scholarly journals Prion Protein Repeat Expansion Results in Increased Aggregation and Reveals Phenotypic Variability

2007 ◽  
Vol 27 (15) ◽  
pp. 5445-5455 ◽  
Author(s):  
Elizabeth M. H. Tank ◽  
David A. Harris ◽  
Amar A. Desai ◽  
Heather L. True
Keyword(s):  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Proteins ◽  
Prion Diseases ◽  
Phenotypic Variability ◽  
Conformational Flexibility ◽  
Repeat Expansion ◽  
Chimeric Proteins ◽  
Prion Conversion ◽  
Aggregate Structures

ABSTRACT Mammalian prion diseases are fatal neurodegenerative disorders dependent on the prion protein PrP. Expansion of the oligopeptide repeats (ORE) found in PrP is associated with inherited prion diseases. Patients with ORE frequently harbor PrP aggregates, but other factors may contribute to pathology, as they often present with unexplained phenotypic variability. We created chimeric yeast-mammalian prion proteins to examine the influence of the PrP ORE on prion properties in yeast. Remarkably, all chimeric proteins maintained prion characteristics. The largest repeat expansion chimera displayed a higher propensity to maintain a self-propagating aggregated state. Strikingly, the repeat expansion conferred increased conformational flexibility, as observed by enhanced phenotypic variation. Furthermore, the repeat expansion chimera displayed an increased rate of prion conversion, but only in the presence of another aggregate, the [RNQ +] prion. We suggest that the PrP ORE increases the conformational flexibility of the prion protein, thereby enhancing the formation of multiple distinct aggregate structures and allowing more frequent prion conversion. Both of these characteristics may contribute to the phenotypic variability associated with PrP repeat expansion diseases.

scholarly journals Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 207
Author(s):  
Diane L. Ritchie ◽  
Marcelo A. Barria
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Experimental Models ◽  
Misfolded Proteins ◽  
Current Evidence

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

scholarly journals Prion protein dynamics before aggregation

2017 ◽  
Vol 114 (14) ◽  
pp. 3572-3577 ◽  
Author(s):  
Kinshuk Raj Srivastava ◽  
Lisa J. Lapidus
Keyword(s):  
Protein Dynamics ◽  
Neurodegenerative Disorders ◽  
Syrian Hamster ◽  
Time Scale ◽  
Molecular Basis ◽  
Prion Proteins ◽  
Prion Diseases ◽  
Hydrophobic Residues ◽  
Protein Deposits ◽  
Polypeptide Backbone

Prion diseases, like Alzheimer’s disease and Parkinson disease, are rapidly progressive neurodegenerative disorders caused by misfolding followed by aggregation and accumulation of protein deposits in neuronal cells. Here we measure intramolecular polypeptide backbone reconfiguration as a way to understand the molecular basis of prion aggregation. Our hypothesis is that when reconfiguration is either much faster or much slower than bimolecular diffusion, biomolecular association is not stable, but as the reconfiguration rate becomes similar to the rate of biomolecular diffusion, the association is more stable and subsequent aggregation is faster. Using the technique of Trp–Cys contact quenching, we investigate the effects of various conditions on reconfiguration dynamics of the Syrian hamster and rabbit prion proteins. This protein exhibits behavior in all three reconfiguration regimes. We conclude that the hamster prion is prone to aggregation at pH 4.4 because its reconfiguration rate is slow enough to expose hydrophobic residues on the same time scale that bimolecular association occurs, whereas the rabbit sequence avoids aggregation by reconfiguring 10 times faster than the hamster sequence.

scholarly journals Prion protein and prion disease at a glance

2021 ◽  
Vol 134 (17) ◽  
Author(s):  
Caihong Zhu ◽  
Adriano Aguzzi
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Future Studies ◽  
Associated Proteins ◽  
Main Component ◽  
Conformational Conversion

ABSTRACT Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main component of prion, PrPSc acts as an infectious template that recruits and converts normal cellular PrPC into its pathogenic, misfolded isoform. Intriguingly, the phenomenon of prionoid, or prion-like, spread has also been observed in many other disease-associated proteins, such as amyloid β (Aβ), tau and α-synuclein. This Cell Science at a Glance and the accompanying poster highlight recently described physiological roles of prion protein and the advanced understanding of pathogenesis of prion disease they have afforded. Importantly, prion protein may also be involved in the pathogenesis of other neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therapeutic studies of prion disease have also exploited novel strategies to combat these devastating diseases. Future studies on prion protein and prion disease will deepen our understanding of the pathogenesis of a broad spectrum of neurodegenerative conditions.

scholarly journals Breaking the Code of Amyloid-βOligomers

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Sylvain E. Lesné
Keyword(s):  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Biological Activities ◽  
Prion Diseases ◽  
Amyloid Proteins ◽  
Biophysical Properties ◽  
Respective Role ◽  
Amyloid Oligomers ◽  
Multiple Conformations ◽  
Frontotemporal Dementias

Departing from the original postulates that defined various neurodegenerative disorders, accumulating evidence supports a major role for soluble forms of amyloid proteins as initiator toxins in Alzheimer’s disease, Parkinson’s disease, frontotemporal dementias, and prion diseases. Soluble multimeric assemblies of amyloid-β, tau,α-synuclein, and the prion protein are generally englobed under the term oligomers. Due to their biophysical properties, soluble amyloid oligomers can adopt multiple conformations and sizes that potentially confer differential biological activities. Therein lies the problem: with sporadic knowledge and limited tools to identify, characterize, and study amyloid oligomers, how can we solve the enigma of their respective role(s) in the pathogenesis of neurodegenerative disorders? To further our understanding of these devastating diseases, the code of the amyloid oligomers must be broken.

