scholarly journals Sporadic Creutzfeldt-Jakob Disease and Other Proteinopathies in Comorbidity

2020 ◽  
Vol 11 ◽  
Author(s):  
Eva Parobkova ◽  
Julie van der Zee ◽  
Lubina Dillen ◽  
Christine Van Broeckhoven ◽  
Robert Rusina ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Prion Diseases ◽  
Missense Variant ◽  
Transmissible Spongiform Encephalopathies ◽  
Disease Genes ◽  
Systematic Analysis ◽  
Spongiform Encephalopathies ◽  
Variant Of Uncertain Significance ◽  
Age Related ◽  
Jakob Disease

Background: Sporadic Creutzfeldt–Jakob disease (sCJD) is the most common type of a group of transmissible spongiform encephalopathies (prion diseases). The etiology of the sporadic form of CJD is still unclear. sCJD can occur in combination with other neurodegenerative diseases, which further complicates the diagnosis. Alzheimer's disease (AD), e.g., is often seen in conjunction with sCJD.Method: In this study, we performed a systematic analysis of 15 genes related to the most important neurodegenerative diseases - AD, frontotemporal dementia, amyotrophic lateral sclerosis, prion disease, and Parkinson's disease - in a cohort of sCJD and sCJD in comorbidity with AD and primary age-related proteinopathy (PART). A total of 30 neuropathologically verified cases of sCJD with and without additional proteinopathies were included in the study. In addition, we compared microtubule-associated protein tau (MAPT) haplotypes between sCJD patients and patients with sCJD and PART or sCJD and AD. Then we studied the interaction between the Apolipoprotein E gene (APOE) and PRNP in sCJD patients.Results: We did not find any causal mutations in the neurodegenerative disease genes. We did detect a p.E318G missense variant of uncertain significance (VUS) in PSEN1 in three patients. In PRNP, we also found a previously described non-pathogenic insertion (p.P84_Q91Q).Conclusion: Our pilot study failed to find any critical differences between pure sCJD and sCJD in conjunction with other comorbid neurodegenerative diseases. Further investigations are needed to better understand this phenomenon.

scholarly journals Making blood safe: A filtration technology for removing infectious prions from red-cell concentrates

2005 ◽  
Vol 27 (4) ◽  
pp. 29-32
Author(s):  
S.O. Sowemimo-Coker
Keyword(s):  
Blood Transfusion ◽  
Neurodegenerative Diseases ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Red Cell ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Filtration Technology

Prion diseases (TSEs, transmissible spongiform encephalopathies) are fatal neurodegenerative diseases that affect both humans and animals, including scrapie in sheep, BSE (bovine spongiform encephalopathy) in cattle and CJD (Creutzfeldt–Jakob disease) and its variant (vCJD) in humans. The recent occurrences of probable cases of transmission of vCJD through blood transfusion raises concerns about the safety of the blood supply and the possibility of transmission of the causative agent by blood transfusion from asymptomatic infected individuals.

scholarly journals Prion Disease Blood Test Using Immunoprecipitation and Improved Quaking-Induced Conversion

mBio ◽  
2011 ◽  
Vol 2 (3) ◽  
Author(s):  
Christina D. Orrú ◽  
Jason M. Wilham ◽  
Lynne D. Raymond ◽  
Franziska Kuhn ◽  
Björn Schroeder ◽  
...  
Keyword(s):  
Real Time ◽  
Blood Test ◽  
Prion Diseases ◽  
Proteinase K ◽  
Transmissible Spongiform Encephalopathies ◽  
Serum Samples ◽  
Spongiform Encephalopathies ◽  
Jakob Disease

