Journal ArticleDOI
Synthetic Mammalian Prions
Giuseppe Legname,Ilia V. Baskakov,Hoang-Oanh B. Nguyen,Detlev Riesner,Fred E. Cohen,Stephen J. DeArmond,Stanley B. Prusiner +6 more
TLDR
The results provide compelling evidence that prions are infectious proteins and suggest that a novel prion strain was created.Abstract:
Recombinant mouse prion protein (recMoPrP) produced in Escherichia coli was polymerized into amyloid fibrils that represent a subset of beta sheet-rich structures. Fibrils consisting of recMoPrP(89-230) were inoculated intracerebrally into transgenic (Tg) mice expressing MoPrP(89-231). The mice developed neurologic dysfunction between 380 and 660 days after inoculation. Brain extracts showed protease-resistant PrP by Western blotting; these extracts transmitted disease to wild-type FVB mice and Tg mice overexpressing PrP, with incubation times of 150 and 90 days, respectively. Neuropathological findings suggest that a novel prion strain was created. Our results provide compelling evidence that prions are infectious proteins.read more
Citations
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Protein Misfolding, Functional Amyloid, and Human Disease
TL;DR: The relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate is discussed and some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior is described.
Journal ArticleDOI
Transmission and spreading of tauopathy in transgenic mouse brain
Florence Clavaguera,Tristan Bolmont,R. Anthony Crowther,Dorothee Abramowski,Stephan Frank,Alphonse Probst,Graham Fraser,Anna K. Stalder,Martin Beibel,Matthias Staufenbiel,Mathias Jucker,Michel Goedert,Markus Tolnay +12 more
TL;DR: Transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein.
Journal ArticleDOI
Self-propagation of pathogenic protein aggregates in neurodegenerative diseases
TL;DR: As a unifying pathogenic principle, the prion paradigm suggests broadly relevant therapeutic directions for a large class of currently intractable diseases.
Journal ArticleDOI
A General Model of Prion Strains and Their Pathogenicity
John Collinge,Anthony R. Clarke +1 more
TL;DR: Recent advances suggest that prions themselves are not directly neurotoxic, but rather their propagation involves production of toxic species, which may be uncoupled from infectivity.
Journal ArticleDOI
Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.
Melanie Meyer-Luehmann,Janaky Coomaraswamy,Tristan Bolmont,Tristan Bolmont,Stephan A. Kaeser,Claudia Schaefer,Ellen Kilger,Anton Neuenschwander,Dorothee Abramowski,Peter Frey,Anneliese L. Jaton,Jean-Marie Vigouret,Paolo Paganetti,Dominic M. Walsh,Paul M. Mathews,Jorge Ghiso,Matthias Staufenbiel,Lary C. Walker,Mathias Jucker,Mathias Jucker +19 more
TL;DR: The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Aβ strains with varying biological activities reminiscent of prion strains.
References
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Journal ArticleDOI
Novel proteinaceous infectious particles cause scrapie
TL;DR: A new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids.
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Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution.
TL;DR: Thioflavine T associates rapidly with aggregated fibrils of the synthetic β/A4‐derived peptides β( 1–28) and β(1–40), giving rise to a new excitation maximum at 450 nm and enhanced emission at 482 nm, as opposed to the 385 nm and 445 nm of the free dye.
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Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie?
TL;DR: It is proposed that this step is mechanistically relevant to amyloid formation in human prion disease and in AD; it is the formation of an ordered nucleus, which is the defining characteristic of a nucleation-dependent polymerization.
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Mice devoid of PrP are resistant to scrapie
Hansruedi Büeler,Adriano Aguzzi,Andreas W. Sailer,R.-A. Greiner,P. Autenried,Michel Aguet,Charles Weissmann +6 more
TL;DR: These experiments show that PrPC, possibly at close to normal levels, is required for the usual susceptibility to scrapie and that lack of homology between incoming prions and the host's PrP genes retards disease.
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Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD
TL;DR: Strain characteristics revealed here suggest that the prion protein may itself encode disease phenotype, consistent with BSE being the source of this new disease.