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The New England Journal of Medicine Nov 2013Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal...
BACKGROUND
Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.
METHODS
We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.
RESULTS
We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.
CONCLUSIONS
Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.).
Topics: Animals; Autonomic Nervous System Diseases; Brain; Diarrhea; Female; Humans; Longitudinal Studies; Male; Mice; Mice, Transgenic; Mutation; Pedigree; Phenotype; Plaque, Amyloid; Prion Diseases; Prion Proteins; Prions
PubMed: 24224623
DOI: 10.1056/NEJMoa1214747 -
Molecular Neurobiology Aug 2017Prion diseases in humans are neurodegenerative diseases which are caused by an accumulation of abnormal, misfolded cellular prion protein known as scrapie prion protein... (Review)
Review
Prion diseases in humans are neurodegenerative diseases which are caused by an accumulation of abnormal, misfolded cellular prion protein known as scrapie prion protein (PrP). Genetic, acquired, or spontaneous (sporadic) forms are known. Pathogenic mutations in the human prion protein gene (PRNP) have been identified in 10-15 % of CJD patients. These mutations may be single point mutations, STOP codon mutations, or insertions or deletions of octa-peptide repeats. Some non-coding mutations and new mutations in the PrP gene have been identified without clear evidence for their pathogenic significance. In the present review, we provide an updated overview of PRNP mutations, which have been documented in the literature until now, describe the change in the DNA, the family history, the pathogenicity, and the number of described cases, which has not been published in this complexity before. We also provide a description of each genetic prion disease type, present characteristic histopathological features, and the PrP isoform expression pattern of various familial/genetic prion diseases.
Topics: Humans; Inheritance Patterns; Mutation; Prion Diseases; Prion Proteins
PubMed: 27324792
DOI: 10.1007/s12035-016-9918-y -
Cells Jun 2021MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of... (Review)
Review
MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target transcripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endogenous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer's. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of deregulated miRNAs on prion diseases, are also discussed. Since a cure or effective treatment for prion disorders still pose challenges, miRNA-based therapies emerge as an interesting alternative strategy to tackle such defying medical conditions.
Topics: Humans; MicroRNAs; Models, Biological; Prion Diseases; Prions; RNA, Circular; Translational Research, Biomedical
PubMed: 34209482
DOI: 10.3390/cells10071620 -
International Journal of Molecular... Aug 2020The normal cellular isoform of prion protein, designated PrP, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP, in prion diseases, which... (Review)
Review
The normal cellular isoform of prion protein, designated PrP, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP is a membrane glycoprotein consisting of the non-structural -terminal domain and the globular C-terminal domain. During conversion of PrP to PrP, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrP. Reverse genetic studies using reconstituted PrP-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrP and the conversion of PrP to PrP. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrP, the conversion of PrP to PrP, and the neurotoxicity of PrP by focusing on the roles of the N-terminal regions in these topics.
Topics: Animals; Humans; Mutation; Prion Diseases; Prion Proteins; Protein Conformation; Protein Domains
PubMed: 32872280
DOI: 10.3390/ijms21176233 -
Virology Journal Nov 2011Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with... (Review)
Review
Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with the accumulation of aggregates of misfolded conformers of host-encoded cellular prion protein (PrPC). Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, transmissible mink encephalopathy, feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, chronic wasting disease of cervids and spongiform encephalopathy of primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, animal prion diseases have basically occurred via the acquisition of infection from contaminated feed or via the exposure to contaminated environment. Scrapie and chronic wasting disease are naturally sustaining epidemics. The transmission of BSE to human has caused more than 200 cases of variant Cruetzfeldt-Jacob disease and has raised serious public health concerns. The present review discusses the epidemiology, clinical neuropathology, transmissibility and genetics of animal prion diseases.
