scholarly journals Prion protein quantification in cerebrospinal fluid as a tool for prion disease drug development

2018 ◽  
Author(s):  
Sonia M Vallabh ◽  
Chloe K Nobuhara ◽  
Franc Llorens ◽  
Inga Zerr ◽  
Piero Parchi ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Protein Quantification ◽  
Enzyme Linked Immunosorbent Assay ◽  
Blood Contamination ◽  
Highly Sensitive ◽  
The Central Nervous System ◽  
Test Retest Reliability

AbstractReduction of native prion protein (PrP) levels in the brain is an attractive and genetically validated strategy for the treatment or prevention of human prion diseases. However, clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction, in the central nervous system (CNS) of a living patient. Here we evaluate the potential of enzyme-linked immunosorbent assay (ELISA)-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS-derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test-retest reliability (mean coefficient of variation 13% in samples collected 8-11 weeks apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, enabling the development of prion disease therapeutics with this mechanism of action.

scholarly journals Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development

2019 ◽  
Vol 116 (16) ◽  
pp. 7793-7798 ◽  
Author(s):  
Sonia M. Vallabh ◽  
Chloe K. Nobuhara ◽  
Franc Llorens ◽  
Inga Zerr ◽  
Piero Parchi ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Prion Protein ◽  
Prion Disease ◽  
Protein Quantification ◽  
Blood Contamination ◽  
Human Cerebrospinal Fluid ◽  
Highly Sensitive ◽  
The Central Nervous System ◽  
Test Retest Reliability ◽  
And Storage

Reduction of native prion protein (PrP) levels in the brain is an attractive strategy for the treatment or prevention of human prion disease. Clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction in the central nervous system (CNS) of a living patient. Here we evaluate the potential of ELISA-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by the addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test–retest reliability (mean coefficient of variation, 13% in samples collected 8–11 wk apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, and will facilitate development of prion disease therapeutics with this mechanism of action.

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.

Genetic Factors in Mammalian Prion Diseases

2019 ◽  
Vol 53 (1) ◽  
pp. 117-147 ◽  
Author(s):  
Simon Mead ◽  
Sarah Lloyd ◽  
John Collinge
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Protein Interactions ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Cellular Functions ◽  
Modifying Factors ◽  
Jakob Disease ◽  
The Central Nervous System

Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene ( PRNP) and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of PRNP, whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non- PRNP factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.

scholarly journals Deletion of Kif5c Does Not Alter Prion Disease Tempo or Spread in Mouse Brain

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1391
Author(s):  
Brent Race ◽  
Katie Williams ◽  
Chase Baune ◽  
James F. Striebel ◽  
Clayton W. Winkler ◽  
...  
Keyword(s):  
Prion Disease ◽  
Molecular Motors ◽  
Prion Diseases ◽  
Mouse Strains ◽  
Survival Times ◽  
Knock Out ◽  
Transport Vesicles ◽  
The Central Nervous System ◽  
Knock Out Mice ◽  
Scrapie Strains

In prion diseases, the spread of infectious prions (PrPSc) is thought to occur within nerves and across synapses of the central nervous system (CNS). However, the mechanisms by which PrPSc moves within axons and across nerve synapses remain undetermined. Molecular motors, including kinesins and dyneins, transport many types of intracellular cargo. Kinesin-1C (KIF5C) has been shown to transport vesicles carrying the normal prion protein (PrPC) within axons, but whether KIF5C is involved in PrPSc axonal transport is unknown. The current study tested whether stereotactic inoculation in the striatum of KIF5C knock-out mice (Kif5c−/−) with 0.5 µL volumes of mouse-adapted scrapie strains 22 L or ME7 would result in an altered rate of prion spreading and/or disease timing. Groups of mice injected with each strain were euthanized at either pre-clinical time points or following the development of prion disease. Immunohistochemistry for PrP was performed on brain sections and PrPSc distribution and tempo of spread were compared between mouse strains. In these experiments, no differences in PrPSc spread, distribution or survival times were observed between C57BL/6 and Kif5c−/− mice.

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.

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 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.

Prion disease

2018 ◽  
Author(s):  
Richard Knight
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Human Diseases ◽  
Brain Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Structural Form ◽  
Spongiform Encephalopathies ◽  
Spongiform Change ◽  
Neurodegenerative Pathology

Prion diseases (also known as transmissible spongiform encephalopathies (TSEs)) affect animals and humans, although only the human diseases will be discussed in this chapter. Despite TSEs having somewhat disparate causes and effects, there are unifying features: TSEs are brain diseases with neurodegenerative pathology, which is typically associated with spongiform change, and, most characteristically, there is tissue deposition of an abnormal structural form of the prion protein. Some of the TSEs are naturally acquired infections and, while others are not, they are potentially transmissible in certain circumstances.

The Neuroimmune Interface in Prion Diseases

Physiology ◽  
2000 ◽  
Vol 15 (5) ◽  
pp. 250-255
Author(s):  
Michael A. Klein ◽  
Adriano Aguzzi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune System ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
The Central Nervous System

Prion diseases are fatal neurodegenerative disorders of animals and humans. Here we address the role of the immune system in the spread of prions from peripheral sites to the central nervous system and its potential relevance to iatrogenic prion disease.

scholarly journals Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 482
Author(s):  
Simote Foliaki ◽  
Bradley Groveman ◽  
Jue Yuan ◽  
Ryan Walters ◽  
Shulin Zhang ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurological Disorders ◽  
Prion Diseases ◽  
Three Dimensional ◽  
Protein Isoforms ◽  
Genetic Modifiers ◽  
Neuronal Tissue ◽  
Prion Infection ◽  
E200k Mutation

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

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