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Acta Neuropathologica Communications Jun 2019For the transmissible, neurogenerative family of prion diseases, few human models of infection exist and none represent structured neuronal tissue. Human cerebral...
For the transmissible, neurogenerative family of prion diseases, few human models of infection exist and none represent structured neuronal tissue. Human cerebral organoids are self-organizing, three-dimensional brain tissues that can be grown from induced pluripotent stem cells. Organoids can model aspects of neurodegeneration in Alzheimer's Disease and Down's Syndrome, reproducing tau hyperphosphorylation and amyloid plaque pathology. To determine whether organoids could be used to reproduce human prion infection and pathogenesis, we inoculated organoids with two sporadic Creutzfeldt-Jakob Disease prion subtypes. Organoids showed uptake, followed by clearance, of the infectious inoculum. Subsequent re-emergence of prion self-seeding activity indicated de novo propagation. Organoid health assays, prion titer, prion protein electrophoretic mobility and immunohistochemistry demonstrated inoculum-specific differences. Our study shows, for the first time, that cerebral organoids can model aspects of human prion disease and thus offer a powerful system for investigating different human prion subtype pathologies and testing putative therapeutics.
Topics: Brain; Creutzfeldt-Jakob Syndrome; Humans; Induced Pluripotent Stem Cells; Organ Culture Techniques; Organoids; Prion Diseases
PubMed: 31196223
DOI: 10.1186/s40478-019-0742-2 -
The Journal of General Virology Aug 2016Prion diseases are a unique group of transmissible, chronic, neurodegenerative disorders. Following peripheral exposure (e.g. oral), prions often accumulate first within... (Review)
Review
Prion diseases are a unique group of transmissible, chronic, neurodegenerative disorders. Following peripheral exposure (e.g. oral), prions often accumulate first within the secondary lymphoid tissues before they infect the central nervous system (CNS). Prion replication within secondary lymphoid tissues is crucial for the efficient spread of disease to the CNS. Once within the CNS, the responses of innate immune cells within it can have a significant influence on neurodegeneration and disease progression. Recently, there have been substantial advances in our understanding of how cross-talk between the host and the vast community of commensal microorganisms present at barrier surfaces such as the gut influences the development and regulation of the host's immune system. These effects are evident not only in the mucosal immune system in the gut, but also in the CNS. The actions of this microbial community (the microbiota) have many important beneficial effects on host health, from metabolism of nutrients and regulation of host development to protection from pathogen infection. However, the microbiota can also have detrimental effects in some circumstances. In this review we discuss the many and varied interactions between prions, the host and the gut microbiota. Particular emphasis is given to the ways by which changes to the composition of the commensal gut microbiota or congruent pathogen infection may influence prion disease pathogenesis and/or disease susceptibility. Understanding how these factors influence prion pathogenesis and disease susceptibility is important for assessing the risk to infection and the design of novel opportunities for therapeutic intervention.
Topics: Animals; Disease Susceptibility; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Prion Diseases
PubMed: 27193137
DOI: 10.1099/jgv.0.000507 -
The Canadian Veterinary Journal = La... Apr 2022
Topics: Animals; Deer; One Health; Prion Diseases; Wasting Disease, Chronic
PubMed: 35368398
DOI: No ID Found -
Acta Neuropathologica Aug 2015Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the... (Review)
Review
Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Sträussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.
Topics: Animals; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic; Prion Diseases; Prion Proteins; Prions
PubMed: 26022925
DOI: 10.1007/s00401-015-1447-7 -
Biochimica Et Biophysica Acta Jun 2007The recognition that variant Creutzfeldt-Jakob disease (vCJD) is caused by the same prion strain as bovine spongiform encephalopathy in cattle has dramatically... (Review)
Review
The recognition that variant Creutzfeldt-Jakob disease (vCJD) is caused by the same prion strain as bovine spongiform encephalopathy in cattle has dramatically highlighted the need for a precise understanding of the molecular biology of human prion diseases. Detailed clinical, pathological and molecular data from a large number of human prion disease patients indicate that phenotypic diversity in human prion disease relates in part to the propagation of disease-related PrP isoforms with distinct physicochemical properties. Incubation periods of prion infection in humans can exceed 50 years and therefore it will be some years before the extent of any human vCJD epidemic can be predicted with confidence.
Topics: Animals; Brain; Cattle; Creutzfeldt-Jakob Syndrome; Encephalopathy, Bovine Spongiform; Humans; Models, Biological; Prion Diseases; Prions
PubMed: 17408929
DOI: 10.1016/j.bbadis.2007.02.010 -
Progress in Neurobiology Nov 2013This paper is intended to discuss some of the scientific and ethical issues that are created by increased research efforts towards earlier diagnosis, as well as to...
This paper is intended to discuss some of the scientific and ethical issues that are created by increased research efforts towards earlier diagnosis, as well as to treatment of, human prion diseases (and related dementias), including the resulting consequences for individuals, their families, and society. Most patients with prion disease currently are diagnosed when they are about 2/3 of the way through their disease course (Geschwind et al., 2010a; Paterson et al., 2012b), when the disease has progressed so far that even treatments that stop the disease process would probably have little benefit. Although there are currently no treatments available for prion diseases, we and others have realized that we must diagnose patients earlier and with greater accuracy so that future treatments have hope of success. As approximately 15% of prion diseases have a autosomal dominant genetic etiology, this further adds to the complexity of ethical issues, particularly regarding when to conduct genetic testing, release of genetic results, and when or if to implement experimental therapies. Human prion diseases are both infectious and transmissible; great care is required to balance the needs of the family and individual with both public health needs and strained hospital budgets. It is essential to proactively examine and address the ethical issues involved, as well as to define and in turn provide best standards of care.
