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Small ruminant nor98 prions share biochemical features with human gerstmann-straussler-scheinker disease and variably protease-sensitive prionopathy.

ABSTRACT: Prion diseases are classically characterized by the accumulation of pathological prion protein (PrP(Sc)) with the protease resistant C-terminal fragment (PrP(res)) of 27-30 kDa. However, in both humans and animals, prion diseases with atypical biochemical features, characterized by PK-resistant PrP internal fragments (PrP(res)) cleaved at both the N and C termini, have been described. In this study we performed a detailed comparison of the biochemical features of PrP(Sc) from atypical prion diseases including human Gerstmann-Sträussler-Scheinker disease (GSS) and variably protease-sensitive prionopathy (VPSPr) and in small ruminant Nor98 or atypical scrapie. The kinetics of PrP(res) production and its cleavage sites after PK digestion were analyzed, along with the PrP(Sc) conformational stability, using a new method able to characterize both protease-resistant and protease-sensitive PrP(Sc) components. All these PrP(Sc) types shared common and distinctive biochemical features compared to PrP(Sc) from classical prion diseases such as sporadic Creutzfeldt-Jakob disease and scrapie. Notwithstanding, distinct biochemical signatures based on PrP(res) cleavage sites and PrP(Sc) conformational stability were identified in GSS A117V, GSS F198S, GSS P102L and VPSPr, which allowed their specific identification. Importantly, the biochemical properties of PrP(Sc) from Nor98 and GSS P102L largely overlapped, but were distinct from the other human prions investigated. Finally, our study paves the way towards more refined comparative approaches to the characterization of prions at the animal-human interface.

SUBMITTER: Pirisinu L

PROVIDER: S-EPMC3691246 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Small ruminant nor98 prions share biochemical features with human gerstmann-sträussler-scheinker disease and variably protease-sensitive prionopathy.

Pirisinu Laura L Nonno Romolo R Esposito Elena E Benestad Sylvie L SL Gambetti Pierluigi P Agrimi Umberto U Zou Wen-Quan WQ

PloS one 20130624 6

Prion diseases are classically characterized by the accumulation of pathological prion protein (PrP(Sc)) with the protease resistant C-terminal fragment (PrP(res)) of 27-30 kDa. However, in both humans and animals, prion diseases with atypical biochemical features, characterized by PK-resistant PrP internal fragments (PrP(res)) cleaved at both the N and C termini, have been described. In this study we performed a detailed comparison of the biochemical features of PrP(Sc) from atypical prion dise ...[more]

PMID: 23826096

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Project description:This study aimed to determine the pattern of [18F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [18F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [18F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer's disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [18F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem. Scans were processed to generate standardized uptake value ratio (SUVR) images. Regional [18F]flortaucipir SUVR was extracted and compared between GSS patients, EOADs, and CNs. Neuropathology and tau immunohistochemistry were carried out post-mortem on a GSS patient who died 9 months after the [18F]flortaucipir scan. The GSS patients were at different stages of disease progression. Patient A was mildly to moderately affected, suffering from cognitive, psychiatric, and ataxia symptoms. Patient B was moderately to severely affected, suffering from ataxia and parkinsonism accompanied by psychiatric and cognitive symptoms. The [18F]flortaucipir scans showed uptake in frontal, cingulate, and insular cortices, as well as in the striatum and thalamus. Uptake was greater in Patient B than in Patient A. Both GSS patients showed greater uptake in the striatum and thalamus than the EOADs and greater uptake in all evaluated regions than the CNs. Thioflavin S fluorescence and immunohistochemistry revealed that the anatomical distribution of tau pathology is consistent with that of [18F]flortaucipir uptake. In GSS patients, the neuroanatomical localization of pathologic tau, as detected by [18F]flortaucipir, suggests correlation with the psychiatric, motor, and cognitive symptoms. The topography of uptake in PRNP F198S GSS is strikingly different from that seen in AD. Further studies of the sensitivity, specificity, and anatomical patterns of tau PET in diseases with tau pathology are warranted.

Dataset Information

Small ruminant nor98 prions share biochemical features with human gerstmann-straussler-scheinker disease and variably protease-sensitive prionopathy.

Publications

Small ruminant nor98 prions share biochemical features with human gerstmann-sträussler-scheinker disease and variably protease-sensitive prionopathy.

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