scholarly journals Distinct Stability States of Disease-Associated Human Prion Protein Identified by Conformation-Dependent Immunoassay

2010 ◽  
Vol 84 (22) ◽  
pp. 12030-12038 ◽  
Author(s):  
Young Pyo Choi ◽  
Alexander H. Peden ◽  
Albrecht Gröner ◽  
James W. Ironside ◽  
Mark W. Head
Keyword(s):  
Prion Protein ◽  
Fragment Size ◽  
Prion Diseases ◽  
Conformational Stability ◽  
Site Occupancy ◽  
Glycosylation Site ◽  
Jakob Disease ◽  
Human Prion Protein ◽  
Conformation Stability ◽  
Codon 129

ABSTRACT The phenotypic and strain-related properties of human prion diseases are, according to the prion hypothesis, proposed to reside in the physicochemical properties of the conformationally altered, disease-associated isoform of the prion protein (PrPSc), which accumulates in the brains of patients suffering from Creutzfeldt-Jakob disease and related conditions, such as Gerstmann-Straussler-Scheinker disease. Molecular strain typing of human prion diseases has focused extensively on differences in the fragment size and glycosylation site occupancy of the protease-resistant prion protein (PrPres) in conjunction with the presence of mutations and polymorphisms in the prion protein gene (PRNP). Here we report the results of employing an alternative strategy that specifically addresses the conformational stability of PrPSc and that has been used previously to characterize animal prion strains transmitted to rodents. The results show that there are at least two distinct conformation stability states in human prion diseases, neither of which appears to correlate fully with the PrPres type, as judged by fragment size or glycosylation, the PRNP codon 129 status, or the presence or absence of mutations in PRNP. These results suggest that conformational stability represents a further dimension to a complete description of potentially phenotype-related properties of PrPSc in human prion diseases.

scholarly journals Codon 129 polymorphism of the human prion protein influences the kinetics of amyloid formation

2006 ◽  
Vol 87 (8) ◽  
pp. 2443-2449 ◽  
Author(s):  
Patrick A. Lewis ◽  
M. Howard Tattum ◽  
Samantha Jones ◽  
Daljit Bhelt ◽  
Mark Batchelor ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Fibrils ◽  
Prion Diseases ◽  
Amyloid Formation ◽  
Native Structure ◽  
Prion Strain ◽  
Profound Influence ◽  
Human Prion Protein ◽  
Kinetics Of ◽  
Codon 129

The human prion protein (PrP) has a common polymorphism at residue 129, which can be valine or methionine. This polymorphism has a strong influence on susceptibility to prion diseases and on prion-strain properties. Previous work has shown that this amino acid variation has no measurable effect on the native structure of cellular PrP (PrPC). Here, it is shown that the polymorphism does not change the efficiency of conversion to the β-PrP conformation or affect the binding of copper(II) ions. However, in a partially denatured conformation, the polymorphic variation has a profound influence on the ability of the protein to form amyloid fibrils spontaneously.

scholarly journals Extracellular Protein Aggregates Colocalization and Neuronal Dystrophy in Comorbid Alzheimer’s and Creutzfeldt–Jakob Disease: A Micromorphological Pilot Study on 20 Brains

2021 ◽  
Vol 22 (4) ◽  
pp. 2099
Author(s):  
Nikol Jankovska ◽  
Tomas Olejar ◽  
Radoslav Matej
Keyword(s):  
Prion Protein ◽  
Fluorescent Microscopy ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Key Characteristics ◽  
Jakob Disease ◽  
Immunohistochemical Methods ◽  
Confocal Fluorescent Microscopy ◽  
Codon 129

Alzheimer’s disease (AD) and sporadic Creutzfeldt–Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins—amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and “compound” plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer’s association guidelines, and prion protein subtype with codon 129 methionine–valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.

scholarly journals Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maxime Bélondrade ◽  
Simon Nicot ◽  
Charly Mayran ◽  
Lilian Bruyere-Ostells ◽  
Florian Almela ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Protein Misfolding Cyclic Amplification ◽  
Bank Voles ◽  
Substrate Dependence ◽  
Brain Extracts ◽  
Jakob Disease ◽  
Human Prion Protein

AbstractUnlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 substrates: 2 from transgenic mice expressing human prion protein (PrP) with either methionine (M) or valine (V) at position 129, and 1 from bank voles. Brain extracts representing the 5 major clinicopathological sCJD subtypes (MM1/MV1, MM2, MV2, VV1, and VV2) all triggered seeded PrPTSE amplification during serial PMCA with strong seed- and substrate-dependence. Remarkably, bank vole PrP substrate allowed the propagation of all sCJD subtypes with preservation of the initial molecular PrPTSE type. In contrast, PMCA in human PrP substrates was accompanied by a PrPTSE molecular shift during heterologous (M/V129) PMCA reactions, with increased permissiveness of V129 PrP substrate to in vitro sCJD prion amplification compared to M129 PrP substrate. Combining PMCA amplification sensitivities with PrPTSE electrophoretic profiles obtained in the different substrates confirmed the classification of 4 distinct major sCJD prion strains (M1, M2, V1, and V2). Finally, the level of sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved.

scholarly journals Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

2021 ◽  
Vol 15 (1) ◽  
pp. 193-196
Author(s):  
Máximo Sanz-Hernández ◽  
Alfonso De Simone
Keyword(s):  
Prion Protein ◽  
Nmr Assignments ◽  
Chemical Shifts ◽  
Prion Diseases ◽  
Random Coil ◽  
Transmissible Spongiform Encephalopathies ◽  
Globular Domain ◽  
Structural Elements ◽  
Spongiform Encephalopathies ◽  
Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

Examination of the human prion protein-like gene Doppel for genetic susceptibility to sporadic and variant Creutzfeldt–Jakob disease

2000 ◽  
Vol 290 (2) ◽  
pp. 117-120 ◽  
Author(s):  
Simon Mead ◽  
Jonathan Beck ◽  
Andrew Dickinson ◽  
Elizabeth M.C Fisher ◽  
John Collinge
Keyword(s):  
Genetic Susceptibility ◽  
Prion Protein ◽  
Jakob Disease ◽  
Human Prion Protein

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.

Inter-Oligomer Interactions of the Human Prion Protein Are Modulated by the Polymorphism at Codon 129

2008 ◽  
Vol 381 (1) ◽  
pp. 212-220 ◽  
Author(s):  
Remo Gerber ◽  
Kislon Voitchovsky ◽  
Clement Mitchel ◽  
Abdessamad Tahiri-Alaoui ◽  
John F. Ryan ◽  
...  
Keyword(s):  
Prion Protein ◽  
Human Prion Protein ◽  
Codon 129

scholarly journals Structural effects of the highly protective V127 polymorphism on human prion protein

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Laszlo L. P. Hosszu ◽  
Rebecca Conners ◽  
Daljit Sangar ◽  
Mark Batchelor ◽  
Elizabeth B. Sawyer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Structural Changes ◽  
Prion Diseases ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Solution Dynamics ◽  
Human Prion Protein ◽  
Prion Transmission

AbstractPrion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease.

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