Search for a Prion-Specific Nucleic Acid

Safar, Jiri; Kellings, Klaus; Serban, Ana; Groth, Darlene; Cleaver, James E.; Prusiner, Stanley B.; Riesner, Detlev

doi:10.1128/jvi.79.16.10796-10806.2005

Cited by 121 publications

(95 citation statements)

References 71 publications

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“…These specific phenotypic traits cannot be encoded by differences in the PrP C sequence since these strains were propagated in inbred mice homozygous for the PrP gene. A possible nucleic acid component in the infectious agent has remained elusive so far [172]. The now widely accepted 'protein-only' hypothesis proposes that these strain-specific properties are enciphered within biologically active, structural differences in the PrP Sc molecules.…”

Section: Transmissibility Strains and Species Barriermentioning

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: Transmissibility Strains and Species Barriermentioning

confidence: 99%

Prion agent diversity and species barrier

2008

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“…[8][9][10][11][12] A specific nucleic acid as a cofactor for the propagation of prion infection has not been identified. 13 PrP C is a cell surface protein and nucleic acids in extracellular circulation can interact with it. 14 However it has been considered that the relevant nucleic acid for PrP C conversion would be of cytoplasmic origin.…”

Section: Introductionmentioning

confidence: 99%

Nucleic acid induced unfolding of recombinant prion protein globular fragment is pH dependent

Bera

Nandi

2014

Protein Science

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Nucleic acid can catalyze the conversion of a-helical cellular prion protein to b-sheet rich Proteinase K resistant prion protein oligomers and amyloid polymers in vitro and in solution. Because unfolding of a protein molecule from its ordered a-helical structure is considered to be a necessary step for the structural conversion to its b-sheet rich isoform, we have studied the unfolding of the a-helical globular 121-231 fragment of mouse recombinant prion protein in the presence of different nucleic acids at neutral and acid pH. Nucleic acids, either single or double stranded, do not have any significant effect on the secondary structure of the protein fragment at neutral pH; however the protein secondary structure is modified by the nucleic acids at pH 5. Nucleic acids do not show any significant effect on the temperature induced unfolding of the globular prion protein domain at neutral pH which, however, undergoes a gross conformational change at pH 5 as evidenced from the lowering of the midpoint of thermal denaturation temperatures, Tm, of the protein. The extent of Tm decrease shows a dependence on the nature of nucleic acid. The interaction of nucleic acid with the nonpolar groups exposed from the protein interior at pH 5 probably contributes substantially to the unfolding process of the protein.

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“…In such a scenario, PrP Sc would exist in the CNS at levels well below those that are infectious (39,40). The slow turnover and multitude of possible structures make PrP Sc an interesting candidate for information storage in short-term memory.…”

Section: A Physiological Function For Prpmentioning

confidence: 99%

Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes

Legname

Nguyen

Peretz

et al. 2006

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

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204

207

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On passaging synthetic prions, two isolates emerged with incubation times differing by nearly 100 days. Using conformational-stability assays, we determined the guanidine hydrochloride (Gdn⅐HCl) concentration required to denature 50% of disease-causing prion protein (PrP Sc ) molecules, denoted as the [Gdn⅐HCl]1/2 value. For the two prion isolates enciphering shorter and longer incubation times, [Gdn⅐HCl]1/2 values of 2.9 and 3.7 M, respectively, were found. Intrigued by this result, we measured the conformational stabilities of 30 prion isolates from synthetic and naturally occurring sources that had been passaged in mice. When the incubation times were plotted as a function of the [Gdn⅐HCl] 1/2 values, a linear relationship was found with a correlation coefficient of 0.93. These findings demonstrate that (i) less stable prions replicate more rapidly than do stable prions, and (ii) a continuum of PrP Sc structural states enciphers a multitude of incubation-time phenotypes. Our data argue that cellular machinery must exist for propagating a large number of different PrP Sc conformers, each of which enciphers a distinct biological phenotype as reflected by a specific incubation time. The biophysical explanation for the unprecedented plasticity of PrP Sc remains to be determined.conformational stability ͉ memory ͉ strain ͉ synthetic prions ͉ tertiary structure

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Search for a Prion-Specific Nucleic Acid

Cited by 121 publications

References 71 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Nucleic acid induced unfolding of recombinant prion protein globular fragment is pH dependent

Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes

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