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Virology Journal Dec 2011Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular... (Review)
Review
Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrP(C). They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrP(C) and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed.
Topics: Animals; Cattle; Creutzfeldt-Jakob Syndrome; Encephalopathy, Bovine Spongiform; Gerstmann-Straussler-Scheinker Disease; Humans; Insomnia, Fatal Familial; Kuru; Prion Diseases; Prions; Public Health
PubMed: 22196171
DOI: 10.1186/1743-422X-8-559 -
Acta Biochimica Et Biophysica Sinica Jun 2013Prion diseases are a group of infectious fatal neurodegenerative diseases. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded... (Review)
Review
Prion diseases are a group of infectious fatal neurodegenerative diseases. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion diseases pathology. Under normal conditions, the high-energy barrier separates PrP(C) from PrP(Sc) isoform. However, pathogenic mutations, modifications as well as some cofactors, such as glycosaminoglycans, nucleic acids, and lipids, could modulate the conformational conversion process. Understanding the mechanism of conformational conversion of prion protein is essential for the biomedical research and the treatment of prion diseases. Particularly, the characterization of cofactors interacting with prion protein might provide new diagnostic and therapeutic strategies.
Topics: Animals; Humans; Models, Molecular; Mutation; Prion Diseases; Prions; Protein Conformation; Protein Processing, Post-Translational
PubMed: 23580591
DOI: 10.1093/abbs/gmt027 -
Journal of Neuropathology and... Sep 2015We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)-like changes. To explore potential...
We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (BrnAggs) to a brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease and found that neurons in human BrnAggs produced many β-amyloid (Aβ; Aβ42) inclusions, whereas uninfected control-exposed human BrnAggs did not. Western blot analysis of 20 pooled Creutzfeldt-Jakob disease-infected BrnAggs verified Aβ42 levels higher than those in controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrP), many Aβ42 intraneuronal inclusions, low apolipoprotein E-4 (APOE-4), and no significant nerve cell loss. Seven patients had high levels of PrP, low Aβ42, high APOE-4, and 40% nerve cell loss, suggesting that APOE-4 and PrP together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls, and 2 controls had few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to those triggered by AD and suggest that PrionD is a disease involving PrP, Aβ42, APOE-4, and abnormal tau.
Topics: Aged; Alzheimer Disease; Animals; Brain; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Prion Diseases
PubMed: 26226132
DOI: 10.1097/NEN.0000000000000228 -
The Journal of Neuroscience : the... May 2023Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the...
Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity , we prion-challenged conditional knockout mice (male and female) having deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrP, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration. Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrP), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrP-mediated neurotoxic signaling.
Topics: Male; Female; Mice; Humans; Animals; Prions; Prion Proteins; Receptors, AMPA; Neurons; Prion Diseases; Neurodegenerative Diseases; Endosomal Sorting Complexes Required for Transport
PubMed: 37019623
DOI: 10.1523/JNEUROSCI.1878-22.2023 -
PLoS Pathogens Mar 2006Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein... (Review)
Review
Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.
Topics: Animals; Cattle; Creutzfeldt-Jakob Syndrome; Deer; Encephalopathy, Bovine Spongiform; Humans; Insomnia, Fatal Familial; PrPSc Proteins; Prion Diseases; Prions; Scrapie; Sheep; Wasting Disease, Chronic
PubMed: 16609731
DOI: 10.1371/journal.ppat.0020026 -
Folia Neuropathologica 2022The pro-inflammatory, innate-immune system ribonucleic acid mediator microRNA-146a, constitutively expressed in the brain and central nervous system (CNS) of both the...
The pro-inflammatory, innate-immune system ribonucleic acid mediator microRNA-146a, constitutively expressed in the brain and central nervous system (CNS) of both the mouse and the human, is pathologically up-regulated in multiple transmissible spongiform encephalopathies (TSEs) to several times its basal level. miRNA-146a: (i) exists as a ~22-ribonucleotide (nt) single-stranded non-coding RNA (sncRNA) whose sequence is unique and highly selected over evolution; (ii) is brain-, CNS- and lymphoid-tissue enriched and exhibits a 100% RNA sequence homology between the mouse and the human; (iii) has been repeatedly shown to play critical immunological and pro-inflammatory roles in the onset and propagation of several human CNS disorders including progressive, incapacitating, and lethal neurological syndromes that include prion disease (PrD) and Alzheimer's disease (AD); (iv) is a fascinating molecular entity because it is representative of the smallest class of soluble, information-carrying, amphipathic sncRNA yet described; (v) has capability to be induced by cellular stressors and the pro-inflammatory transcription factor NF-kB (p50/p65); (vi) has capability to post-transcriptionally regulate multiple mRNAs and cellular processes in neurological health and disease; (vii) is upregulated in human host cells after viral invasion by single-stranded RNA (ssRNA) or double-stranded DNA (dsDNA) neurotropic viruses; and (viii) has an immense potential in neuro-degenerative disease therapeutics via anti-NF-kB and/or anti-miRNA-146a treatment strategies. In this short communication we provide for the first time evidence that miRNA-146a is a prominent sncRNA species in experimental murine prion disease, progressively increasing in the pre-symptomatic stages in C57BL/6J, SJL/J or Swiss Albino murine scrapie prion models. The highest miRNA-146a levels were quantified in these three different murine scrapie models exhibiting full symptomology of prion infection. The results suggest that miRNA-146a levels in the brain may be useful as an accessory diagnostic, prognostic or response-to-treatment biomarker to monitor the onset and development of PrD in experimental murine models that may also be extrapolated to be a relevant adjunct biomarker in human TSEs.
