scholarly journals Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1794
Author(s):  
Nicholas Brennecke ◽  
Ignazio Cali ◽  
Tze Mok ◽  
Helen Speedy ◽  
Laszlo Hosszu ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Genetic Variant ◽  
Molecular Subtype ◽  
Case Series ◽  
Low Risk ◽  
Proteinase K ◽  
Jakob Disease ◽  
Insight Into

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.

scholarly journals Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin

2008 ◽  
Vol 416 (2) ◽  
pp. 297-305 ◽  
Author(s):  
Sabrina Cronier ◽  
Nathalie Gros ◽  
M. Howard Tattum ◽  
Graham S. Jackson ◽  
Anthony R. Clarke ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Rocky Mountain ◽  
Proteinase K ◽  
Spongiform Encephalopathy ◽  
Prion Strains ◽  
Human Counterpart ◽  
Jakob Disease ◽  
The Brain

Disease-related PrPSc [pathogenic PrP (prion protein)] is classically distinguished from its normal cellular precursor, PrPC(cellular PrP) by its detergent insolubility and partial resistance to proteolysis. Although molecular diagnosis of prion disease has historically relied upon detection of protease-resistant fragments of PrPSc using PK (proteinase K), it is now apparent that a substantial fraction of disease-related PrP is destroyed by this protease. Recently, thermolysin has been identified as a complementary tool to PK, permitting isolation of PrPSc in its full-length form. In the present study, we show that thermolysin can degrade PrPC while preserving both PK-sensitive and PK-resistant isoforms of disease-related PrP in both rodent and human prion strains. For mouse RML (Rocky Mountain Laboratory) prions, the majority of PK-sensitive disease-related PrP isoforms do not appear to contribute significantly to infectivity. In vCJD (variant Creutzfeldt–Jakob disease), the human counterpart of BSE (bovine spongiform encephalopathy), up to 90% of total PrP present in the brain resists degradation with thermolysin, whereas only ∼15% of this material resists digestion by PK. Detection of PK-sensitive isoforms of disease-related PrP using thermolysin should be useful for improving diagnostic sensitivity in human prion diseases.

scholarly journals Genetic human prion disease modelled in PrP transgenic Drosophila

2017 ◽  
Vol 474 (19) ◽  
pp. 3253-3267 ◽  
Author(s):  
Alana M. Thackray ◽  
Alzbeta Cardova ◽  
Hanna Wolf ◽  
Lydia Pradl ◽  
Ina Vorberg ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Principal Component ◽  
Site Directed Mutagenesis ◽  
Host Protein ◽  
Therapeutic Interventions ◽  
Proteinase K ◽  
Human Prion Disease ◽  
Transgenic Drosophila

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt–Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrPSc, an abnormal isomer of the normal host protein PrPC, in the brain of affected individuals. PrPSc is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, Drosophila has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in Drosophila. We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila. Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host.

The neuroepidemiology of human prion disease

2020 ◽  
pp. 367-378
Author(s):  
Patrick JM Urwin ◽  
Anna M Molesworth
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Prion Protein Gene ◽  
Human Prion Disease ◽  
Disease States ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
Sporadic Disease

Human prion diseases comprise a number of rare and fatal neurodegenerative conditions that result from the accumulation in the central nervous system of an abnormal form of a naturally occurring protein, called the prion protein. The diseases occur in genetic, sporadic, and acquired forms: genetic disease is associated with mutations in the prion protein gene (PRNP); sporadic disease is thought to result from a spontaneous protein misfolding event; acquired disease results from transmission of infection from an animal or another human. The potential transmissibility of the prion in any of these forms, either in disease states or during the incubation period, has implications for public health. Here we focus on Creutzfeldt-Jakob Disease (CJD), including variant Creutzfeldt-Jakob Disease (vCJD), although we will also discuss other forms of human prion disease.

scholarly journals Molecular Characterization of the Danish Prion Diseases Cohort With Special Emphasis on Rare and Unique Cases

2019 ◽  
Vol 78 (11) ◽  
pp. 980-992 ◽  
Author(s):  
Aušrinė Areškevičiūtė ◽  
Helle Broholm ◽  
Linea C Melchior ◽  
Anna Bartoletti-Stella ◽  
Piero Parchi ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Prion Disease ◽  
Prion Diseases ◽  
The Past ◽  
Disease Biology ◽  
Fresh Frozen ◽  
Jakob Disease ◽  
Disease Subtypes ◽  
Codon 129

Abstract The purpose of this study was to perform an updated reclassification of all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over the past 40 years, putting a special emphasis on the molecular characterization of novel disease subtypes. Investigation of the Danish prion diseases cohort revealed rare sporadic Creutzfeldt-Jakob disease cases with mixed subtypes and subtypes with previously uncharacterized white matter plaques, a new case of sporadic fatal insomnia, and 3 novel mutations, including 2 large octapeptide repeat insertions, and a point mutation in the prion protein gene. The evaluation of methionine and valine distribution at codon 129 among the prion disease patients in the cohort revealed the increased prevalence of methionine homozygotes compared to the general population. This observation was in line with the prevalence reported in other Caucasian prion disease cohort studies. Reclassification of the old prion diseases cohort revealed unique cases, the molecular characterization of which improves prion diseases classification, diagnostic accuracy, genetic counseling of affected families, and the understanding of disease biology.

