Does the Agent of Scrapie Replicate without Nucleic Acid ?

Alper, Tikvah; Cramp, W.A.; Haig, D.A.; Clarke, Martin

doi:10.1038/214764a0

Cited by 610 publications

(269 citation statements)

References 16 publications

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“…The unusual properties of the scrapie agent early on gave rise to speculations that it might be devoid of nucleic acid [8]. Currently, the most widely accepted proposal is the 'protein only' hypothesis, first outlined in general terms by Griffith [9] and enunciated in its updated and detailed form by Prusiner [10,11].…”

Section: Hypotheses About the Nature Of The Scrapie Agentmentioning

confidence: 99%

Molecular biology of transmissible spongiform encephalopathies

1996

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The prion, the transmissible agent that causes spongiform encephalopathies such as serapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease, is believed to be devoid of nucleic acid and identical with PrP so, a modified form of the normal host protein PrP ¢ which is encoded by the single cop~v gene Prnp. The 'protein only" hypothesis proposes that PrP ~c, when introduced into a normal host, causes the conversion of PrP c into prpS~; it therefore predicts that an animal devoid of PrP c should be resistant to prion diseases. We generated homozygous Prnp °1° ('PrP knockout') mice and showed that, after inoculation with prions, they remained free of scrapie for at least 2 years while wild-type controls all died within 6 months. There was no propagation of prions in the Prnp °t° animals. Surprisingly, heterozygous Prnp °t+ mice, which express PrP c at about half the normal level, also showed enhanced resistance to scrapie disease despite high levels of infectious agent and PrP ~c in the brain early on. After introduction of murine PrP transgenes Prnp °t° mice became highly susceptible to mouse but not to hamster prions, while the insertion of Syrian hamster PrP transgenes rendered them susceptible to hamster but to a much lesser extent to mouse prions. These complementation experiments paved the way to the application of reverse genetics. We have prepared animals transgenic for genes encoding PrP with amino terminal deletions of various lengths and have found that PrP lacking 48 amino proximal amino acids, which comprise four of the five octa repeats of PrP, is still biologically active.

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Section: Hypotheses About the Nature Of The Scrapie Agentmentioning

confidence: 99%

Molecular biology of transmissible spongiform encephalopathies

1996

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“…These results, and numerous unsuccessful attempts to detect a scrapiespecific nucleic acid (36)(37)(38)(39)(40), militate against a foreign nucleic acid as an essential component of the "infectious" prion, despite proposals to the contrary (32, [41][42][43] …”

Section: Methodsmentioning

confidence: 99%

Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein.

Hsiao

Groth

Scott

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

259

134

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“…These prion diseases can arise spontaneously as a rare 'sporadic' disorder, caused by hereditary or somatic mutations, or through infectious transmission. The notion that the infectious disease agent in TSE could be devoid of nucleic acids and primarily exists of protein, the so-called protein-only hypothesis, was first advanced in the 1960s based on experimental observations [1] and theory [2]. Prusiner and colleagues later showed that a particular protein was indeed required for infectivity [3][4][5].…”

Section: Introductionmentioning

confidence: 99%