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Prion Dissemination through the Environment and Medical Practices: Facts and Risks for Human Health.Clinical Microbiology Reviews Dec 2021Prion diseases are a group of fatal, infectious neurodegenerative disorders affecting various species of mammals, including humans. The infectious agent in these... (Review)
Review
Prion diseases are a group of fatal, infectious neurodegenerative disorders affecting various species of mammals, including humans. The infectious agent in these diseases, termed prion, is composed exclusively of a misfolded protein that can spread and multiply in the absence of genetic materials. In this article, we provide an overview of the mechanisms of prion replication, interindividual transmission, and dissemination in communities. In particular, we review the potential role of the natural environment in prion transmission, including the mechanisms and pathways for prion entry and accumulation in the environment as well as its roles in prion mutation, adaptation, evolution, and transmission. We also discuss the transmission of prion diseases through medical practices, scientific research, and use of biological products. Detailed knowledge of these aspects is crucial to limit the spreading of existing prion diseases as well as to prevent the emergence of new diseases with possible catastrophic consequences for public health.
Topics: Animals; Humans; Prion Diseases; Prions
PubMed: 34319151
DOI: 10.1128/CMR.00059-19 -
Viruses Nov 2019The prion-like spreading and accumulation of specific protein aggregates appear to be central to the pathogenesis of many human diseases, including Alzheimer's and... (Review)
Review
The prion-like spreading and accumulation of specific protein aggregates appear to be central to the pathogenesis of many human diseases, including Alzheimer's and Parkinson's. Accumulating evidence indicates that inoculation of tissue extracts from diseased individuals into suitable experimental animals can in many cases induce the aggregation of the disease-associated protein, as well as related pathological lesions. These findings, together with the history of the prion field, have raised the questions about whether such disease-associated protein aggregates are transmissible between humans by casual or iatrogenic routes, and, if so, do they propagate enough in the new host to cause disease? These practical considerations are important because real, and perhaps even only imagined, risks of human-to-human transmission of diseases such as Alzheimer's and Parkinson's may force costly changes in clinical practice that, in turn, are likely to have unintended consequences. The prion field has taught us that a single protein, PrP, can aggregate into forms that can propagate exponentially in vitro, but range from being innocuous to deadly when injected into experimental animals in ways that depend strongly on factors such as conformational subtleties, routes of inoculation, and host responses. In assessing the hazards posed by various disease-associated, self-propagating protein aggregates, it is imperative to consider both their actual transmissibilities and the pathological consequences of their propagation, if any, in recipient hosts.
Topics: Alzheimer Disease; Amyloid; Animals; Humans; Membrane Proteins; Parkinson Disease; Prion Diseases; Prions; Protein Aggregates; Protein Folding; Scrapie; Synucleins; Virulence
PubMed: 31717531
DOI: 10.3390/v11111044 -
PLoS Biology Jun 2020The prion protein, PrP, can adopt at least 2 conformations, the overwhelmingly prevalent cellular conformation (PrPC) and the scrapie conformation (PrPSc). PrPC features...
The prion protein, PrP, can adopt at least 2 conformations, the overwhelmingly prevalent cellular conformation (PrPC) and the scrapie conformation (PrPSc). PrPC features a globular C-terminal domain containing 3 α-helices and a short β-sheet and a long flexible N-terminal tail whose exact conformation in vivo is not yet known and a metastable subdomain with β-strand propensity has been identified within it. The PrPSc conformation is very rare and has the characteristics of an amyloid. Furthermore, PrPSc is a prion, i.e., it is infectious. This involves 2 steps: (1) PrPSc can template PrPC and coerce it to adopt the PrPSc conformation and (2) PrPSc can be transmitted between individuals, by oral, parenteral, and other routes and thus propagate as an infectious agent. However, this is a simplification: On the one hand, PrPSc is not a single conformation, but rather, a set of alternative similar but distinct conformations. Furthermore, other amyloid conformations of PrP exist with different biochemical and propagative properties. In this issue of PLOS Biology, Asante and colleagues describe the first murine model of familial human prion disease and demonstrate the emergence and propagation of 2 PrP amyloid conformers. Of these, one causes neurodegeneration, whereas the other does not. With its many conformers, PrP is a truly protean protein.
