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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 -
Progress in Molecular Biology and... 2017Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal diseases that affect the nervous system of many mammals including humans.... (Review)
Review
Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal diseases that affect the nervous system of many mammals including humans. The key molecular event in the pathogenesis of TSEs is the conversion of the cellular prion protein PrP into a disease-associated isoform PrP. The "protein-only hypothesis" argues that PrP itself is the infectious agent. In effect, PrP can adopt several structures that represent different prion strains. The interspecies transmission of TSEs is difficult because of differences between the host and donor primary PrP sequence. However, transmission is not impossible as this occurred when bovine spongiform encephalopathy spread to humans causing variant Creutzfeldt-Jakob disease (vCJD). This event determined a need for a thorough understanding of prion replication and transmission so that we could be one step ahead of further threats for human health. This chapter focuses on these concepts and on new insights gained into prion propagation mechanisms.
Topics: Animals; Humans; Models, Biological; Polymorphism, Genetic; Prion Diseases; Prions; Species Specificity
PubMed: 28838661
DOI: 10.1016/bs.pmbts.2017.06.014 -
Progress in Molecular Biology and... 2017Prion diseases are progressive fatal encephalopathies characterized by a neurodegenerative pathology, the tissue deposition of abnormally folded prion protein and, in... (Review)
Review
Prion diseases are progressive fatal encephalopathies characterized by a neurodegenerative pathology, the tissue deposition of abnormally folded prion protein and, in general, potential transmissibility. Creutzfeldt-Jakob disease (CJD) is the commonest human prion disease and occurs in three principal forms: sporadic (idiopathic), acquired (infectious), and inherited (genetic). This chapter concerns the sporadic and acquired forms. Sporadic CJD occurs worldwide and affects mainly the middle aged and elderly. There are recognized genetic risk factors-most importantly the PRNP-129 polymorphism. The acquired forms of CJD consist of iatrogenic CJD (accidental transmission of CJD via medical or surgical procedures) and variant CJD (vJCD) (which originated as a zoonosis via bovine spongiform encephalopathy (BSE)-contamination of human food). The main causes of iatrogenic CJD are cadaveric-derived human growth hormone treatment and dura mater surgical grafts. The PRNP-129 polymorphism has important effects on iatrogenic infection, including overall susceptibility and incubation period. vCJD, resulting from dietary exposure to BSE, has affected mostly the United Kingdom, followed by France. All tested cases were originally PRNP-129MM, although two MV cases have been identified recently (one possible; one definite). vCJD has been secondarily transmitted via blood transfusion and a blood product. There is continuing concern over secondary transmission since there is evidence-from lymphoreticular tissue studies-of extensive subclinical infection in the UK general population, although a further recent study has caused uncertainty over the significance of the previous studies. While definitive diagnosis of CJD is pathological, recent developments in protein amplification and detection have led to significantly better clinical diagnosis.
Topics: Animals; Creutzfeldt-Jakob Syndrome; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Prion Diseases
PubMed: 28838665
DOI: 10.1016/bs.pmbts.2017.06.010 -
Cold Spring Harbor Perspectives in... Jul 2018Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in... (Review)
Review
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α-synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA-derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed propagation, like PrP prions. Almost 20 years after α-synuclein was discovered as the primary component of GCIs, α-synuclein aggregates isolated from MSA patient samples were shown to infect cultured mammalian cells and also to transmit neurological disease to transgenic mice. These findings argue that α-synuclein becomes a prion in MSA patients. In this review, we discuss the in vitro and in vivo data supporting the recent classification of MSA as a prion disease.
Topics: Animals; Cells, Cultured; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Multiple System Atrophy; Prion Diseases; Prions; alpha-Synuclein
PubMed: 28213437
DOI: 10.1101/cshperspect.a024588 -
Internal Medicine Journal Jul 2021Indigenous Australians are at increased risk of developing dementia - Alzheimer disease and mixed dementia diagnoses are the most common. While prion diseases have been...
BACKGROUND
Indigenous Australians are at increased risk of developing dementia - Alzheimer disease and mixed dementia diagnoses are the most common. While prion diseases have been reported in Indigenous peoples of Papua New Guinea and the United States, the occurrence and phenotype of prion disease in Indigenous Australians is hitherto unreported.
AIM
To report the incidence rate and clinical phenotype of Creutzfeldt-Jakob disease (CJD) in Indigenous Australians.
METHOD
Crude sporadic CJD (sCJD) incidence rates and indirect age standardisation of all CJD were assessed to calculate the standardised mortality ratio (SMR) of the Indigenous Australian population in comparison to the all-resident Australian population, along with analysis of clinical phenotypes.
