Journal ArticleDOI
Prion protein is necessary for normal synaptic function
John Collinge,Miles A. Whittington,Katie C. L. Sidle,Corinne J. Smith,Mark S. Palmer,Anthony R. Clarke,John G. R. Jefferys +6 more
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TLDR
It is argued that loss of function of PrPc may contribute to the early synaptic loss3 and neuronal degeneration seen in Creutzfeldt–Jakob disease and scrapie and bovine spongiform encephalopathy in animals.Abstract:
THE prion diseases are neurodegenerative conditions, transmissible by inoculation, and in some cases inherited as an autosomal dominant disorder. They include Creutzfeldt–Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. The prion consists principally of a post-translationally modified form of a host-encoded glycoprotein (PrPc), designated PrPSc (ref. 1); the normal cellular function of PrPc is, however, unknown. Although PrP is highly conserved among mammals and widely expressed in early embryogenesis, mice homozygous for disrupted PrP genes appear developmentally and behaviourally normal2. PrP is a protein anchored to the neuronal surface by glycosylphosphatidylinositol, suggesting a role in cell signalling or adhesion. Here we report that hippocampal slices from PrP null mice have weakened GABAA (γ-aminobutyric acid type A) receptor-mediated fast inhibition and impaired long-term potentiation. This impaired synaptic inhibition may be involved in the epileptiform activity seen in Creutzfeldt–Jakob disease and we argue that loss of function of PrPc may contribute to the early synaptic loss3 and neuronal degeneration seen in these diseases.read more
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Journal ArticleDOI
The cellular prion protein binds copper in vivo
David R. Brown,Kefeng Qin,Jochen Herms,Axel Madlung,Jean Manson,Robert Strome,Paul E. Fraser,T. P. A. Kruck,A von Bohlen,Walter J. Schulz-Schaeffer,Armin Giese,David Westaway,Hans A. Kretzschmar +12 more
TL;DR: Findings indicate that PrPC can exist in a Cu-metalloprotein form in vivo, and that its amino terminus contains the octapeptide PHGGGWGQ, which is among the best-preserved regions of mammalian PrPC.
Journal ArticleDOI
Prion Diseases of Humans and Animals: Their Causes and Molecular Basis
TL;DR: The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the molecular basis of prion propagation, pathogenesis, andThe barriers limiting intermammalian transmission.
Journal ArticleDOI
NMR structure of the mouse prion protein domain PrP(121–231)
TL;DR: The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP domain contains most of the point-mutation sites that have been linked, in human PrP, to the occurrence of familial prion diseases, and shows that these mutations occur within, or directly adjacent to, regular secondary structures.
Journal ArticleDOI
Prion protein biology.
TL;DR: This research was supported by grants from the National Institute of Aging and the National institute of Neurologic Diseases and Stroke of the National Institutes of Health, International Human Frontiers of Science Program, and American Health Assistance Foundation, as well as by gifts from the Sherman Fairchild Foundation, Keck Foundation, G. Mathers Foundation, Bernard Osher Foundation, and Centeon.
References
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Journal ArticleDOI
A synaptic model of memory: long-term potentiation in the hippocampus
TL;DR: The best understood form of long-term potentiation is induced by the activation of the N-methyl-d-aspartate receptor complex, which allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and post Synaptic mechanisms to generate a persistent increase in synaptic strength.
Journal ArticleDOI
Molecular biology of prion diseases
TL;DR: Understanding prion diseases may advance investigations of other neurodegenerative disorders and of the processes by which neurons differentiate, function for decades, and then grow senescent.
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Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein
Hansruedi Büeler,Marek Fischer,Yolande Lang,Yolande Lang,Horst Bluethmann,Horst Bluethmann,Hans-Peter Lipp,Stephen J. DeArmond,Stephen J. DeArmond,Stanley B. Prusiner,Stanley B. Prusiner,Michel Aguet,Charles Weissmann +12 more
TL;DR: It is now feasible to determine whether mice devoid of PrPc can propagate prions and are susceptible to scrapie pathogenesis.
Journal ArticleDOI
Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication.
Stanley B. Prusiner,Michael R. Scott,Dallas Foster,Keh-Ming Pan,Darlene Groth,Carol Mirenda,Marilyn Torchia,Shu-Lian Yang,Dan Serban,George A. Carlson,Peter Hoppe,David Westaway,Stephen J. DeArmond +12 more
TL;DR: The results argue that species specificity of scrapie prions resides in the PrP sequence and prion synthesis is initiated by a species-specific interaction between PrPSc in the inoculum and homologous PrPC.
Journal ArticleDOI
Homozygous prion protein genotype predisposes to sporadic creutzfeldt-jakob disease
TL;DR: It is argued that homozygosity predisposes towards sporadic CJD and that this directly supports the hypothesis that interaction between prion protein molecules underlies the disease process.