signal Transducing↗
Small is not beautiful: antagonizing functions for the prion protein PrP(C) and its homologue Dpl.
A conformational variant of the normal prion protein PrP(C) is believed to be identical to PrP(Sc), the agent that causes prion diseases. Recently, a novel protein, named Doppel (Dpl), was identified that shares significant biochemical and structural homology with PrP(C). In specific strains of PrP(C)-deficient mouse lines, Dpl is overexpressed and causes a neurological disease. Dpl neurotoxicity is counteracted and prevented by PrP(C), but the mechanism of antagonistic PrP(C)-Dpl interaction remains elusive. In contrast to its homologue PrP(C), initial studies suggest that Dpl is dispensable for prion disease progression and for the generation of PrP(Sc). Although we are only beginning to understand its function, the discovery of Dpl has already provided some answers to long-standing questions and is transforming our understanding of prion biology.
Animals↗
Chronic subclinical prion disease induced by low-dose inoculum.
We have compared the transmission characteristics of the two mouse-adapted scrapie isolates, ME7 and Rocky Mountain Laboratory (RML), in tga20 mice. These mice express elevated levels of PrP protein compared to wild-type mice and display a relatively short disease incubation period following intracerebral prion inoculation. Terminal prion disease in tga20 mice induced by ME7 or RML was characterized by a distinct pattern of clinical signs and different incubation times. High-dose RML inoculated intracerebrally into tga20 mice induced the most rapid onset of clinical signs, with mice succumbing to terminal disease after only 58 +/- 3 days. In contrast, high-dose ME7 gave a mean time to terminal disease of 74 +/- 0 days. Histological examination of brain sections from prion-inoculated tga20 mice at terminal disease showed that ME7 gave rise to a more general and extensive pattern of vacuolation than RML. Low-dose inoculum failed to induce terminal disease but did cause preclinical symptoms, including the appearance of reversible clinical signs. Some mice oscillated between showing no clinical signs and early clinical signs for many months but never progressed to terminal disease. Brain tissue from these mice with chronic subclinical prion disease, sacrificed at >200 days postinoculation, contained high levels of infectivity and showed the presence of PrP(Sc). Parallel analysis of brain tissue from mice with terminal disease showed similar levels of infectivity and detectable PrP(Sc). These results show that high levels of infectivity and the presence of the abnormal isomer of PrP can be detected in mice with subclinical disease following low-dose prion inoculation.
Animals↗