Conversion Efficiency of Bank Vole Prion Protein in Vitro Is Determined by Residues 155 and 170, but Does Not Correlate with the High Susceptibility of Bank Voles to Sheep Scrapie in Vivo

Piening, Niklas; Nonno, Romolo; Bari, Michele Di; Wälter, Stephanie; Windl, Otto; Agrimi, Umberto; Kretzschmar, Hans A.; Bertsch, Uwe

doi:10.1074/jbc.m512239200

Cited by 49 publications

(62 citation statements)

References 66 publications

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“…Prions can transmit between different species; however, infection of a new species is typically characterized by prolonged, variable incubation periods and low attack rates (41,42). Known determinants of interspecies prion conversion are (a) PrP C and PrP Sc sequence similarity and (b) the conformation of the infectious prion (43,44). Here we propose to add a third determinant, the presence of glutamines or asparagines in host PrP C within key interaction segments.…”

Section: Discussionmentioning

confidence: 99%

Human prion protein sequence elements impede cross-species chronic wasting disease transmission

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Human prion protein sequence elements impede cross-species chronic wasting disease transmission

et al. 2015

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“…The β2-α2 loop is part of a surface epitope that has attracted keen interest with regard to its potential role in the onset of TSEs. (i) Specific amino acid types in positions 167 and 170 have been related to high susceptibility for interspecies transmission to bank voles (49,50) and spontaneous TSE in transgenic mice expressing designed variants of mPrP (11,13,14). (ii) The residue position 168 is polymorphic in sheep PrP, and the residue type in this position affects susceptibility of sheep to scrapie (51)(52)(53)(54).…”

Section: Resultsmentioning

confidence: 99%

Structural plasticity of the cellular prion protein and implications in health and disease

Christen¹,

Damberger²,

Pérez³

et al. 2013

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

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Two lines of transgenic mice expressing mouse/elk and mouse/ horse prion protein (PrP) hybrids, which both form a well-structured β2-α2 loop in the NMR structures at 20°C termed rigid-loop cellular prion proteins (RL-PrP C ), presented with accumulation of the aggregated scrapie form of PrP in brain tissue, and the mouse/ elk hybrid has also been shown to develop a spontaneous transmissible spongiform encephalopathy. Independently, there is in vitro evidence for correlations between the amino acid sequence in the β2-α2 loop and the propensity for conformational transitions to disease-related forms of PrP. To further contribute to the structural basis for these observations, this paper presents a detailed characterization of RL-PrP C conformations in solution. A dynamic local conformational polymorphism involving the β2-α2 loop was found to be evolutionarily preserved among all mammalian species, including those species for which the WT PrP forms an RL-PrP C . The interconversion between two ensembles of PrP C conformers that contain, respectively, a 3 10 -helix turn or a type I β-turn structure of the β2-α2 loop, exposes two different surface epitopes, which are analyzed for their possible roles in the still evasive function of PrP C in healthy organisms and/or at the onset of a transmissible spongiform encephalopathy. Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, bovine spongiform encephalopathy in cattle, and chronic wasting disease (CWD) in elk and deer (1-3). A common feature of these diseases is the conversion of the cellular form of the prion protein (PrP C ) found in healthy organisms into aggregated isoforms (PrP Sc ), which are deposited primarily in the brain of the diseased individuals (1, 4). Despite extensive investigations, the physiological function of PrP C in healthy organisms as well as the mechanistic aspects of its pathophysiological role remain elusive (4-9). Although the PrP Sc form found in diseased tissue has been intensively studied, other approaches underline the importance of PrP C as a potential target for TSE prevention and medical intervention after outbreak of the disease (10-12), with a special focus on rigid-loop cellular prion proteins (RL-PrP C s) (11,(13)(14)(15), which are investigated in this paper.A common PrP C fold for a globular domain formed by the polypeptide segment of residues 125-228 in mouse PrP (mPrP) [see Schätzl et al. (16) for the numeration in different species], with three α-helices and a short two-stranded antiparallel β-sheet, has been observed for the cellular prion proteins of all mammalian species studied so far (17-27). For WT PrP of most species, parts of the backbone amide group NMR signals of residues in a loop between a β-strand, β2, and a helix, α2, are not observable in NMR spectra recorded with aqueous solutions at pH 4.5 and 20°C at a 1 H resonance frequency of 500 MHz (or higher) because of line broadening by conformational exchange; therefore, the β2-α2 loop in these PrP C s is poorly defined in NMR structures determined un...

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“…Interestingly, bank voles (Clethrionomys glareolus), are readily infected with CWD and sheep scrapie by intracerebral inoculation ( [64]; U. Agrimi, unpublished data) and are considered as a potential reservoir for sheep scrapie [64]. Many vole species occur in North America [65,83] and further research may determine whether voles enhance CWD or scrapie spread through environmental contamination.…”

Section: Interspecies Cwd Transmissionmentioning

confidence: 99%

A prion disease of cervids: Chronic wasting disease

2008

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-Chronic wasting disease (CWD) is a prion disease of deer, elk, and moose, initially recognized in Colorado mule deer. The discovery of CWD beyond the borders of Colorado and Wyoming, in Canada and as far east as New York, has led to its emergence as a prion disease of international importance. Epidemiological studies indicate that CWD is horizontally transmitted among free-ranging animals, potentially indirectly by prion-containing secreta or excreta contaminating the environment. Experimental CWD transmission attempts to other wild and domestic mammals and to transgenic mice expressing the prion protein of cattle, sheep, and humans have shed light on CWD species barriers. Transgenic mice expressing the cervid prion protein have proven useful for assessing the genetic influences of Prnp polymorphisms on CWD susceptibility. Accumulating evidence of CWD pathogenesis indicates that the misfolded prion protein or prion infectivity seems to be widely disseminated in many nonneural organs and in blood. This review highlights contemporary research findings in this prion disease of free-ranging wildlife.

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Conversion Efficiency of Bank Vole Prion Protein in Vitro Is Determined by Residues 155 and 170, but Does Not Correlate with the High Susceptibility of Bank Voles to Sheep Scrapie in Vivo

Cited by 49 publications

References 66 publications

Human prion protein sequence elements impede cross-species chronic wasting disease transmission

Human prion protein sequence elements impede cross-species chronic wasting disease transmission

Structural plasticity of the cellular prion protein and implications in health and disease

A prion disease of cervids: Chronic wasting disease

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