Variable Protease-Sensitive Prionopathy Transmission to Bank Voles

Nonno, Romolo; Notari, Silvio; Bari, Michele Angelo Di; Calì, Ignazio; Pirisinu, Laura; D’Agostino, Claudia; Cracco, Laura; Kofskey, Diane; Vanni, Ilaria; Lavrich, Jody; Parchi, Piero; Agrimi, Umberto

doi:10.3201/eid2501.180807

Cited by 29 publications

(28 citation statements)

References 40 publications

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“…It has been shown that the infectivity of VPSPr is lower, if present, compared to that of sCJD [ 29 , 30 , 31 ]. To compare aggregation seeding activity of PrP Sc of VPSPr with that of PrP Sc from other more common sporadic and familial prion diseases, we conducted a RT-QuIC assay of serial dilutions of brain homogenate seeds with three genotypes of VPSPr, sCJDMV2 and GSS linked to PrP P102L mutation.…”

Section: Resultsmentioning

confidence: 99%

Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy

et al. 2021

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Prion is an infectious protein (PrPSc) that is derived from a cellular glycoprotein (PrPC) through a conformational transition and associated with a group of prion diseases in animals and humans. Characterization of proteinase K (PK)-resistant PrPSc by western blotting has been critical to diagnosis and understanding of prion diseases including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker (GSS) disease in humans. However, formation as well as biochemical and biological properties of the glycoform-selective PrPSc in variably protease-sensitive prionopathy (VPSPr) remain poorly understood. Here we reveal that formation of the ladder-like PrPSc in VPSPr is a PK-dependent two-step process, which is enhanced by basic pH. Two sets of PrPSc fragments can be identified with antibodies directed against an intermediate or a C-terminal domain of the protein. Moreover, antibodies directed against specific PrP glycoforms reveal faster electrophoretic migrations of PrP fragments mono-glycosylated at residue 181 and 197 in VPSPr than those in sporadic CJD (sCJD). Finally, RT-QuIC assay indicates that PrPSc-seeding activity is lower and its lag time is longer in VPSPr than in sCJD. Our results suggest that the glycoform-selective PrPSc in VPSPr is associated with altered glycosylation, resulting in different PK-truncation and aggregation seeding activity compared to PrPSc in sCJD.

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Section: Resultsmentioning

confidence: 99%

Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy

et al. 2021

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“…The use of bank voles as a model system has certainly been pivotal for the present study. Indeed, bank voles and transgenic mice expressing bank vole PrP have been shown to faithfully propagate prion strains from various species ( 26 , 31 , 32 ), including prion strains that are difficult to transmit in other animal models ( 33 , 34 ). We based our conclusions on a careful comparison of incubation times and pathological phenotypes induced by natural CWD isolates along three serial passages in the new host.…”

Section: Discussionmentioning

confidence: 99%

Studies in bank voles reveal strain differences between chronic wasting disease prions from Norway and North America

Nonno

Bari

Pirisinu

et al. 2020

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

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Chronic wasting disease (CWD) is a relentless epidemic disorder caused by infectious prions that threatens the survival of cervid populations and raises increasing public health concerns in North America. In Europe, CWD was detected for the first time in wild Norwegian reindeer (Rangifer tarandus) and moose (Alces alces) in 2016. In this study, we aimed at comparing the strain properties of CWD prions derived from different cervid species in Norway and North America. Using a classical strain typing approach involving transmission and adaptation to bank voles (Myodes glareolus), we found that prions causing CWD in Norway induced incubation times, neuropathology, regional deposition of misfolded prion protein aggregates in the brain, and size of their protease-resistant core, different from those that characterize North American CWD. These findings show that CWD prion strains affecting Norwegian cervids are distinct from those found in North America, implying that the highly contagious North American CWD prions are not the proximate cause of the newly discovered Norwegian CWD cases. In addition, Norwegian CWD isolates showed an unexpected strain variability, with reindeer and moose being caused by different CWD strains. Our findings shed light on the origin of emergent European CWD, have significant implications for understanding the nature and the ecology of CWD in Europe, and highlight the need to assess the zoonotic potential of the new CWD strains detected in Europe.

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“…These results showed striking similarities to those obtained in a subgroup of GSS cases. More recently, VPSPr inocula efficiently transmitted the disease to bank voles (Bv109M, Bv109I) [180]. Despite the low attack rate after the first passage (5% for Bv109M, 35% Bv109I), all inoculated animals developed the disease and showed dramatically reduced survival times (about 50%) after the secondary transmission, suggesting a consistent species barrier between humans and bank voles.…”

Section: Characterization Of Human Prion Strains By Experimental Tmentioning

confidence: 99%

“…Despite the low attack rate after the first passage (5% for Bv109M, 35% Bv109I), all inoculated animals developed the disease and showed dramatically reduced survival times (about 50%) after the secondary transmission, suggesting a consistent species barrier between humans and bank voles. Intriguingly, the affected animals showed three histo-molecular phenotypes, apparently unrelated to genotype at codon 129, with transmission characteristics reproducing those of PrP Sc type 1 (21 kDa) and 2 (19 kDa) sCJD, and GSS expressing the ~7 kDa PrP Sc fragment [180].…”

Section: Characterization Of Human Prion Strains By Experimental Tmentioning

confidence: 99%

Understanding Prion Strains: Evidence from Studies of the Disease Forms Affecting Humans

Rossi

Baiardi

Parchi

2019

Viruses

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Prion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded protease-resistant prion protein (PrPSc), a broad spectrum of disease phenotypes and a variable efficiency of disease propagation in vivo. The dominant clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. Prion disease propagation into susceptible hosts led to the isolation and characterization of prion strains, initially operatively defined as “isolates” causing diseases with distinctive characteristics, such as the incubation period, the pattern of PrPSc distribution, and the regional severity of neuropathological changes after injection into syngeneic hosts. More recently, the structural basis of prion strains has been linked to amyloid polymorphs (i.e., variant amyloid protein conformations) and the concept extended to all protein amyloids showing polymorphic structures and some evidence of in vivo or in vitro propagation by seeding. Despite the significant advances, however, the link between amyloid structure and disease is not understood in many instances. Here we reviewed the most significant contributions of human prion disease studies to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective.

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Variable Protease-Sensitive Prionopathy Transmission to Bank Voles

Cited by 29 publications

References 40 publications

Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy

Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy

Studies in bank voles reveal strain differences between chronic wasting disease prions from Norway and North America

Understanding Prion Strains: Evidence from Studies of the Disease Forms Affecting Humans

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