Topics: Animals; Biomedical Research; Humans; Neurology; Prion Diseases
PubMed: 23906487
DOI: 10.1016/j.pneurobio.2013.07.001 -
The Journal of Clinical Investigation Feb 2014The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the...
The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains.
Topics: Animals; Arvicolinae; Brain; Cell Line; Creutzfeldt-Jakob Syndrome; Disease Progression; Down-Regulation; Glycosylation; Humans; Mesocricetus; Mice; Mice, Transgenic; PrPC Proteins; PrPSc Proteins; Prion Diseases; Protein Isoforms; Scrapie; Signal Transduction; Time Factors; Wasting Disease, Chronic
PubMed: 24430187
DOI: 10.1172/JCI72241 -
Journal of Geriatric Psychiatry and... Dec 2010The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of the prion protein (PrP), a normal... (Review)
Review
The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of the prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human prion diseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histopathology. Evidence suggests these phenotypes are defined by differences in the pathogenic conformation of misfolded PrP. Although the vast majority of cases are sporadic, 10% to 15% result from an autosomal dominant mutation of the PrP gene (PRNP). General phenotype-genotype correlations can be made for the major subtypes of CJD, GSS, and FI. This paper will review some of the general background related to prion biology and detail the clinical and pathologic features of the major prion diseases, with a particular focus on the genetic aspects that result in prion disease or modification of its risk or phenotype.
Topics: Animals; Brain; Brain Stem; Cerebellum; Creutzfeldt-Jakob Syndrome; Gerstmann-Straussler-Scheinker Disease; Humans; Insomnia, Fatal Familial; Kuru; Mutation; Phenotype; Prion Diseases; Prion Proteins; Prions; Risk Factors; Severity of Illness Index; Thalamus
PubMed: 20938044
DOI: 10.1177/0891988710383576 -
Progress in Molecular Biology and... 2017The human prion diseases comprise sporadic, genetic, and acquired disorders. These are rare conditions with a heterogeneous clinicopathologic phenotype, which can make... (Review)
Review
The human prion diseases comprise sporadic, genetic, and acquired disorders. These are rare conditions with a heterogeneous clinicopathologic phenotype, which can make diagnosis challenging. A combined clinical, genetic, neuropathologic and biochemical approach to diagnosis is therefore essential. Since prion infectivity is the highest in tissues from the central nervous system, special laboratory precautions are required for the safe handling of these tissues. Neuropathologic assessment is generally performed following autopsy, when the fixed brain should be adequately sampled and studied by conventional stains and immunohistochemistry for the abnormal form of the prion protein. Frozen brain tissue is also required for DNA extraction for prion protein gene sequencing and for Western blot analysis of protease-resistant prion protein. The microscopic assessment of the nature and degree of spongiform change, neuronal loss, gliosis, and abnormal prion protein deposition in the brain can be used to determine the major categories of human prion disease. This information can be combined with clinical, genetic data, and biochemical data to allow an accurate diagnosis of a human prion disease and facilitates subclassification into recognized disease subtypes, for example in sporadic Creutzfeldt-Jakob disease. The spectrum of human prion diseases continues to expand and neuropathology will play a key role in the recognition and understanding of any further novel entities or disease variants that may emerge in the future.
Topics: Autopsy; Brain; Humans; PrPSc Proteins; Prion Diseases
PubMed: 28838666
DOI: 10.1016/bs.pmbts.2017.06.011 -
Acta Neuropathologica Jan 2011The transmissible spongiform encephalopathies (TSEs) or prion diseases of animals are characterised by CNS spongiform change, gliosis and the accumulation of... (Review)
Review
The transmissible spongiform encephalopathies (TSEs) or prion diseases of animals are characterised by CNS spongiform change, gliosis and the accumulation of disease-associated forms of prion protein (PrP(d)). Particularly in ruminant prion diseases, a wide range of morphological types of PrP(d) depositions are found in association with neurons and glia. When light microscopic patterns of PrP(d) accumulations are correlated with sub-cellular structure, intracellular PrP(d) co-localises with lysosomes while non-intracellular PrP(d) accumulation co-localises with cell membranes and the extracellular space. Intracellular lysosomal PrP(d) is N-terminally truncated, but the site at which the PrP(d) molecule is cleaved depends on strain and cell type. Different PrP(d) cleavage sites are found for different cells infected with the same agent indicating that not all PrP(d) conformers code for different prion strains. Non-intracellular PrP(d) is full-length and is mainly found on plasma-lemmas of neuronal perikarya and dendrites and glia where it may be associated with scrapie-specific membrane pathology. These membrane changes appear to involve a redirection of the predominant axonal trafficking of normal cellular PrP and an altered endocytosis of PrP(d). PrP(d) is poorly excised from membranes, probably due to increased stabilisation on the membrane of PrP(d) complexed with other membrane ligands. PrP(d) on plasma-lemmas may also be transferred to other cells or released to the extracellular space. It is widely assumed that PrP(d) accumulations cause neurodegenerative changes that lead to clinical disease. However, when different animal prion diseases are considered, neurological deficits do not correlate well with any morphological type of PrP(d) accumulation or perturbation of PrP(d) trafficking. Non-PrP(d)-associated neurodegenerative changes in TSEs include vacuolation, tubulovesicular bodies and terminal axonal degeneration. The last of these correlates well with early neurological disease in mice, but such changes are absent from large animal prion disease. Thus, the proximate cause of clinical disease in animal prion disease is uncertain, but may not involve PrP(d).
Topics: Animals; Cell Membrane; Disease Models, Animal; Humans; Nerve Degeneration; Neurons; PrPSc Proteins; Prion Diseases; Protein Conformation; Protein Transport
PubMed: 20532540
DOI: 10.1007/s00401-010-0700-3