Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease.

Manuelidis, Laura; Sklaviadis, Theodoros; Akowitz, Alfred; Fritch, William

doi:10.1073/pnas.92.11.5124

Cited by 78 publications

(78 citation statements)

References 23 publications

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“…Many additional experiments have demonstrated separation of most pathologic PrP from infectious particles (1,29), and over the last 20 years no form of PrP itself has ever reproduced infection in normal animals (1). Hence, one cannot exclude a viral agent, particularly because intact viruses are often resistant to nuclease digestion, and intact, but not CJD-specific, endogenous retroviral particles cosediment with CJD infectivity after nuclease treatment (29).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Hence, one cannot exclude a viral agent, particularly because intact viruses are often resistant to nuclease digestion, and intact, but not CJD-specific, endogenous retroviral particles cosediment with CJD infectivity after nuclease treatment (29). Furthermore, most PrP can be dissociated from infectivity, whereas treatments that disrupt cosedimenting viral particles reduce CJD infectivity by Ͼ99.5% (29). However, it is the biology of these agents: their evolution (21), spread, cell specificity, latency, virus-like interference capabilities (15,16,30), and occasional mutation (31), as well as the principle of parsimony, which continues to indicate a viral causative agent.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, pathological PrP may be the end result of a host defense mechanism that ultimately traps infectious particles in an insoluble mass of amyloid junk (33,34). This conclusion seems plausible because infectious agent is released when PrP amyloid is disaggregated (1,29). A PrP-trapping mechanism may also protect these agents from clearance and detection during cellto-cell surface spread (35).…”

Section: Discussionmentioning

confidence: 99%

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Two Creutzfeldt–Jakob disease agents reproduce prion protein-independent identities in cell cultures

Arjona

Simarro

Islinger

et al. 2004

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

125

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Human Creutzfeldt-Jakob disease (CJD) and similar neurodegenerative diseases such as sheep scrapie are caused by a variety of related infectious agents. They are associated with abnormal host prion protein (PrP), which is assessed by limited proteolysis to yield resistant PrP bands (PrP-res). Although PrP-res has been posited as the infectious agent, purified PrP-res itself is not infectious. To establish the independence of CJD agent characteristics from those of PrP-res, two different mouse-passaged CJD strains were propagated in neuronal cell lines whose PrP-res patterns differ markedly from each other and from those found in infected brain. In mouse brain, the fast CJD strain, FU, elicits many PrP-res deposits, whereas the slow SY strain elicits few. Both strains evoked PrP-res in cultured murine cells, although SY induced PrP-res only transiently. PrP-res patterns in FU-and SY-infected GT1 cells were identical, and were significantly different from those in brain and in N2a cells. Nevertheless, all FU-infected cell lines reproduced their original fast disease in mice, even after extensive subculture, whereas SY-infected cells produced only slow disease. These data indicate PrP-res neither encodes nor alters agent-specific characteristics. PrP-res was also a poor predictor of infectivity because SY cells that had lost PrP-res were Ϸ10-fold more infectious than PrP-res-positive cultures. Furthermore, FU titers increased 650-fold, whereas PrP-res remained constant. Passaged FU-infected cells had titers comparable to brain, and >30% of cells displayed abundant cytoplasmic PrP-res aggregates that may trap agent. The continuous substantial replication of CJD in monotypic cells will further the discrimination of agent-specific molecules from pathological host responses to infection. transmissible encephalopathies ͉ agent strains ͉ in vitro propagation ͉ high infectivity ͉ in situ detection

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Two Creutzfeldt–Jakob disease agents reproduce prion protein-independent identities in cell cultures

Arjona

Simarro

Islinger

et al. 2004

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

125

View full text Add to dashboard Cite

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“…These small nucleic acids were of variable length and are thought to be degradation byproducts generated during purification of prions. Failure to find a bona fide genome was attributed to the unusual properties of the putative viral nucleic acid or technical incompetence on the part of the investigators who were unable to find it (63,115).…”

mentioning

confidence: 99%

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Chisholm

Dahlbeck

Krishnamurthy

et al. 2005

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

137

138

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Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high ␤-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

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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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Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease.

Abstract: Several models have been proposed for the infectious agents that cause human Creutzfeldt-Jakob disease (CJD) and sheep scrapie. Purified

Cited by 78 publications

References 23 publications

Two Creutzfeldt–Jakob disease agents reproduce prion protein-independent identities in cell cultures

Two Creutzfeldt–Jakob disease agents reproduce prion protein-independent identities in cell cultures

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

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

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