-
Nature Reviews. Neurology Feb 2013Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, describe a group of fatal neurodegenerative disorders affecting both humans and animals.... (Review)
Review
Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, describe a group of fatal neurodegenerative disorders affecting both humans and animals. Accumulation of misfolded prion proteins is the pathological hallmark of these disorders; such accumulation occurs in lymphoreticular tissue prior to CNS involvement in scrapie, experimental models and human variant Creutzfeldt-Jakob disease. Lymphoreticular accumulation of misfolded prion protein has not been demonstrated in human sporadic or genetic forms of TSE. Once clinical symptoms develop, all prion disorders have a rapidly progressive and lethal course, and no effective therapy exists. In the past 10 years, antibody-based immunotherapy has been considered for other neurodegenerative disorders associated with protein misfolding and, therefore, might also be an effective approach to prevention or treatment of prion disease. Self-tolerance to endogenous prion protein is, however, a major challenge to the development of effective immunotherapy, as is the risk of adverse effects from active immunization. This Review summarizes the evidence that immunization could slow disease progression or increase lifespan in animal models of prion diseases. The therapeutic potential of these strategies in treating patients with prion diseases is also discussed.
Topics: Animals; Humans; Immunization, Passive; Immunotherapy; Prion Diseases; Prions; Vaccination
PubMed: 23247613
DOI: 10.1038/nrneurol.2012.258 -
Rinsho Shinkeigaku = Clinical Neurology Nov 2010Human prion diseases are classified into 3 categories according to etiologies: idiopathic of unknown cause, acquired of infectious origin, and genetic by PRNP mutation.... (Review)
Review
Human prion diseases are classified into 3 categories according to etiologies: idiopathic of unknown cause, acquired of infectious origin, and genetic by PRNP mutation. The surveillance committee have analyzed 2,494 cases and identified 1,402 as prion diseases. Most of them are idiopathic, namely sporadic CJD (77%) with less genetic and acquired prion diseases (17% and 5%, respectively). The number of patients identified by the surveillance committee in these years is about 120 which are less than the number of annual death of prion disease. The difference might be due to partly the fact our surveillance need the consent from patients' family and is not complete. The mean age at onset of prion disease is late 60s while the range is fairly wide. Brain MRIs and increase of CSF 14-3-3 and tau protein levels are very characteristic. Classical sporadic CJD could show completely normal T1WI with patchy high signals in the cerebral cortex and basal ganglia on DWI. In Japan, classical sporadic CJD (MM1) is most popular but there are some rare atypical subtypes. Among them, MM2-thalamic CJD is hardest to diagnose because it shows no high intensity signals on DWI, in addition to frequent absence of CSF and EEG characteristics. In this case, CBF decrease in the thalamus on SPECT is very helpful. Genetic prion diseases in Japan are quite distinct from those in Europe. V180I and M232R mutations are unique to Japan and show sporadic CJD phenotype. Dura graft-associated CJD (dCJD) are composed of 67% of classical sporadic CJD phenotype and 33% of atypical phenotype showing slower progression with amyloid plaques. Trace-back experiments suggested the PrP(sc) of the atypical dCJD was likely to be modified from infection of abnormal VV2 protein. Although there are some atypical forms of prion diseases as mentioned above, almost all prion cases could be diagnosed with EEG, MRI, genetic test, CSF test and SPECT. We also have some incidents in which brain surgery was done before the diagnosis of prion disease and many other patients were operated using the same operating instruments before their sterilization against prion disease had been done. The explanation of possibility of prion disease infection to the patients and their follow-up was started by the incident committee. It is very important for all the nations to cooperate with each other in order to overcome this intractable disease.
Topics: 14-3-3 Proteins; Aged; Animals; Biomarkers; Cattle; Creutzfeldt-Jakob Syndrome; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Electroencephalography; Gerstmann-Straussler-Scheinker Disease; Humans; Insomnia, Fatal Familial; Middle Aged; Mutation; PrPSc Proteins; Prion Diseases; Prions; Tomography, Emission-Computed, Single-Photon; tau Proteins
PubMed: 21921445
DOI: No ID Found -
Current Opinion in Pharmacology Feb 2019Prion diseases are devastating neurodegenerative disorders for which no drugs are available. The successful development of therapeutics depends on drug screening... (Review)
Review
Prion diseases are devastating neurodegenerative disorders for which no drugs are available. The successful development of therapeutics depends on drug screening platforms and preclinical models that recapitulate key molecular and pathological features of the disease. Innovative experimental tools have been developed over the last few years that might facilitate drug discovery, including cell-free prion replication assays and prion-infected flies. However, there is still room for improvement. Animal models of genetic prion disease are few, and only partially recapitulate the complexity of the human disorder. Moreover, we still lack a human cell culture model suitable for high-content anti-prion drug screening. This review provides an overview of the models currently used in prion research, and discusses their promise and limitations for drug discovery.
