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91.
The accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1β. The NLRP3 inflammasome was reported to be essential for IL 1β release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1β at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases. 相似文献
92.
Mridula Swayampakula Pravas Kumar Baral Adriano Aguzzi Nat N. V. Kav Michael N. G. James 《Protein science : a publication of the Protein Society》2013,22(7):893-903
Prion diseases are progressive, infectious neurodegenerative disorders caused primarily by the misfolding of the cellular prion protein (PrPc) into an insoluble, protease‐resistant, aggregated isoform termed PrPsc. In native conditions, PrPc has a structured C‐terminal domain and a highly flexible N‐terminal domain. A part of this N‐terminal domain consists of 4–5 repeats of an unusual glycine‐rich, eight amino acids long peptide known as the octapeptide repeat (OR) domain. In this article, we successfully report the first crystal structure of an OR of PrPc bound to the Fab fragment of the POM2 antibody. The structure was solved at a resolution of 2.3 Å by molecular replacement. Although several studies have previously predicted a β‐turn‐like structure of the unbound ORs, our structure shows an extended conformation of the OR when bound to a molecule of the POM2 Fab indicating that the bound Fab disrupts any putative native β turn conformation of the ORs. Encouraging results from several recent studies have shown that administering small molecule ligands or antibodies targeting the OR domain of PrP result in arresting the progress of peripheral prion infections both in ex vivo and in in vivo models. This makes the structural study of the interactions of POM2 Fab with the OR domain very important as it would help us to design smaller and tighter binding OR ligands. 相似文献
93.
Magdalini Polymenidou Rita Moos Mike Scott Christina Sigurdson Yong-zhong Shi Bill Yajima Iva Hafner-Bratkovi? Roman Jerala Simone Hornemann Kurt Wuthrich Anne Bellon Martin Vey Graciela Garen Michael N. G. James Nat Kav Adriano Aguzzi 《PloS one》2008,3(12)
PrPSc, a misfolded and aggregated form of the cellular prion protein PrPC, is the only defined constituent of the transmissible agent causing prion diseases. Expression of PrPC in the host organism is necessary for prion replication and for prion neurotoxicity. Understanding prion diseases necessitates detailed structural insights into PrPC and PrPSc. Towards this goal, we have developed a comprehensive collection of monoclonal antibodies denoted POM1 to POM19 and directed against many different epitopes of mouse PrPC. Three epitopes are located within the N-terminal octarepeat region, one is situated within the central unstructured region, and four epitopes are discontinuous within the globular C-proximal domain of PrPC. Some of these antibodies recognize epitopes that are resilient to protease digestion in PrPSc. Other antibodies immunoprecipitate PrPC, but not PrPSc. A third group was found to immunoprecipitate both PrP isoforms. Some of the latter antibodies could be blocked with epitope-mimicking peptides, and incubation with an excess of these peptides allowed for immunochromatography of PrPC and PrPSc. Amino-proximal antibodies were found to react with repetitive PrPC epitopes, thereby vastly increasing their avidity. We have also created functional single-chain miniantibodies from selected POMs, which retained the binding characteristics despite their low molecular mass. The POM collection, thus, represents a unique set of reagents allowing for studies with a variety of techniques, including western blotting, ELISA, immunoprecipitation, conformation-dependent immunoassays, and plasmon surface plasmon resonance-based assays. 相似文献
94.
Endogenous cardiac activity rhythms of continental slope Nephrops norvegicus (decapoda: nephropidae)
Jacopo Aguzzi Pere Abell Michael H. Depledge 《Marine and Freshwater Behaviour and Physiology》2004,37(1):55-64
The endogenous cardiac activity rhythm of the Norway lobster Nephrops norvegicus was studied under constant conditions of darkness by means of a computer-aided monitoring system (CAPMON). Time series recordings of the heart rate (beats min-1) were obtained from 47 adult males freshly collected from the continental slope (400-430 m) in the western Mediterranean. Periodogram analysis revealed the occurrence of circadian periodicity (of around 24 h) in most cases. A large percentage of animals showed significant ultradian periods (of around 12 and 18 h). The analysis of the circadian time series revealed the occurrence of peaks of heart rate activity during the expected night phase of the cycle. These results are discussed in relation to the emergence and locomotor activity rhythms of the species. 相似文献
95.