ABSTRACT A key challenge in managing transmissible spongiform encephalopathies (TSEs) or prion diseases in medicine, agriculture, and wildlife biology is the development of practical tests for prions that are at or below infectious levels. Of particular interest are tests capable of detecting prions in blood components such as plasma, but blood typically has extremely low prion concentrations and contains inhibitors of the most sensitive prion tests. One of the latter tests is quaking-induced conversion (QuIC), which can be as sensitive as in vivo bioassays, but much more rapid, higher throughput, and less expensive. Now we have integrated antibody 15B3-based immunoprecipitation with QuIC reactions to increase sensitivity and isolate prions from inhibitors such as those in plasma samples. Coupling of immunoprecipitation and an improved real-time QuIC reaction dramatically enhanced detection of variant Creutzfeldt-Jakob disease (vCJD) brain tissue diluted into human plasma. Dilutions of 1014-fold, containing ~2 attogram (ag) per ml of proteinase K-resistant prion protein, were readily detected, indicating ~10,000-fold greater sensitivity for vCJD brain than has previously been reported. We also discriminated between plasma and serum samples from scrapie-infected and uninfected hamsters, even in early preclinical stages. This combined assay, which we call “enhanced QuIC” (eQuIC), markedly improves prospects for routine detection of low levels of prions in tissues, fluids, or environmental samples. IMPORTANCE Transmissible spongiform encephalopathies (TSEs) are largely untreatable and are difficult to diagnose definitively prior to irreversible clinical decline or death. The transmissibility of TSEs within and between species highlights the need for practical tests for even the smallest amounts of infectivity. A few sufficiently sensitive in vitro methods have been reported, but most have major limitations that would preclude their use in routine diagnostic or screening applications. Our new assay improves the outlook for such critical applications. We focused initially on blood plasma because a practical blood test for prions would be especially valuable for TSE diagnostics and risk reduction. Variant Creutzfeldt-Jakob disease (vCJD) in particular has been transmitted between humans via blood transfusions. Enhanced real-time quaking-induced conversion (eRTQ) provides by far the most sensitive detection of vCJD to date. The 15B3 antibody binds prions of multiple species, suggesting that our assay may be useful for clinical and fundamental studies of a variety of TSEs of humans and animals.

scholarly journals Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 469
Author(s):  
Hasier Eraña ◽  
Jorge M. Charco ◽  
Ezequiel González-Miranda ◽  
Sandra García-Martínez ◽  
Rafael López-Moreno ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Immunohistochemical Analysis ◽  
Body Fluids ◽  
Detection Methods ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Prion Propagation

Transmissible spongiform encephalopathies or prion diseases are rapidly progressive neurodegenerative diseases, the clinical manifestation of which can resemble other promptly evolving neurological maladies. Therefore, the unequivocal ante-mortem diagnosis is highly challenging and was only possible by histopathological and immunohistochemical analysis of the brain at necropsy. Although surrogate biomarkers of neurological damage have become invaluable to complement clinical data and provide more accurate diagnostics at early stages, other neurodegenerative diseases show similar alterations hindering the differential diagnosis. To solve that, the detection of the pathognomonic biomarker of disease, PrPSc, the aberrantly folded isoform of the prion protein, could be used. However, the amounts in easily accessible tissues or body fluids at pre-clinical or early clinical stages are extremely low for the standard detection methods. The solution comes from the recent development of in vitro prion propagation techniques, such as Protein Misfolding Cyclic Amplification (PMCA) and Real Time-Quaking Induced Conversion (RT-QuIC), which have been already applied to detect minute amounts of PrPSc in different matrixes and make early diagnosis of prion diseases feasible in a near future. Herein, the most relevant tissues and body fluids in which PrPSc has been detected in animals and humans are being reviewed, especially those in which cell-free prion propagation systems have been used with diagnostic purposes.

Copper and prion diseases

2002 ◽  
Vol 30 (4) ◽  
pp. 742-745 ◽  
Author(s):  
D. R. Brown
Keyword(s):  
Prion Protein ◽  
Strong Evidence ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Normal Brain ◽  
Spongiform Encephalopathies ◽  
Metal Metabolism ◽  
Jakob Disease ◽  
Anti Oxidant ◽  
Experimental Mouse

Transmissible spongiform encephalopathies are diseases of animals and humans that are also termed prion diseases. These diseases are linked together because a normal brain glycoprotein termed the prion protein is converted to a readily detectable protease-resistant isoform. There is now strong evidence to suggest that apart from this difference in resistance a major difference between the isoforms is that the normal prion protein binds copper and has an anti-oxidant function. Brains from Creutzfeldt-Jakob disease patients and brains from mice with experimental mouse scrapie have been shown to have changes in the levels of both copper and manganese. There is growing evidence that links prion diseases to disturbances of metal metabolism.

scholarly journals Prion protein interconversions†

2001 ◽  
Vol 356 (1406) ◽  
pp. 197-202 ◽  
Author(s):  
Byron Caughey
Keyword(s):  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Biological Parameters ◽  
Spongiform Encephalopathies ◽  
Lead Compounds ◽  
Resistant Form

The transmissible spongiform encephalopathies (TSEs), or prion diseases, remain mysterious neurodegenerative diseases that involve perturbations in prion protein (PrP) structure. This article summarizes our use of in vitro models to describe how PrP is converted to the disease–associated, protease–resistant form. These models reflect many important biological parameters of TSE diseases and have been used to identify inhibitors of the PrP conversion as lead compounds in the development of anti–TSE drugs.

scholarly journals Creutzfeldt–Jakob disease surveillance in Australia: update to December 2017