scholarly journals Postmortem Quantitative Analysis of Prion Seeding Activity in the Digestive System

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4601 ◽  
Author(s):  
Katsuya Satoh ◽  
Takayuki Fuse ◽  
Toshiaki Nonaka ◽  
Trong Dong ◽  
Masaki Takao ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Quantitative Analysis ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Digestive System ◽  
Prion Diseases ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
Almost All

Human prion diseases are neurodegenerative disorders caused by prion protein. Although infectivity was historically detected only in the central nervous system and lymphoreticular tissues of patients with sporadic Creutzfeldt-Jakob disease, recent reports suggest that the seeding activity of Creutzfeldt-Jakob disease prions accumulates in various non-neuronal organs including the liver, kidney, and skin. Therefore, we reanalyzed autopsy samples collected from patients with sporadic and genetic human prion diseases and found that seeding activity exists in almost all digestive organs. Unexpectedly, activity in the esophagus reached a level of prion seeding activity close to that in the central nervous system in some CJD patients, indicating that the safety of endoscopic examinations should be reconsidered.

scholarly journals Prion protein and its role in signal transduction

2013 ◽  
Vol 18 (2) ◽  
Author(s):  
Alessandro Didonna
Keyword(s):  
Signal Transduction ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Physiological Function ◽  
Prion Diseases ◽  
Etiologic Agent ◽  
Cellular Prion Protein ◽  
Considerable Effort ◽  
Unique Nature ◽  
First Time

AbstractPrion diseases are a class of fatal neurodegenerative disorders that can be sporadic, genetic or iatrogenic. They are characterized by the unique nature of their etiologic agent: prions (PrPSc). A prion is an infectious protein with the ability to convert the host-encoded cellular prion protein (PrPC) into new prion molecules by acting as a template. Since Stanley B. Prusiner proposed the “protein-only” hypothesis for the first time, considerable effort has been put into defining the role played by PrPC in neurons. However, its physiological function remains unclear. This review summarizes the major findings that support the involvement of PrPC in signal transduction.

scholarly journals Ethanolamine Is a New Anti-Prion Compound

2021 ◽  
Vol 22 (21) ◽  
pp. 11742
Author(s):  
Keiji Uchiyama ◽  
Hideyuki Hara ◽  
Junji Chida ◽  
Agriani Dini Pasiana ◽  
Morikazu Imamura ◽  
...  
Keyword(s):  
Drinking Water ◽  
Oral Administration ◽  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Mouse Neuroblastoma ◽  
Conformational Conversion ◽  
The Brain ◽  
Cells Cultured

Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrPSc. PrPSc is produced through conformational conversion of the cellular isoform of prion protein, PrPC, in the brain. To date, no effective therapies for prion diseases have been developed. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrPSc levels when cultured in advanced Dulbecco’s modified eagle medium (DMEM) but not in classic DMEM. PrPC levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrPSc levels in N2aC24L1-3 cells, but not PrPC levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound.

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.

Rapid quantification of prion proteins using resistive pulse sensing

The Analyst ◽  
2020 ◽  
Vol 145 (7) ◽  
pp. 2595-2601 ◽  
Author(s):  
Matthew J. Healey ◽  
Muttuswamy Sivakumaran ◽  
Mark Platt
Keyword(s):  
Prion Protein ◽  
Prion Proteins ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Resistive Pulse ◽  
Neurological Conditions ◽  
Resistive Pulse Sensing ◽  
Rapid Quantification

Prion diseases are a group of fatal transmissible neurological conditions caused by the change in conformation of intrinsic cellular prion protein (PrPC).

Biophysical characterization of oligomerization and fibrillization of the G131V pathogenic mutant of human prion protein

2019 ◽  
Author(s):  
Meilan Zhang ◽  
Haoran Zhang ◽  
Hongwei Yao ◽  
Chenyun Guo ◽  
Donghai Lin
Keyword(s):  
Prion Protein ◽  
Tertiary Structure ◽  
Prion Proteins ◽  
Prion Diseases ◽  
Guanidine Hydrochloride ◽  
Point Mutations ◽  
Cellular Prion Protein ◽  
Human Prion Protein ◽  
Α Helix ◽  
Conformational Conversion

Abstract The pathogenesis of fatal neurodegenerative prion diseases is closely associated with the conversion of α-helix-rich cellular prion protein into β-sheet-rich scrapie form. Pathogenic point mutations of prion proteins usually promote the conformational conversion and trigger inherited prion diseases. The G131V mutation of human prion protein (HuPrP) was identified to be involved in Gerstmann–Sträussler–Scheinker syndrome. Few studies have been carried out to address the pathogenesis of the G131V mutant. Here, we addressed the effects of the G131V mutation on oligomerization and fibrillization of the full-length HuPrP(23–231) and truncated HuPrP(91–231) proteins. The G131V mutation promotes the oligomerization but alleviates the fibrillization of HuPrP, implying that the oligomerization might play a crucial role in the pathogenic mechanisms of the G131V mutant. Moreover, the flexible N-terminal fragment in either the wild-type or the G131V mutant HuPrP increases the oligomerization tendencies but decreases the fibrillization tendencies. Furthermore, this mutation significantly alters the tertiary structure of human PrPC and might distinctly change the conformational conversion tendency. Interestingly, both guanidine hydrochloride denaturation and thermal denaturation experiments showed that the G131V mutation does not significantly change the thermodynamic stabilities of the HuPrP proteins. This work may be of benefit to a mechanistic understanding of the conformational conversion of prion proteins and also provide clues for the prevention and treatment of prion diseases.

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