Topics: Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Prion Diseases; Prion Proteins; Prions; Scrapie
PubMed: 32584805
DOI: 10.1371/journal.pbio.3000754 -
Pros and cons in prion diseases abatement: Insights from nanomedicine and transmissibility patterns.International Journal of Biological... Feb 2020Ample research progress with nanotechnology applications in health and medicine implies precision and accuracy in the scenario of neurodegenerative disorders, for which... (Review)
Review
Ample research progress with nanotechnology applications in health and medicine implies precision and accuracy in the scenario of neurodegenerative disorders, for which impending research in ultimate and complete cure has been the vision worldwide. The complexity of prion disease has been unravelled by scientists and demarcated for efficient abatement protocols, but which are still under research and clinical trials. Drug delivery strategies combating prion diseases across the blood brain barrier, the efficacy of drugs and biocompatibility remain a serious question to be thoroughly studied for effective diagnosis and treatment. The present review compiles comprehensively the current treatment modalities against prion diseases and future prospects of nanotechnology addressing diagnosis and treatment of prion diseases with a special emphasis on transmissibility. Further, approaches for anti-prion technology, immunotherapy, and hindrances in vaccine development are discussed.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Drug Delivery Systems; Humans; Nanomedicine; Nanoparticles; Nanotechnology; Prion Diseases
PubMed: 31866542
DOI: 10.1016/j.ijbiomac.2019.12.150 -
Prion Dec 2021Transformation of astrocytes into reactive states is considered one of the major pathological hallmarks of prion and other neurodegenerative diseases. Recent years... (Review)
Review
Transformation of astrocytes into reactive states is considered one of the major pathological hallmarks of prion and other neurodegenerative diseases. Recent years witnessed a growing appreciation of the view that reactive astrocytes are intimately involved in chronic neurodegeneration; however, little is known about their role in disease pathogenesis. The current article reviews the progress of the last few years and critically discusses controversial questions of whether reactive astrocytes associated with prion diseases are neurotoxic or neuroprotective and whether bidirectional A1-A2 model is applicable for describing polarization of astrocytes. Moreover, other important topics, including reversibility of a transition to a reactive state, along with the role of microglia and other stimuli in triggering astrocyte activation are reviewed. Defining the role of reactive astrocytes in pathogenesis of neurodegenerative diseases will open unrealized opportunities for developing new therapeutic approaches against prion and other neurodegenerative diseases.
Topics: Astrocytes; Humans; Microglia; Neurodegenerative Diseases; Prion Diseases; Prions
PubMed: 34057026
DOI: 10.1080/19336896.2021.1930852 -
Brain : a Journal of Neurology Apr 2022Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data...
Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.
Topics: Biomarkers; Creutzfeldt-Jakob Syndrome; Humans; Insomnia, Fatal Familial; Prion Diseases; Prion Proteins; Prions; alpha-Synuclein
PubMed: 35288744
DOI: 10.1093/brain/awab350 -
Journal of Visualized Experiments : JoVE May 2023Abnormal prion proteins (PrP) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs)....
Abnormal prion proteins (PrP) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs). These neurodegenerative diseases affect humans and several animal species and include scrapie, zoonotic bovine spongiform encephalopathy (BSE), chronic wasting disease of cervids (CWD), and the newly identified camel prion disease (CPD). Diagnosis of TSEs relies on immunodetection of PrP by application of both immunohistochemistry (IHC) and western immunoblot methods (WB) on encephalon tissues, namely, the brainstem (obex level). IHC is a widely used method that uses primary antibodies (monoclonal or polyclonal) against antigens of interest in cells of a tissue section. The antibody-antigen binding can be visualized by a color reaction that remains localized in the area of the tissue or cell where the antibody was targeted. As such, in prion diseases, as in other fields of research, the immunohistochemistry techniques are not solely used for diagnostic purposes but also in pathogenesis studies. Such studies involve detecting the PrP patterns and types from those previously described to identify the new prion strains. As BSE can infect humans, it is recommended that biosafety laboratory level-3 (BSL-3) facilities and/or practices are used to handle cattle, small ruminants, and cervid samples included in the TSE surveillance. Additionally, containment and prion-dedicated equipment are recommended, whenever possible, to limit contamination. The PrP IHC procedure consists of a formic acid epitope-demasking step also acting as a prion inactivation measure, as formalin-fixed and paraffin-embedded tissues used in this technique remain infectious. When interpreting the results, care must be taken to distinguish non-specific immunolabeling from target labeling. For this purpose, it is important to recognize artifacts of immunolabeling obtained in known TSE-negative control animals to differentiate those from specific PrP immunolabeling types, which can vary between TSE strains, host species, and prnp genotype, further described herein.
Topics: Animals; Sheep; Cattle; Humans; Prion Proteins; Immunohistochemistry; Prion Diseases; Scrapie; Prions; Encephalopathy, Bovine Spongiform; Wasting Disease, Chronic; Deer
PubMed: 37212578
DOI: 10.3791/64560 -
Voprosy Virusologii 2020The review presents the current state of the problem of prions and prion diseases with an emphasis on theepidemiological and epizootological risks of pathogens that... (Review)
Review
The review presents the current state of the problem of prions and prion diseases with an emphasis on theepidemiological and epizootological risks of pathogens that cause fatal neurodegenerative diseases in humans and animals. The results of molecular genetic studies of the conversion of normal PrP prion protein molecules to infectious forms of PrP, resistance to physical disinfection methods, in particular exceptional thermal stability, and their ability to overcome interspecific barriers, while increasing virulence, are described. The possibility of infection not only by nutrition, when eating even heat-treated meat of sick animals, but also due to surgical interventions, especially neurosurgical and ophthalmic, as well as the use of immunobiological preparations, are emphasized. Since there are currently no means for the effective treatment of prion diseases in the world, attention is drawn to the high degree of relevance for the biosafety of the country to develop domestic highly sensitive test systems that can effectively detect prion infectious protein at the preclinical stage of the disease. The latest methods of automatic protein amplification and identification of prion proteins are briefly described as the most promising areas of research in the field of diagnosis of prion diseases.
