The Unfolding of the Prion Protein Sheds Light on the Mechanisms of Prion Susceptibility and Species Barrier

Biochemistry ◽  
2009 ◽  
Vol 48 (36) ◽  
pp. 8551-8558 ◽  
Author(s):  
Philip J. Robinson ◽  
Teresa J. T. Pinheiro
Keyword(s):  
Prion Protein ◽  
Species Barrier

scholarly journals Experimental Transmission of the Chronic Wasting Disease Agent to Swine after Oral or Intracranial Inoculation

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
S. Jo Moore ◽  
M. Heather West Greenlee ◽  
Naveen Kondru ◽  
Sireesha Manne ◽  
Jodi D. Smith ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Chronic Wasting Disease ◽  
Mouse Bioassay ◽  
Lymphoid Tissues ◽  
Species Barrier ◽  
Wasting Disease ◽  
Disease Agent ◽  
Domestic Swine

ABSTRACT Chronic wasting disease (CWD) is a naturally occurring, fatal neurodegenerative disease of cervids. The potential for swine to serve as hosts for the agent of CWD is unknown. The purpose of this study was to investigate the susceptibility of swine to the CWD agent following experimental oral or intracranial inoculation. Crossbred piglets were assigned to three groups, intracranially inoculated (n = 20), orally inoculated (n = 19), and noninoculated (n = 9). At approximately the age at which commercial pigs reach market weight, half of the pigs in each group were culled (“market weight” groups). The remaining pigs (“aged” groups) were allowed to incubate for up to 73 months postinoculation (mpi). Tissues collected at necropsy were examined for disease-associated prion protein (PrPSc) by Western blotting (WB), antigen capture enzyme immunoassay (EIA), immunohistochemistry (IHC), and in vitro real-time quaking-induced conversion (RT-QuIC). Brain samples from selected pigs were also bioassayed in mice expressing porcine prion protein. Four intracranially inoculated aged pigs and one orally inoculated aged pig were positive by EIA, IHC, and/or WB. By RT-QuIC, PrPSc was detected in lymphoid and/or brain tissue from one or more pigs in each inoculated group. The bioassay was positive in four out of five pigs assayed. This study demonstrates that pigs can support low-level amplification of CWD prions, although the species barrier to CWD infection is relatively high. However, detection of infectivity in orally inoculated pigs with a mouse bioassay raises the possibility that naturally exposed pigs could act as a reservoir of CWD infectivity. IMPORTANCE We challenged domestic swine with the chronic wasting disease agent by inoculation directly into the brain (intracranially) or by oral gavage (orally). Disease-associated prion protein (PrPSc) was detected in brain and lymphoid tissues from intracranially and orally inoculated pigs as early as 8 months of age (6 months postinoculation). Only one pig developed clinical neurologic signs suggestive of prion disease. The amount of PrPSc in the brains and lymphoid tissues of positive pigs was small, especially in orally inoculated pigs. Regardless, positive results obtained with orally inoculated pigs suggest that it may be possible for swine to serve as a reservoir for prion disease under natural conditions.

scholarly journals Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice Overexpressing Human Prion Protein

2015 ◽  
Vol 89 (11) ◽  
pp. 6022-6032 ◽  
Author(s):  
Brent Race ◽  
Katie Phillips ◽  
Kimberly Meade-White ◽  
James Striebel ◽  
Bruce Chesebro
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Transgenic Mice ◽  
Prion Protein ◽  
Prion Diseases ◽  
Human Species ◽  
Species Barrier ◽  
Gpi Anchor ◽  
Prion Infection ◽  
Barrier Model

ABSTRACTPrion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previousin vivostudies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8- to 16-fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2- to 4-fold above normal.IMPORTANCEPrion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by mice expressing only anchorless PrP were more infectious than prions produced in mice expressing anchored PrP. Thus, the lack of the GPI anchor on prions reduced the effect of the mouse-human species barrier. Our results suggest that prion diseases that produce higher levels of anchorless PrP may pose an increased risk for cross-species infection.

scholarly journals Species specificity in the cell-free conversion of prion protein to protease-resistant forms: a model for the scrapie species barrier.

1995 ◽  
Vol 92 (9) ◽  
pp. 3923-3927 ◽  
Author(s):  
D. A. Kocisko ◽  
S. A. Priola ◽  
G. J. Raymond ◽  
B. Chesebro ◽  
P. T. Lansbury ◽  
...  
Keyword(s):  
Prion Protein ◽  
Species Specificity ◽  
Species Barrier

scholarly journals Species barrier in prion diseases: a kinetic interpretation based on the conformational adaptation of the prion protein

1998 ◽  
Vol 334 (3) ◽  
pp. 539-545 ◽  
Author(s):  
Nicolas KELLERSHOHN ◽  
Michel LAURENT
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Infectious Agent ◽  
Cellular Protein ◽  
Cellular Prion Protein ◽  
Interspecies Transmission ◽  
Rate Equations ◽  
Differential Rate ◽  
Species Barrier ◽  
Brain Extracts