Topics: Alzheimer Disease; Animals; Biomarkers; Mice; Mice, Inbred C57BL; MicroRNAs; Prion Diseases
PubMed: 35359143
DOI: 10.5114/fn.2022.113561 -
Biomolecules Jan 2022Naturally occurring neuron-abundant proteins including amyloid Aβ42 peptide and the microtubule-associated protein tau (MAPT) can, over time and under pathological...
Naturally occurring neuron-abundant proteins including amyloid Aβ42 peptide and the microtubule-associated protein tau (MAPT) can, over time and under pathological situations, assume atypical conformations, altering their normal biological structure and function, and causing them to aggregate into insoluble and neurotoxic intracellular inclusions. These misfolded proteins ultimately contribute to the pathogenesis of several progressive, age-related and ultimately lethal human neurodegenerative disorders. The molecular mechanism of this pathological phenomenon of neuronal protein misfolding lends support to the '', which predicts that the aberrant folding of endogenous natural protein structures into unusual pathogenic isoforms can induce the atypical folding of other similar brain-abundant proteins, underscoring the age-related, progressive nature and potential transmissible and spreading capabilities of the aberrant protein isoforms that drive these invariably fatal neurological syndromes. The abnormal folding and aggregation of host proteins is a consistent feature of both amyloidopathies and tauopathies that encompass a continuous spectrum of brain diseases that include Alzheimer's disease (AD), prion disorders (PrD) such as scrapie in sheep and goats (), experimental prion infection of rodents (), Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) in humans (, and other fatal prion-driven neurological disorders. Because AD patients accumulate both misfolded tau and Aβ peptides, AD may be somewhat unique as the first example of a ''. This commentary will examine current research trends in this fascinating research area, with a special emphasis on AD and PrD, and the novel pathological misfolded protein processes common to both intractable neurological disorders.
Topics: Alzheimer Disease; Animals; Creutzfeldt-Jakob Syndrome; Humans; Prion Diseases; Prions; Scrapie; Sheep
PubMed: 35204666
DOI: 10.3390/biom12020166 -
Nature Reviews. Neurology Jun 2021Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal and transmissible neurodegenerative disease associated with the accumulation of misfolded prion protein... (Review)
Review
Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal and transmissible neurodegenerative disease associated with the accumulation of misfolded prion protein in the CNS. International CJD surveillance programmes have been active since the emergence, in the mid-1990s, of variant CJD (vCJD), a disease linked to bovine spongiform encephalopathy. Control measures have now successfully contained bovine spongiform encephalopathy and the incidence of vCJD has declined, leading to questions about the requirement for ongoing surveillance. However, several lines of evidence have raised concerns that further cases of vCJD could emerge as a result of prolonged incubation and/or secondary transmission. Emerging evidence from peripheral tissue distribution studies employing high-sensitivity assays suggests that all forms of human prion disease carry a theoretical risk of iatrogenic transmission. Finally, emerging diseases, such as chronic wasting disease and camel prion disease, pose further risks to public health. In this Review, we provide an up-to-date overview of the transmission of prion diseases in human populations and argue that CJD surveillance remains vital both from a public health perspective and to support essential research into disease pathophysiology, enhanced diagnostic tests and much-needed treatments.
Topics: Animals; Cattle; Creutzfeldt-Jakob Syndrome; Humans; Internationality; Population Surveillance; Prion Diseases; Prions
PubMed: 33972773
DOI: 10.1038/s41582-021-00488-7 -
Biochimica Et Biophysica Acta Mar 2011Transmissible spongiform encephalopathies (TSEs), otherwise known as prion disorders, are fatal diseases causing neurodegeneration in a wide range of mammalian hosts,... (Review)
Review
Transmissible spongiform encephalopathies (TSEs), otherwise known as prion disorders, are fatal diseases causing neurodegeneration in a wide range of mammalian hosts, including humans. The causative agents - prions - are thought to be composed of a rogue isoform of the endogenous prion protein (PrP). Beyond these and other basic concepts, fundamental questions in prion biology remain unanswered, such as the physiological function of PrP, the molecular mechanisms underlying prion pathogenesis, and the origin of prions. To date, the occurrence of TSEs in lower vertebrates like fish and birds has received only limited attention, despite the fact that these animals possess bona fide PrPs. Recent findings, however, have brought fish before the footlights of prion research. Fish models are beginning to provide useful insights into the roles of PrP in health and disease, as well as the potential risk of prion transmission between fish and mammals. Although still in its infancy, the use of fish models in TSE research could significantly improve our basic understanding of prion diseases, and also help anticipate risks to public health. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.
Topics: Animals; Fishes; Humans; Models, Biological; Prion Diseases; Prions
PubMed: 20933080
DOI: 10.1016/j.bbadis.2010.09.013 -
The Western Journal of Medicine Sep 1994Prion diseases include kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia of humans as well as scrapie and bovine... (Review)
Review
Prion diseases include kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia of humans as well as scrapie and bovine spongiform encephalopathy of animals. For many years, the prion diseases were thought to be caused by viruses despite evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve aberrant metabolism of the prion protein. In many cases, the cellular prion protein is converted into the scrapie variant by a process after translation that involves a conformational change. Often the human prion diseases are transmissible experimentally to animals, and all of the inherited prion diseases segregate with prion protein gene mutations.
Topics: Animals; Humans; Nerve Degeneration; Prion Diseases; Prions
PubMed: 7975565
DOI: No ID Found