Transgenic Mice Expressing Hamster Prion Protein Produce Species -Specific Scrapie Infectivity and Amyloid Plaques

Scott, Michael; Foster, Dallas; Mirenda, C.; Serban, Dan; Coufal, Frank; Wälchli, Monika; Torchia, Marilyn; Groth, Darlene; Carlson, George A.; DeArmond, Stephen J.; Westaway, David; Prusiner, Stanley B.

doi:10.1097/00005072-199005000-00158

Cited by 67 publications

(91 citation statements)

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“…In seminal experiments, Scott et al [173] abrogated the recognized [89,131], the mechanisms of prion replication may proceed through the binding of monomeric PrP C (possibly a partially unfolded species of the protein) onto an aggregated PrP Sc seed, followed by in situ conversion into a conformation similar to PrP Sc . Incorporation of the PrP C molecules constantly renewed by the host concurs to further growing of the aggregate.…”

Section: Influence Of the Prp Genementioning

confidence: 99%

Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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Section: Influence Of the Prp Genementioning

confidence: 99%

Prion agent diversity and species barrier

2008

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“…The incubation period on passage of an agent from one species to another is extremely long for the initial passage and quickly decreases on subsequent passages to a comparatively low and stable level (Dickinson, 1976;Kimberlin, 1979). The development of transgenic mice expressing the hamster PrP gene (Scott et al, 1989;Prusiner et al, 1990) has demonstrated that PrP is a controlling factor in delineating species barriers in mice and hamsters. The mechanism whereby PrP controls the species barrier is not clear.…”

Section: Short Communicationmentioning

confidence: 99%

Demonstration of scrapie strain diversity in infected PC12 cells

Rubenstein

Deng

Race

et al. 1992

Journal of General Virology

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Scrapie strain replication in the nerve growth factorinduced, differentiated PC12 cell culture system was examined. Differences in replication between mousederived agents were demonstrated, with the 139A scrapie strain yielding 100-to 1000-fold higher levels of infectivity than the ME7 scrapie strain. Replication was not detected in PC 12 cells infected with either the hamster-derived 263K or rat-derived 139R scrapie strains. Studies on the neurotransmitters in infected PC12 cells demonstrated that the adrenergic pathway was unchanged but the cholinergic pathway was altered. Furthermore, the degree of alteration correlated with the level of scrapie strain replication.Comparison of infectivity titres and enzymatic changes in ME7-infected PC12 cells with those in Chandler agent-infected mouse neuroblastoma cells suggests that the significant changes in neurotransmitter levels in cultures exhibiting low titres of infectivity involve factors in addition to strain replication. The variation in the range of scrapie strain replication in PC 12 cells is discussed in relationship to species barrier, cell targeting, genetic susceptibility and species strain specificity. These studies further emphasize the value of the PC 12 cell model system in examining the scrapie strain-host cell interaction and in addition support the concept of variation among scrapie strains.

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“…Although the theory remains controversial, evidence in support of the protein-only model is substantial (Bolton et al, , 1987(Bolton et al, , 1991McKinley et al, 1983 ;Prusiner et al, 1984 ;Hsiao et al, 1989Hsiao et al, , 1990Scott et al, 1989Scott et al, , 1993Meyer et al, 1991 ;Bu$ eler et al, 1992).…”

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Prion distribution in hamster lung and brain following intraperitoneal inoculation.

Bolton¹

1998

Journal of General Virology

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Prion titres were measured in the lungs and brains of Syrian hamsters after intraperitoneal inoculation with sucrose gradient-purified 263K prions (" 10 8 LD 50 ). Prions were detected in the lung of one hamster on day 7, but were not detected in the lungs of any other hamster until day 71. Prions were detected in the lungs of all hamsters sampled thereafter but titres remained low through day 127. Prions were first detected in the brain on day 35 and brain titres increased exponentially until day 127 with a doubling time of about 4n5 days. On day 133, titres averaged 10 8n0 LD 50 /g in brain and 10 5n0 LD 50 /g in lung. Two out of the five remaining hamsters were clinically normal but prion titres were not significantly different from those in the clinically affected hamsters. Thus, significant prion titres may be found outside the CNS in clinically normal hamsters.

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Transgenic Mice Expressing Hamster Prion Protein Produce Species -Specific Scrapie Infectivity and Amyloid Plaques

Cited by 67 publications

References 0 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Demonstration of scrapie strain diversity in infected PC12 cells

Prion distribution in hamster lung and brain following intraperitoneal inoculation.

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