2019 ◽  
Vol 43 ◽  
Author(s):  
Christiane Stehmann ◽  
Shannon Sarros ◽  
Matteo Senesi ◽  
Victoria Lewis ◽  
Marion Simpson ◽  
...  
Keyword(s):  
Prion Disease ◽  
Disease Surveillance ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Annual Number ◽  
Prospective Surveillance ◽  
Surveillance Period ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Neuropathological Examination

Nationwide surveillance of human prion diseases (also known as transmissible spongiform encephalopathies), the most common being Creutzfeldt–Jakob disease (CJD), is performed by the Australian National Creutzfeldt–Jakob Disease Registry (ANCJDR), based at the University of Melbourne. National surveillance encompasses the period since 1970, with prospective surveillance occurring from 1993 onwards. Over this prospective surveillance period considerable developments have occurred, especially in relation to pre-mortem diagnostics, the delineation of new disease subtypes and a heightened awareness of prion diseases in the health care setting. The surveillance practices of the ANCJDR have evolved and adapted accordingly. Since the ANCJDR began offering cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased to a maximum of 508 in 2017. The number of CSF test referrals in 2017 represents a 20% increase compared to that of 2016. In 2017, there was an overall stabilisation of the annual incidence rate of confirmed prion disease in Australia at expected levels; 72 persons with suspected human prion disease were added to the national register, with 72% of all suspected CJD cases undergoing neuropathological examination. The majority of the 72 suspected cases added to the register are as of 31 December 2017 still classified as “incomplete” (47 cases), while four cases were excluded by either detailed clinical follow-up (1 case) or neuropathological examination (3 cases); 19 cases were classified as definite and two as probable prion disease. No cases of variant CJD (vCJD) were confirmed.

scholarly journals C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1188 ◽  
Author(s):  
Carl Alexander Sandhof ◽  
Simon Oliver Hoppe ◽  
Jessica Tittelmeier ◽  
Carmen Nussbaum-Krammer
Keyword(s):  
Neurodegenerative Diseases ◽  
Model Organism ◽  
Model Systems ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Population Demographics ◽  
C Elegans ◽  
Age Related ◽  
Bona Fide ◽  
High Degree

A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.

scholarly journals Persistent Propagation of Variant Creutzfeldt-Jakob Disease Agent in Murine Spleen Stromal Cell Culture with Features of Mesenchymal Stem Cells

2008 ◽  
Vol 82 (21) ◽  
pp. 10959-10962 ◽  
Author(s):  
Sergey Akimov ◽  
Oksana Yakovleva ◽  
Irina Vasilyeva ◽  
Carroll McKenzie ◽  
Larisa Cervenakova
Keyword(s):  
Cell Cultures ◽  
Stromal Cell ◽  
Ex Vivo ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Murine Spleen ◽  
Stromal Cell Culture ◽  
Jakob Disease ◽  
Disease Agent

ABSTRACT The transmission of variant Creutzfeldt-Jakob disease (vCJD) through blood transfusions has created new concerns about the iatrogenic spread of transmissible spongiform encephalopathies (TSEs)/prion diseases through blood and plasma-derived products and has increased the need to develop efficient methods for detection of the agent in biologics. Here, we report the first successful generation of spleen-derived murine stromal cell cultures that persistently propagate two mouse-adapted isolates of human TSE agents, mouse-adapted vCJD, and Fukuoka 1. These new cell cultures can be used efficiently for studies of the pathogenesis of the disease, for development of diagnostics and therapeutics, and as a rapid ex vivo assay for TSE inactivation/removal procedures.

Human Prion Diseases

2013 ◽  
pp. 149-160
Author(s):  
James W. Ironside ◽  
Matthew P. Frosch ◽  
Bernardino Ghetti
Keyword(s):  
Prion Diseases ◽  
Neuronal Loss ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Pituitary Hormone ◽  
Human Pituitary ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Prnp Codon ◽  
Codon 129

This chapter describes and illustrates the neuropathology of prion diseases, also known as transmissible spongiform encephalopathies. These diseases are characterized pathologically by varying combinations of spongiform change, neuronal loss, reactive gliosis, and prion protein (PrP) deposition. The morphologic pattern depends on the etiology of the disease and the genotype of the patient. Different clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (CJD) have been described depending on the PRNP codon 129 genotype and the PrP isotype. A novel form known as variably protease-sensitive prionopathy has been recently identified. Familial prion diseases include familial CJD, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Over 40 different PRNP mutations have been identified. Acquired prion diseases include Kuru; iatrogenic CJD, particularly in recipients of contaminated human pituitary hormone, and variant CJD, which seems closely related to bovine spongiform encephalopathy.

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