96.
von Poser-Klein C Flechsig E Hoffmann T Schwarz P Harms H Bujdoso R Aguzzi A Klein MA 《Journal of virology》2008,82(7):3791-3795
Acquired forms of prion diseases or transmissible spongiform encephalopathies are believed to occur following peripheral exposure. Prions initially accumulate in the lymphoid system before spreading to the nervous system, but the underlying mechanisms for prion transfer between the two systems are still elusive. Here we show that ablation of the B-cell-specific transmembrane protein CD19, a coreceptor of the complement system, results in an acceleration of prion neuroinvasion. This appears to be due to an alteration of the follicular dendritic cell (FDC) network within the lymphoid tissue, thereby reducing the distance between FDCs and adjacent nerve fibers that mediate prion neuroinvasion. 相似文献
97.
Normal neurogenesis and scrapie pathogenesis in neural grafts lacking the prion protein homologue Doppel 总被引:3,自引:0,他引:3 下载免费PDF全文
The agent that causes prion diseases is thought to be identical to PrPSc, a conformer of the normal prion protein PrPC. Recently a novel protein, termed Doppel (Dpl), was identified that shares significant biochemical and structural homology with PrPC. To investigate the function of Dpl in neurogenesis and in prion pathology, we generated embryonic stem (ES) cells harbouring a homozygous disruption of the Prnd gene that encodes Dpl. After in vitro differentiation and grafting into adult brains of PrPC-deficient Prnp0/0 mice, Dpl-deficient ES cell-derived grafts contained all neural lineages analyzed, including neurons and astrocytes. When Prnd-deficient neural tissue was inoculated with scrapie prions, typical features of prion pathology including spongiosis, gliosis and PrPSc accumulation, were observed. Therefore, Dpl is unlikely to exert a cell-autonomous function during neural differentiation and, in contrast to its homologue PrPC, is dispensable for prion disease progression and for generation of PrPSc. 相似文献
98.
Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion 总被引:13,自引:0,他引:13
Transmissible spongiform encephalopathies are commonly propagated by extracerebral inoculation of the infectious agent. Indirect evidence suggests that entry into the central nervous system occurs via the peripheral nervous system. Here we have investigated the role of the sympathetic nervous system in prion neuroinvasion. Following intraperitoneal prion inoculation, chemical or immunological sympathectomy delayed or prevented scrapie. Prion titers in spinal cords were drastically reduced at early time points after inoculation. Instead, keratin 14-NGF transgenic mice, whose lymphoid organs are hyperinnervated by sympathetic nerves, showed reduction in scrapie incubation time and, unexpectedly, much higher titers of prion infectivity in spleens. We conclude that sympathetic innervation of lymphoid organs is rate limiting for prion neuroinvasion and that splenic sympathetic nerves may act as extracerebral prion reservoirs. 相似文献
99.
Mammalian prion biology: one century of evolving concepts 总被引:36,自引:0,他引:36
Prions have been responsible for an entire century of tragic episodes. Fifty years ago, kuru decimated the population of Papua New Guinea. Then, iatrogenic transmission of prions caused more than 250 cases of Creutzfeldt-Jakob disease. More recently, transmission of bovine spongiform encephalopathy to humans caused a widespread health scare. On the other hand, the biology of prions represents a fascinating and poorly understood phenomenon, which may account for more than just diseases and may represent a fundamental mechanism of crosstalk between proteins. The two decades since Stanley Prusiner's formulation of the protein-only hypothesis have witnessed spectacular advances, and yet some of the most basic questions in prion science have remained unanswered. 相似文献
100.
Prion diseases are often caused by peripheral uptake of the infectious agent. To reach their ultimate target, the central nervous system (CNS), prions enter their host, replicate in lymphoid organs and spread via peripheral nerves. Once the agent has reached the CNS disease progression is rapid, resulting in neurodegeneration and death. many of these mechanisms have been uncovered using genetically modified mice. A recently published study demonstrated the presence of pathological prion protein in sympathetic ganglia of patients suffering from variant Creutzfeldt-Jakob disease, suggesting that these mechanisms might apply to humans. 相似文献