Scrapie Prions

Prusiner, S. B.

doi:10.1146/annurev.mi.43.100189.002021

Cited by 249 publications

(87 citation statements)

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“…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]. The virino hypothesis holds that the infectious agent consists of a scrapie-specific nucleic acid genome and hostderived PrP so, which is recruited as some sort of coat [12].…”

Section: Hypotheses About the Nature Of The Scrapie Agentmentioning

confidence: 99%

“…The 'protein only' hypothesis proposes that the prion contains no nucleic acid and is identical with PrP sc, a modified form of PrP c [10]. PrP c is a normal host protein [14][15][16] found predominantly on the outer surface of neurons ( Fig.…”

Section: Hypotheses About the Nature Of The Scrapie Agentmentioning

confidence: 99%

“…In the case of certain mutations in PrP c, spontaneous conversion to PrP sc may occur as a rare event, explaining why familial CJD or GSS arise spontaneously, albeit late in life. Sporadic CJD may come about when an extremely rare event (occurring in one among a million individuals per year) leads to spontaneous conversion of PrP c to PrP s~ and gives rise to a conversion cascade [10,35]. (b).…”

Section: Biosynthesis Of Prp C and Prp Scmentioning

confidence: 99%

“…Prusiner [10,39] proposed that the mutations allow spontaneous conversion of PrP ¢ into PrP s~ with a frequency sufficient to allow expression of the disease within the lifetime of the individual. Sporadic CJD could be attributed to rare instances of spontaneous conversion of PrP c into PrP sc or rare somatic mutations in the Prnp gene.…”

Section: Genetic Evidence Linking the Prp Gene With Prion Diseasementioning

confidence: 99%

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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%

Section: Hypotheses About the Nature Of The Scrapie Agentmentioning

confidence: 99%

Section: Biosynthesis Of Prp C and Prp Scmentioning

confidence: 99%

Section: Genetic Evidence Linking the Prp Gene With Prion Diseasementioning

confidence: 99%

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Molecular biology of transmissible spongiform encephalopathies

1996

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“…In Creutzfeldt-Jakob disease (CJD) and scrapie the infectious agent is often considered to exhibit unusual resistance to physical and chemical treatments. These indirect data, as well as the assumption that nuclease or Zn2+ treatment effectively cleaves all nucleic acids to fragments <50 bp (3), is often cited in the litany of "evidence" for an infectious host protein or "prion" (4,5). However, such preparations have contained as much as 1-10 ug of nucleic acid per .…”

mentioning

confidence: 99%

Nucleic acid binding proteins in highly purified Creutzfeldt-Jakob disease preparations.

Sklaviadis

Akowitz

Manuelidis

et al. 1993

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

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The nature of the infectious agent causing human Creutzfeldt-Jakob disease (CJD), a slowly progressive dementia, is controversial. As in scrapie, no agent-specific proteins or nucleic acids have been identified. However, biological features of exponential replication and agent strain variation, as well as physical size and density data, are most consistent with a viral structure--i.e., a nucleic acid-protein complex. It is often assumed that nuclease treatment, which does not reduce infectious titer, leaves no nucleic acids of > 50 bp. However, nucleic acids of 500-6000 bp can be extracted from highly purified infectious complexes with a mass of approximately 1.5 x 10(7) daltons. It was therefore germane to search for nucleic acid binding proteins that might protect an agent genome. We here use Northwestern blotting to show that there are low levels of nonhistone nucleic acid binding proteins in highly purified infectious 120S gradient fractions. Several nucleic acid binding proteins were clearly host encoded, whereas others were apparent only in CJD, but not in parallel preparations from uninfected brain. Small amounts of residual host Gp34 (prion protein) did not bind any 32P-labeled nucleic acid probes. Most of the minor "CJD-specific" proteins had an acidic pI, a characteristic of many viral core proteins. Such proteins deserve further study, as they probably contribute to unique properties of resistance described for these agents. It remains to be seen if any of these proteins are agent encoded.

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Molecular dynamics of mouse and Syrian hamster PrP: Implications for activity

Parchment

Essex

2000

Proteins

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Molecular dynamics computer simulations have been performed on Mouse (Mo) and Syrian Hamster (SHa) prion proteins. These proteins differ, primarily, in that the SHa form incorporates additional residues at the C-terminus and also includes a segment of the unstructured N-terminal region that is required for infectivity. The 1-ns simulations have been analyzed by using a combination of dynamical cross-correlation maps, residue-residue contact plots, digital filtering, and residue-based root-mean-square deviations. The results show that the extra residues present in the SHa form at the C- and N-termini produce changes in the stability of key regions of the protein. The loop region between strand S2 and helix B that contains part of the proposed discontinuous binding site for the chaperone, protein X, is found to be more stable in SHa than in the Mo protein; these results are consistent with the NMR data of James et al. (James et al. Proc Natl Acad Sci USA 1997;94:10086-10091). In addition, a degree of flexibility within the region between and including strand S1 and helix A is also shown in SHa, which is not present in the Mo form; the cross-correlation maps suggest that this is a consequence of the additional unstructured N-terminal region. Furthermore, the extra residues in the N-terminal region of SHa are found to form a beta-bridge with the beta-sheet, within which critical point mutations associated with prion diseases lie. The implications of these results for the conformational interconversion pathway of the prion protein are discussed.

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Scrapie Prions

Cited by 249 publications

References 0 publications

Molecular biology of transmissible spongiform encephalopathies

Molecular biology of transmissible spongiform encephalopathies

Nucleic acid binding proteins in highly purified Creutzfeldt-Jakob disease preparations.

Molecular dynamics of mouse and Syrian hamster PrP: Implications for activity

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