Enzymatic detergent treatment protocol that reduces protease-resistant prion protein load and infectivity from surgical-steel monofilaments contaminated with a human-derived prion strain

2007 ◽  
Vol 88 (10) ◽  
pp. 2905-2914 ◽  
Author(s):  
Victoria A. Lawson ◽  
James D. Stewart ◽  
Colin L. Masters
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Disease Transmission ◽  
Prion Diseases ◽  
Medical Instrument ◽  
Treatment Protocol ◽  
Infectious Agent ◽  
Surgical Instruments ◽  
Prion Strain ◽  
Jakob Disease

The unconventional nature of the infectious agent of prion diseases poses a challenge to conventional infection control methodologies. The extraneural tissue distribution of variant and sporadic Creutzfeldt–Jakob disease has increased concern regarding the risk of prion disease transmission via general surgical procedures and highlighted the need for decontamination procedures that can be incorporated into routine processing. In this study, the ability of preparations of enzymatic medical instrument cleaners to reduce the infectivity associated with a rodent-adapted strain of human prion disease, previously reported to be resistant to decontamination, was tested. Efficient degradation of the disease-associated prion protein by enzymatic cleaning preparations required high treatment temperatures (50–60 °C). Standard decontamination methods (1 M NaOH for 1 h or autoclaving at 134 °C for 18 min) reduced infectivity associated with the human-derived prion strain by less than 3 log10 LD50. In contrast, a 30 min treatment with the optimized enzymatic cleaning preparation protocols reduced infectivity by more than 3 log10 LD50 and when used in conjunction with autoclave cycles eliminated detectable levels of infectivity. The development of prion decontamination procedures that are compatible with routine cleaning and sterilization of medical and surgical instruments may reduce the risk of the transmission of prion disease in general surgery.

scholarly journals Prion protein in the cerebrospinal fluid of healthy and naturally scrapie-affected sheep

2006 ◽  
Vol 87 (12) ◽  
pp. 3723-3727 ◽  
Author(s):  
Nicole Picard-Hagen ◽  
Véronique Gayrard ◽  
Catherine Viguié ◽  
Mohammed Moudjou ◽  
Chantal Imbs ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Physicochemical Properties ◽  
Prion Protein ◽  
Prion Disease ◽  
Genetic Variants ◽  
Proteinase K ◽  
Soluble Form ◽  
C Terminus ◽  
The Mean ◽  
Mean Concentration

The aim of this study was to characterize the cerebrospinal fluid (CSF) prion protein (PrP) of healthy and naturally scrapie-affected sheep. The soluble form of CSF PrPC immunoblotted with an anti-octarepeat and an anti-C terminus mAb showed two isoforms of approximately 33 and 26 kDa, corresponding to the biglycosylated and unglycosylated isoforms of brain PrPC. Neither the mean concentration nor the electrophoretic profile of CSF PrP differed between healthy and scrapie-affected sheep, whereas a slightly increased resistance of CSF PrP to mild proteolysis by proteinase K was evident in the CSF of scrapie-affected sheep. No difference in susceptibility to proteolysis was observed between the two ARR and VRQ genetic variants of the purified prokaryote recombinant PrP. It was concluded that the physicochemical properties of PrPC in the CSF could be altered during scrapie and that these changes might reflect the physiopathological process of prion disease.

scholarly journals Characterization of proteinase K-resistant N- and C-terminally truncated PrP in Nor98 atypical scrapie

2006 ◽  
Vol 87 (6) ◽  
pp. 1751-1760 ◽  
Author(s):  
Mikael Klingeborn ◽  
Lotta Wik ◽  
Magnus Simonsson ◽  
Lena H. M. Renström ◽  
Therese Ottinger ◽  
...  
Keyword(s):  
Prion Protein ◽  
Structural Gene ◽  
Proteinase K ◽  
Atypical Scrapie ◽  
Antigenic Composition ◽  
Electrophoretic Profile ◽  
Brain Extracts ◽  
Overlapping Region