Topics: Animals; Containment of Biohazards; Humans; Neurodegenerative Diseases; Prion Diseases; Prions
PubMed: 32515562
DOI: 10.36233/0507-4088-2020-65-2-71-76 -
Progress in Molecular Biology and... 2020Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), atypical parkinsonisms, frontotemporal dementia (FTLD) and prion diseases... (Review)
Review
Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), atypical parkinsonisms, frontotemporal dementia (FTLD) and prion diseases are characterized by the accumulation of misfolded proteins in the central nervous system (CNS). Although the cause for the initiation of protein aggregation is not well understood, these aggregates are disease-specific. For instance, AD is characterized by the intraneuronal accumulation of tau and extracellular deposition of amyloid-β (Aβ), PD is marked by the intraneuronal accumulation of α-synuclein, many FTLD are associated with the accumulation of TDP-43 while prion diseases show aggregates of misfolded prion protein. Hence, misfolded proteins are considered disease-specific biomarkers and their identification and localization in the CNS, collected postmortem, is required for a definitive diagnosis. With the development of two innovative cell-free amplification techniques named Protein Misfolding Cyclic Amplification (PMCA) and Real-Time Quaking-Induced Conversion (RT-QuIC), traces of disease-specific biomarkers were found in CSF and other peripheral tissues (e.g., urine, blood, and olfactory mucosa) of patients with different NDs. These techniques exploit an important feature shared by many misfolded proteins, that is their ability to interact with their normally folded counterparts and force them to undergo similar structural rearrangements. Essentially, RT-QuIC and PMCA mimic in vitro the same pathological processes of protein misfolding which occur in vivo in a very rapid manner. For this reason, they have been employed for studying different aspects of protein misfolding but, overall, they seem to be very promising for the premortem diagnosis of NDs.
Topics: Animals; Cell-Free System; Humans; PrPSc Proteins; Prion Diseases; Prions; Protein Folding
PubMed: 32958239
DOI: 10.1016/bs.pmbts.2020.08.005 -
The Journal of Hospital Infection Jan 2020Several guidelines recommend specific treatments for endoscopes, procedures of quarantine for endoscopes, or additional treatments for the endoscope washer disinfector... (Review)
Review
Several guidelines recommend specific treatments for endoscopes, procedures of quarantine for endoscopes, or additional treatments for the endoscope washer disinfector (EWD) in suspected or confirmed cases of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD) but vary in many details. This study therefore reviewed guidelines on reprocessing flexible endoscopes after use in patients with suspected or confirmed prion disease. In addition, a literature search was performed in Medline on prion, CJD, vCJD, chemical inactivation, transmission healthcare, epidemiology healthcare, concentration tissue human and endoscope. Thus far, no case of CJD or vCJD transmitted by flexible endoscope has been reported. In animals it has been shown that oral uptake of 0.1-5 g of bovine spongiform encephalopathy (BSE)-infected brain homogenate is necessary for transmission. The maximum prion concentration in other tissues (e.g., terminal ileum) is at least 100-fold lower. Automated cleaning of endoscopes alone results in very low total residual protein ≤5.6 mg per duodenoscopes. Recommendations vary between countries, sometimes with additional cleaning, use of alkaline cleaners, no use of cleaners with fixative properties, use of disinfectants without fixative properties or single-use disinfectants. Sodium hydroxide (1 M) and sodium hypochlorite (10,000 and 25,000 mg/L) are very effective in preventing transmission via contaminated wires implanted into animal brains, but their relevance for endoscopes is questionable. Based on circumstantial evidence, it is proposed to consider validated reprocessing as appropriate in the case of delayed suspected prion disease when immediate bedside cleaning, routine use of alkaline cleaners, no fixative agents anywhere prior to disinfection and single use brushes and cleaning solutions can be assured.
Topics: Animals; Caustics; Creutzfeldt-Jakob Syndrome; Disinfectants; Disinfection; Duodenoscopes; Endoscopes; Guidelines as Topic; Humans; Prion Diseases; Risk Assessment; Sodium Hydroxide; Sodium Hypochlorite
PubMed: 31408691
DOI: 10.1016/j.jhin.2019.08.005