Topics: Animals; Biological Assay; Drug Discovery; Humans; In Vitro Techniques; Models, Biological; Prion Diseases
PubMed: 30878006
DOI: 10.1016/j.coph.2019.02.002 -
Viruses Dec 2012Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused... (Review)
Review
Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis.
Topics: Animals; Host-Pathogen Interactions; Humans; Immunity, Innate; Prion Diseases
PubMed: 23342365
DOI: 10.3390/v4123389 -
Journal of Clinical Microbiology Oct 2019Prion diseases are a group of rapidly progressive and always fatal neurodegenerative disorders caused by misfolded prion protein in the brain. Although autopsy remains... (Review)
Review
Prion diseases are a group of rapidly progressive and always fatal neurodegenerative disorders caused by misfolded prion protein in the brain. Although autopsy remains the gold-standard diagnostic tool, antemortem laboratory testing can be performed to aid in the diagnosis of prion disease. This review is meant to help laboratory directors and physicians in their interpretation of test results. Laboratory assays to detect both nonspecific biomarkers of prion disease and prion-specific biomarkers can be used. The levels of nonspecific biomarkers in cerebrospinal fluid (CSF) are elevated when rapid neurodegeneration is occurring in the patient, and these markers include 14-3-3, tau, neuron-specific enolase, S100B, and alpha-synuclein. These markers have various sensitivities and specificities but are overall limited, as the levels of any of these analytes can be elevated in nonprion disease that is causing rapid damage of brain tissue. Prion-specific assays used in clinical laboratory testing are currently limited to two options. The first option is second-generation real-time quaking-induced conversion (RT-QuIC) performed on CSF, and the second option is Western blotting of a brain biopsy specimen used to detect protease-resistant prion protein. Although both tests have exquisite specificity, RT-QuIC has a sensitivity of 92 to 97.2% in symptomatic individuals, compared to the brain biopsy Western blot sensitivity of 20 to 60%. RT-QuIC was added to the Centers for Disease Control and Prevention's diagnostic criteria for prion disease in 2018. Other caveats of laboratory testing need to be considered, as sporadic, genetic, and acquired forms of prion disease have different clinical and laboratory presentations, and these caveats are discussed. Laboratory testing plays an important role in the diagnosis of prion disease, which is often challenging to diagnose.
Topics: Autopsy; Biomarkers; Clinical Laboratory Techniques; Diagnosis, Differential; Diagnostic Tests, Routine; Disease Susceptibility; Electroencephalography; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Molecular Diagnostic Techniques; Prion Diseases; Sensitivity and Specificity
PubMed: 31366689
DOI: 10.1128/JCM.00769-19 -
Brain Pathology (Zurich, Switzerland) May 2013Research on prions, the infectious agents of devastating neurological diseases in humans and animals, has been in the forefront of developing the concept of protein... (Review)
Review
Research on prions, the infectious agents of devastating neurological diseases in humans and animals, has been in the forefront of developing the concept of protein aggregation diseases. Prion diseases are distinguished from other neurodegenerative diseases by three peculiarities. First, prion diseases, in addition to being sporadic or genetic like all other neurodegenerative diseases, are infectious diseases. Animal models were developed early on (a long time before the advent of transgenic technology), and this has made possible the discovery of the prion protein as the infectious agent. Second, human prion diseases have true equivalents in animals, such as scrapie, which has been the subject of experimental research for many years. Variant Creutzfeldt-Jakob disease (vCJD) is a zoonosis caused by bovine spongiform encephalopathy (BSE) prions. Third, they show a wide variety of phenotypes in humans and animals, much wider than the variants of any other sporadic or genetic neurodegenerative disease. It has now become firmly established that particular PrP(Sc) isoforms are closely related to specific human prion strains. The variety of human prion diseases, still an enigma in its own right, is a focus of this article. Recently, a series of experiments has shown that the concept of aberrant protein folding and templating, first developed for prions, may apply to a variety of neurodegenerative diseases. In the wake of these discoveries, the term prion has come to be used for Aβ, α-synuclein, tau and possibly others. The self-propagation of alternative conformations seems to be the common denominator of these "prions," which in future, in order to avoid confusion, may have to be specified either as "neurodegenerative prions" or "infectious prions."
Topics: Animals; Blood-Brain Barrier; Creutzfeldt-Jakob Syndrome; Genome-Wide Association Study; Humans; Kuru; PrPC Proteins; Prion Diseases; Protein Folding; Proteostasis Deficiencies
PubMed: 23587138
DOI: 10.1111/bpa.12045 -
Viruses Apr 2021Prion diseases are difficult to recognize as many symptoms are shared among other neurologic pathologies and the full spectra of symptoms usually do not appear until... (Review)
Review
Prion diseases are difficult to recognize as many symptoms are shared among other neurologic pathologies and the full spectra of symptoms usually do not appear until late in the disease course. Additionally, many commonly used laboratory markers are non-specific to prion disease. The recent introduction of second-generation real time quaking induced conversion (RT-QuIC) has revolutionized pre-mortem diagnosis of prion disease due to its extremely high sensitivity and specificity. However, RT-QuIC does not provide prognostic data and has decreased diagnostic accuracy in some rarer, atypical prion diseases. The objective of this review is to provide an overview of the current clinical utility of fluid-based biomarkers, neurodiagnostic testing, and brain imaging in the diagnosis of prion disease and to suggest guidelines for their clinical use, with a focus on rarer prion diseases with atypical features. Recent advancements in laboratory-based testing and imaging criteria have shown improved diagnostic accuracy and prognostic potential in prion disease, but because these diagnostic tests are not sensitive in some prion disease subtypes and diagnostic test sensitivities are unknown in the event that CWD transmits to humans, it is important to continue investigations into the clinical utility of various testing modalities.