An increasing number of scrapie cases with atypical characteristics, designated Nor98, have recently been recognized. Here, the proteinase K (PK)-resistant prion protein (PrP) fragments from two Swedish cases of Nor98 atypical scrapie have been characterized. The prominent, fast-migrating band in the distinct Nor98 Western immunoblot electrophoretic profile was determined to be of 7 kDa in size and was accordingly designated Nor98-PrP7. The antigenic composition of Nor98-PrP7, as assayed by a panel of anti-PrP antibodies, revealed that this fragment comprised a mid-region of PrP from around aa 85 to 148. N- and C-terminally truncated fragments spanning the mid-region of PrP have only been observed in the genetic prion disorder Gerstmann–Sträussler–Scheinker disease. It is shown here that the long-term PK resistance of Nor98-PrP7 is reduced compared with that of PrPres in classical scrapie. Enzymic deglycosylation did not change the distinct electrophoretic profile of Nor98-PrP7. A previously unidentified, PK-resistant, C-terminal PrP fragment of around 24 kDa was detected and its PK resistance was investigated. After deglycosylation, this fragment migrated as a 14 kDa polypeptide and was designated PrP-CTF14. Antigenic determination and the size of 14 kDa suggested a fragment spanning approximately aa 120–233. The existence of two PK-resistant PrP fragments, Nor98-PrP7 and PrP-CTF14, that share an overlapping region suggests that at least two distinct PrP conformers with different PK-resistant cores are present in brain extracts from Nor98-affected sheep. The structural gene of PrP in three Nor98-affected sheep was analysed, but no mutations were found that could be correlated to the aberrant PK-resistant profile observed.

scholarly journals Characterization of Truncated Forms of Abnormal Prion Protein in Creutzfeldt-Jakob Disease

2008 ◽  
Vol 283 (45) ◽  
pp. 30557-30565 ◽  
Author(s):  
Silvio Notari ◽  
Rosaria Strammiello ◽  
Sabina Capellari ◽  
Armin Giese ◽  
Maura Cescatti ◽  
...  
Keyword(s):  
Prion Protein ◽  
Jakob Disease

scholarly journals Impaired transmissibility of atypical prions from genetic CJDG114V

2018 ◽  
Vol 4 (4) ◽  
pp. e253 ◽  
Author(s):  
Ignazio Cali ◽  
Fadi Mikhail ◽  
Kefeng Qin ◽  
Crystal Gregory ◽  
Ani Solanki ◽  
...  
Keyword(s):  
Prion Disease ◽  
Protein Misfolding ◽  
Proteinase K ◽  
Progressive Dementia ◽  
Replication Studies ◽  
Jakob Disease ◽  
Transmission Studies

ObjectiveTo describe the clinicopathologic, molecular, and transmissible characteristics of genetic prion disease in a young man carrying the PRNP-G114V variant.MethodsWe performed genetic, histologic, and molecular studies, combined with in vivo transmission studies and in vitro replication studies, to characterize this genetic prion disease.ResultsA 24-year-old American man of Polish descent developed progressive dementia, aphasia, and ataxia, leading to his death 5 years later. Histologic features included widespread spongiform degeneration, gliosis, and infrequent PrP plaque-like deposits within the cerebellum and putamen, best classifying this as a Creutzfeldt-Jakob disease (CJD) subtype. Molecular typing of proteinase K-resistant PrP (resPrPSc) revealed a mixture of type 1 (∼21 kDa) and type 2 (∼19 kDa) conformations with only 2, rather than the usual 3, PrPSc glycoforms. Brain homogenates from the proband failed to transmit prion disease to transgenic Tg(HuPrP) mice that overexpress human PrP and are typically susceptible to sporadic and genetic forms of CJD. When subjected to protein misfolding cyclic amplification, the PrPSc type 2 (∼19 kDa) was selectively amplified.ConclusionsThe features of genetic CJDG114V suggest that residue 114 within the highly conserved palindromic region (113-AGAAAAGA-120) plays an important role in prion conformation and propagation.

Prion Diseases

2017 ◽  
Author(s):  
James A. Mastrianni ◽  
Joshuae G. Gallardo
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Protein Gene ◽  
Prion Diseases ◽  
Prion Protein Gene ◽  
Secondary Transmission ◽  
Jakob Disease

Prion diseases are transmissible fatal neurodegenerative disorders resulting from the accumulation of misfolded prion protein. Although primarily sporadic diseases, 5% to 10% result from a mutation of the prion protein gene (PRNP), and less than 1% occur from exposure to prions. The current family of prion diseases includes Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal insomnia (FI), variant CJD (vCJD), and variably protease-sensitive prionopathy (VPSPr). Kuru is a disease of historical interest that was transmitted through cannibalistic rituals. Iatrogenic CJD (iCJD) is the result of secondary transmission of prion disease from contaminated biologicals.

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