RESULTS
We report an illustrative case of an Indigenous Australian from regionally remote Western Australia dying from typical 'probable' sCJD 2 months after disease onset, with Australian National CJD Registry (ANCJDR) surveillance overall demonstrating eight Indigenous Australians dying from sCJD (five post-mortem confirmed, three classified as 'probable') with a clinical phenotype similar to non-indigenous people, including median age at death of 61 years (interquartile range IQR = 16 years) and median duration of illness of 3 months (IQR = 1.6 months). Indigenous Australians with sCJD were geographically dispersed throughout Australia. The calculated overall crude annual rate of sCJD in Indigenous Australians compared to the remainder of the Australian population was not significantly different (0-3.87/million for Indigenous Australians; 0.94-1.83/million for non-indigenous). The overall indirect age-standardised CJD mortality ratio for the indigenous population for the years 2006-2018 was 1.49 (95% CI, 0.75-2.98), also not significantly different to the all-resident Australian population.
CONCLUSION
CJD occurs in Indigenous Australians with clinical phenotype and occurrence rates similar to non-Indigenous Australians. These findings contrast with a previous report where the incidence rate of CJD in a non-Australian indigenous population was reported to be decreased.
Topics: Australia; Creutzfeldt-Jakob Syndrome; Humans; Incidence; Infant; Prion Diseases; Registries
PubMed: 32237029
DOI: 10.1111/imj.14835 -
Viruses Jan 2019Prion disorders are transmissible diseases caused by a proteinaceous infectious agent that can infect the lymphatic and nervous systems. The clinical features of prion... (Review)
Review
Prion disorders are transmissible diseases caused by a proteinaceous infectious agent that can infect the lymphatic and nervous systems. The clinical features of prion diseases can vary, but common hallmarks in the central nervous system (CNS) are deposition of abnormally folded protease-resistant prion protein (PrPres or PrPSc), astrogliosis, microgliosis, and neurodegeneration. Numerous proinflammatory effectors expressed by astrocytes and microglia are increased in the brain during prion infection, with many of them potentially damaging to neurons when chronically upregulated. Microglia are important first responders to foreign agents and damaged cells in the CNS, but these immune-like cells also serve many essential functions in the healthy CNS. Our current understanding is that microglia are beneficial during prion infection and critical to host defense against prion disease. Studies indicate that reduction of the microglial population accelerates disease and increases PrPSc burden in the CNS. Thus, microglia are unlikely to be a foci of prion propagation in the brain. In contrast, neurons and astrocytes are known to be involved in prion replication and spread. Moreover, certain astrocytes, such as A1 reactive astrocytes, have proven neurotoxic in other neurodegenerative diseases, and thus might also influence the progression of prion-associated neurodegeneration.
Topics: Animals; Astrocytes; Brain; Humans; Inflammation; Mice; Microglia; Neurodegenerative Diseases; Neurons; PrPSc Proteins; Prion Diseases; Prions
PubMed: 30650564
DOI: 10.3390/v11010065 -
Annual Review of Genetics Dec 2019Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including... (Review)
Review
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 () and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of , 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- factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.
Topics: Animals; Cattle; Disease Models, Animal; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Goats; Humans; Mammals; Mice; Polymorphism, Genetic; Prion Diseases; Prion Proteins; Selection, Genetic; Sheep
PubMed: 31537104
DOI: 10.1146/annurev-genet-120213-092352 -
Prion Dec 2022Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and... (Review)
Review
Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP) into scrapie isoform (PrP) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP to PrP conversion, increasing PrP removal, and PrP stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity , only a few were effective and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.
Topics: Animals; Sheep; Humans; Prions; Prion Proteins; Prion Diseases; Scrapie
PubMed: 36515657
DOI: 10.1080/19336896.2022.2153551 -
Journal of Neuropathology and... May 2018Prion diseases comprise a group of transmissible degenerative encephalopathies resulting from propagation of a misfolded cellular protein of uncertain function. As is... (Review)
Review
Prion diseases comprise a group of transmissible degenerative encephalopathies resulting from propagation of a misfolded cellular protein of uncertain function. As is generally the case with rare diseases, lack of institutional experience compromises individual familiarity with the varying, and apparently protean, manifestations of prion diseases, both clinically and pathologically. Coupled with the documented transmissibility of these diseases both within and between species, the Centers for Disease Control and Prevention (CDC) has established the National Prion Disease Pathology Surveillance Center to both aid with diagnosis of prion disease and to survey the United States for evidence of zoonotic transmission. We have assembled this primer with the hope that our accumulated experience will enable the neuropathological community to help the CDC "save lives and protect people."
Topics: Animals; Animals, Wild; Humans; Prion Diseases; Prions
PubMed: 29608707
DOI: 10.1093/jnen/nly019 -
Cell and Tissue Research Apr 2023Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular... (Review)
Review
Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrP) into the pathological PrP isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrP and PrP share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrP-directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.
Topics: Animals; Cattle; Humans; Sheep; Goals; Prion Diseases; Prions; Encephalopathy, Bovine Spongiform; Wasting Disease, Chronic; Deer; Vaccines; Goats
PubMed: 36764940
DOI: 10.1007/s00441-023-03749-7