Topics: Animals; Cats; Cattle; Goats; Mink; Primates; Prion Diseases; Sheep
PubMed: 22044871
DOI: 10.1186/1743-422X-8-493 -
Cell and Tissue Research Apr 2023Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are invariably fatal and pathogenic neurodegenerative disorders caused by the self-propagated... (Review)
Review
Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are invariably fatal and pathogenic neurodegenerative disorders caused by the self-propagated misfolding of cellular prion protein (PrP) to the neurotoxic pathogenic form (PrP) via a yet undefined but profoundly complex mechanism. Despite several decades of research on PrD, the basic understanding of where and how PrP is transformed to the misfolded, aggregation-prone and pathogenic PrP remains elusive. The primary clinical hallmarks of PrD include vacuolation-associated spongiform changes and PrP accumulation in neural tissue together with astrogliosis. The difficulty in unravelling the disease mechanisms has been related to the rare occurrence and long incubation period (over decades) followed by a very short clinical phase (few months). Additional challenge in unravelling the disease is implicated to the unique nature of the agent, its complexity and strain diversity, resulting in the heterogeneity of the clinical manifestations and potentially diverse disease mechanisms. Recent advances in tissue isolation and processing techniques have identified novel means of intercellular communication through extracellular vesicles (EVs) that contribute to PrP transmission in PrD. This review will comprehensively discuss PrP transmission and neurotoxicity, focusing on the role of EVs in disease progression, biomarker discovery and potential therapeutic agents for the treatment of PrD.
Topics: Humans; Prion Diseases; Prions; Prion Proteins; Extracellular Vesicles
PubMed: 35394216
DOI: 10.1007/s00441-022-03621-0 -
Emerging Infectious Diseases Jun 2018Prions cause fatal and transmissible neurodegenerative diseases, including Creutzfeldt-Jakob disease in humans, scrapie in small ruminants, and bovine spongiform...
Prions cause fatal and transmissible neurodegenerative diseases, including Creutzfeldt-Jakob disease in humans, scrapie in small ruminants, and bovine spongiform encephalopathy (BSE). After the BSE epidemic, and the associated human infections, began in 1996 in the United Kingdom, general concerns have been raised about animal prions. We detected a prion disease in dromedary camels (Camelus dromedarius) in Algeria. Symptoms suggesting prion disease occurred in 3.1% of dromedaries brought for slaughter to the Ouargla abattoir in 2015-2016. We confirmed diagnosis by detecting pathognomonic neurodegeneration and disease-specific prion protein (PrP) in brain tissues from 3 symptomatic animals. Prion detection in lymphoid tissues is suggestive of the infectious nature of the disease. PrP biochemical characterization showed differences with BSE and scrapie. Our identification of this prion disease in a geographically widespread livestock species requires urgent enforcement of surveillance and assessment of the potential risks to human and animal health.
Topics: Algeria; Animal Diseases; Animals; Biopsy; Camelus; Cattle; Encephalopathy, Bovine Spongiform; Immunohistochemistry; Prion Diseases; Prion Proteins; Sequence Analysis, DNA; Zoonoses
PubMed: 29652245
DOI: 10.3201/eid2406.172007 -
Biomolecules Mar 2020Transmissible spongiform encephalopathies or prion diseases are rapidly progressive neurodegenerative diseases, the clinical manifestation of which can resemble other... (Review)
Review
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, PrP, 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 PrP 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 PrP 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.
Topics: Cell-Free System; Humans; PrPSc Proteins; Prion Diseases
PubMed: 32204429
DOI: 10.3390/biom10030469 -
BMC Medicine Jun 2020Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient...
BACKGROUND
Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population.
METHODS
We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months.
RESULTS
CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.
CONCLUSIONS
CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.
Topics: Adult; Biomarkers; Cohort Studies; Female; Humans; Longitudinal Studies; Male; Neurodegenerative Diseases; Prion Diseases; Reproducibility of Results; Risk Factors
PubMed: 32552681
DOI: 10.1186/s12916-020-01608-8 -
Acta Neuropathologica Jan 2011Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification... (Comparative Study)
Comparative Study Review
Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification according to molecular criteria. Considerable experimental evidence suggests that phenotypic diversity in human prion disease relates in significant part to the existence of distinct human prion strains encoded by abnormal PrP isoforms with differing physicochemical properties. To date, however, the conformational repertoire of pathological isoforms of wild-type human PrP and the various forms of mutant human PrP has not been fully defined. Efforts to produce a unified international classification of human prion disease are still ongoing. The ability of genetic background to influence prion strain selection together with knowledge of numerous other factors that may influence clinical and neuropathological presentation strongly emphasises the requirement to identify distinct human prion strains in appropriate transgenic models, where host genetic variability and other modifiers of phenotype are removed. Defining how many human prion strains exist allied with transgenic modelling of potentially zoonotic prion strains will inform on how many human infections may have an animal origin. Understanding these relationships will have direct translation to protecting public health.
Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Humans; Prion Diseases; Prions; Protein Isoforms
PubMed: 20694796
DOI: 10.1007/s00401-010-0735-5