Topics: Animals; Biomarkers; Creutzfeldt-Jakob Syndrome; Diagnosis, Differential; Diagnostic Tests, Routine; Disease Susceptibility; Electroencephalography; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Neurodegenerative Diseases; Prion Diseases; Prions; Quality Improvement; Sensitivity and Specificity; Zoonoses
PubMed: 33925126
DOI: 10.3390/v13050789 -
Advances in Neurobiology 2017Prion diseases are a group of invariably fatal and transmissible neurodegenerative disorders that are associated with the misfolding of the normal cellular prion... (Review)
Review
Prion diseases are a group of invariably fatal and transmissible neurodegenerative disorders that are associated with the misfolding of the normal cellular prion protein, with the misfolded conformers constituting an infectious unit referred to as a "prion". Prions can spread within an affected organism by directly propagating this misfolding within and between cells and can transmit disease between animals of the same and different species. Prion diseases have a range of clinical phenotypes in humans and animals, with a principle determinant of this attributed to different conformations of the misfolded protein, referred to as prion strains. This chapter will describe the different clinical manifestations of prion diseases, the evidence that these diseases can be transmitted by an infectious protein and how the misfolding of this protein causes disease.
Topics: Animals; Astrocytes; Cattle; Creutzfeldt-Jakob Syndrome; Deer; Encephalopathy, Bovine Spongiform; Gliosis; Humans; Hyperplasia; Hypertrophy; Prion Diseases; Prion Proteins; Protein Aggregation, Pathological; Protein Folding; Scrapie; Wasting Disease, Chronic
PubMed: 28674988
DOI: 10.1007/978-3-319-57193-5_13 -
Brain Research Bulletin May 2001The prion protein is a cell surface glyco-protein expressed by neurones. Its function has remained elusive until it was recently shown to be a copper binding protein.... (Review)
Review
The prion protein is a cell surface glyco-protein expressed by neurones. Its function has remained elusive until it was recently shown to be a copper binding protein. There is now strong evidence that the prion protein has a role in normal brain copper metabolism. Prion protein expression alters copper uptake into cells and enhances copper incorporation into superoxide dismutase. Furthermore the prion protein itself can act as a superoxide dismutase. One aspect of prion disease is the conversion of functional prion protein into an aggregated amyloid. This conversion may alter the function of the prion protein or abolish it. These results suggest that prion disease may involve disturbance to brain copper homeostasis.
Topics: Animals; Brain; Copper; Humans; Metalloproteins; Nerve Degeneration; Oxidative Stress; Prion Diseases; Prions; Protein Isoforms; Superoxide Dismutase
PubMed: 11470312
DOI: 10.1016/s0361-9230(01)00453-1 -
Current Opinion in Infectious Diseases Jun 2019Prion diseases are rapidly progressive neurodegenerative conditions that can be difficult to diagnose and are transmissible under specific circumstances. The authors... (Review)
Review
PURPOSE OF REVIEW
Prion diseases are rapidly progressive neurodegenerative conditions that can be difficult to diagnose and are transmissible under specific circumstances. The authors will provide background regarding prion disease and focus on diagnostic tools.
RECENT FINDINGS
Prion disease is caused by misfolded prion protein. The three possible causes of prion disease include sporadic (85%), genetic (10-15%), and acquired (<1%). Acquired prion diseases include kuru, iatrogenic, and variant Creutzfeldt-Jakob disease. Prion diseases differ in their clinical manifestation, neuropathology, and diagnostic test results. A variety of recent diagnostic tools have evolved that allow more reliable antemortem diagnosis of prion disease such as brain MRI and cerebrospinal fluid real-time quaking-induced conversion. Special infectivity guidelines must be followed when dealing with central nervous system tissue, but only standard precautions are needed for routine clinical care of patients with prion disease.
SUMMARY
The only way to definitely diagnose prion disease and determine its type is via neuropathologic examination. However, brain MRI and cerebrospinal fluid real-time quaking-induced conversion have drastically increased diagnostic accuracy and are important tests to use when evaluating patients with suspected prion disease.
Topics: Brain; Cerebrospinal Fluid; Diagnostic Tests, Routine; Humans; Magnetic Resonance Imaging; Prion Diseases; Prion Proteins
PubMed: 31008724
DOI: 10.1097/QCO.0000000000000552