Prion diseases are thought to result from the conformational change of the normal cellular prion protein to a pathogenic protease-resistant isoform. However, brain extracts not containing the protease-resistant isoform of the prion protein can be infectious following interspecies transmission. The ‘protein-only ’ hypothesis of pathogenesis is extended to provide possible explanations which could be interpreted in terms of a different infectious agent. It is proposed that normal cellular protein (PrPC) may be transformed into a form (PrP*) that is conformationally distinct from the host-specific abnormal isoform (PrPSc). In infection from a heterologous donor, the dimeric forms of heterologous PrPSc, which may catalyse the formation of host PrP* from PrPC, host PrP* and host PrPSc are all considered to be capable of catalysing, to some extent, the conversion of PrPC into PrPSc. However, depending on the species involved, PrP* may, or may not, be pathogenic, and may, or may not, be sensitive to proteolysis. It is shown, by numerical integration of the differential rate equations derived from this model, that a strain may be stabilized after two or three passages through a different species and that transmission might occur in the absence of detectable protease-resistant prion protein. The natural transmission of scrapie to cattle is discussed in relation to the model.

scholarly journals Sialylation of Prion Protein Controls the Rate of Prion Amplification, the Cross-Species Barrier, the Ratio of PrPSc Glycoform and Prion Infectivity

2014 ◽  
Vol 10 (9) ◽  
pp. e1004366 ◽  
Author(s):  
Elizaveta Katorcha ◽  
Natallia Makarava ◽  
Regina Savtchenko ◽  
Alessandra d′Azzo ◽  
Ilia V. Baskakov
Keyword(s):  
Prion Protein ◽  
Species Barrier ◽  
Prion Infectivity ◽  
The Cross

scholarly journals Contributions of the Prion Protein Sequence, Strain, and Environment to the Species Barrier

2015 ◽  
Vol 291 (3) ◽  
pp. 1277-1288 ◽  
Author(s):  
Aditi Sharma ◽  
Kathryn L. Bruce ◽  
Buxin Chen ◽  
Stefka Gyoneva ◽  
Sven H. Behrens ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Sequence ◽  
Species Barrier

scholarly journals Prion protein NMR structure and species barrier for prion diseases

1997 ◽  
Vol 94 (14) ◽  
pp. 7281-7285 ◽  
Author(s):  
M. Billeter ◽  
R. Riek ◽  
G. Wider ◽  
S. Hornemann ◽  
R. Glockshuber ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Protein Nmr ◽  
Nmr Structure ◽  
Species Barrier

Intermediate states and implications for the species barrier of the human prion protein revealed by high pressure NMR

2004 ◽  
Vol 2004 (Fall) ◽  
Author(s):  
Norman Kachel ◽  
Werner Kremer ◽  
Ralph Zahn ◽  
Hans Robert Kalbitzer
Keyword(s):  
High Pressure ◽  
Prion Protein ◽  
Species Barrier ◽  
Intermediate States ◽  
Human Prion Protein

scholarly journals Complementation between pathological prion protein subassemblies to cross existing species barriers

2019 ◽  
Author(s):  
Angélique Igel-Egalon ◽  
Florent Laferrière ◽  
Philippe Tixador ◽  
Mohammed Moudjou ◽  
Laetitia Herzog ◽  
...  
Keyword(s):  
Prion Protein ◽  
Species Concept ◽  
Structural Heterogeneity ◽  
Size Fractionation ◽  
Species Barrier ◽  
Size Dependent ◽  
Prion Strains ◽  
Insight Into ◽  
Relative Capacity ◽  
Transmission Barrier

AbstractBackgroundprion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrPC into misfolded, polydisperse PrPSc conformers. Structurally distinct PrPSc conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative efficacy and specific infectivity) of PrPSc assemblies is size-dependent and thus reflects an intrinsic structural heterogeneity. The contribution of such PrPSc heterogeneity across species prion adaptation, - which is believed to be based on fit-adjustment between PrPSc template(s) and host PrPC -, has not been explored.Methodsto define the structural-to-fitness PrPSc landscape, we measured the relative capacity of size-fractionated PrPSc assemblies from different prion strains to cross mounting species barriers in transgenic mice expressing foreign PrPc.Resultsin the absence of a transmission barrier, the relative efficacy of the isolated PrPSc assemblies to induce the disease is superimposable to the efficacy observed in the homotypic context. However, in the presence of a transmission barrier, size fractionation overtly delays and even abrogates prion pathogenesis in both neural and extraneural, prion-permissive tissues, for reason independent of the infectivity load of the isolated assemblies. This suggests that a synergy between structurally distinct PrPSc assemblies in the inoculum is requested for crossing the species barrier. We further strengthen this hypothesis by showing that altering, by serial dilution, PrPSc assemblies content of unfractionated inocula reduce their specific infectivity in an aberrant manner, solely in the presence of a transmission barrier.Conclusionsour data support a mechanism whereby overcoming prion species barrier requires complementation between structurally distinct PrPSc assemblies. This work provides key insight into the “quasi-species” concept applied to prions, which would not necessarily rely on prion sub-strains as constituent but on structural PrPSc heterogeneity within prion population.

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