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Biomolecules Feb 2021The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer's disease (Aβ... (Review)
Review
The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer's disease (Aβ and tau), Parkinson's disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Creutzfeldt-Jakob Syndrome; Humans; Mice; Neurodegenerative Diseases; Phenotype; Plaque, Amyloid; Prion Diseases; Prion Proteins; Prions; Protein Denaturation; Protein Folding; alpha-Synuclein; tau Proteins
PubMed: 33540845
DOI: 10.3390/biom11020207 -
Prion 2015Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of...
Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.
Topics: Amyloid; Animals; Cattle; Dogs; Encephalopathy, Bovine Spongiform; Humans; Mice; Prion Diseases; Prions; Swine
PubMed: 26218890
DOI: 10.1080/19336896.2015.1065373 -
PLoS Pathogens Jul 2021Prions are comprised solely of PrPSc, the misfolded self-propagating conformation of the cellular protein, PrPC. Synthetic prions are generated in vitro from minimal...
Prions are comprised solely of PrPSc, the misfolded self-propagating conformation of the cellular protein, PrPC. Synthetic prions are generated in vitro from minimal components and cause bona fide prion disease in animals. It is unknown, however, if synthetic prions can cross the species barrier following interspecies transmission. To investigate this, we inoculated Syrian hamsters with murine synthetic prions. We found that all the animals inoculated with murine synthetic prions developed prion disease characterized by a striking uniformity of clinical onset and signs of disease. Serial intraspecies transmission resulted in a rapid adaptation to hamsters. During the adaptation process, PrPSc electrophoretic migration, glycoform ratios, conformational stability and biological activity as measured by protein misfolding cyclic amplification remained constant. Interestingly, the strain that emerged shares a strikingly similar transmission history, incubation period, clinical course of disease, pathology and biochemical and biological features of PrPSc with 139H, a hamster adapted form of the murine strain 139A. Combined, these data suggest that murine synthetic prions are comprised of bona fide PrPSc with 139A-like strain properties that efficiently crosses the species barrier and rapidly adapts to hamsters resulting in the emergence of a single strain. The efficiency and specificity of interspecies transmission of murine synthetic prions to hamsters, with relevance to brain derived prions, could be a useful model for identification of structure function relationships between PrPSc and PrPC from different species.
Topics: Animals; Cricetinae; Mice; PrPC Proteins; PrPSc Proteins; Prion Diseases; Species Specificity
PubMed: 34260664
DOI: 10.1371/journal.ppat.1009765 -
Cellular and Molecular Life Sciences :... Dec 2007From Creutzfeldt-Jakob disease (CJD) to variant CJD through Gerstmann-Sträussler-Scheinker syndrome, kuru and fatal familial insomnia, the journey leading to current... (Review)
Review
From Creutzfeldt-Jakob disease (CJD) to variant CJD through Gerstmann-Sträussler-Scheinker syndrome, kuru and fatal familial insomnia, the journey leading to current understanding of the basic aspects of human prion diseases has been full of unexpected, but often dramatic and always fascinating twists. Recent progress in modeling prion diseases and characterization of the various prion protein forms reveal that such a wide spectrum of the diseases is associated with the chameleon-like conformational features of prions.
Topics: Animals; Humans; Models, Biological; Prion Diseases; Prions
PubMed: 17965827
DOI: 10.1007/s00018-007-7380-8 -
Molecular and Cellular Neurosciences May 2015Prion diseases are fatal neurodegenerative disorders. Pathology is closely linked to the misfolding of native cellular PrP(C) into the disease-associated form PrP(Sc)... (Review)
Review
Prion diseases are fatal neurodegenerative disorders. Pathology is closely linked to the misfolding of native cellular PrP(C) into the disease-associated form PrP(Sc) that accumulates in the brain as disease progresses. Although treatments have yet to be developed, strategies aimed at stimulating the degradation of PrP(Sc) have shown efficacy in experimental models of prion disease. Here, we describe the cellular pathways that mediate PrP(Sc) degradation and review possible targets for therapeutic intervention. This article is part of a Special Issue entitled 'Neuronal Protein'.
Topics: Animals; Humans; Prion Diseases; Prions; Signal Transduction
PubMed: 25584786
DOI: 10.1016/j.mcn.2014.12.009 -
The Neurologist Mar 2011Rapidly progressive dementia (RPD) is a unique set of disorders resulting in cognitive, behavioral, and motor decline within 2 years. A variety of etiologies may... (Review)
Review
BACKGROUND
Rapidly progressive dementia (RPD) is a unique set of disorders resulting in cognitive, behavioral, and motor decline within 2 years. A variety of etiologies may contribute to RPD including neurodegenerative, inflammatory, infectious, and toxic-metabolic conditions. Jakob-Creutzfeldt disease (CJD) is frequently the most concerning diagnosis on the differential. The challenge for the neurologist is distinguishing prion disease from reversible processes that result in dementia.
REVIEW SUMMARY
This review discusses the clinical aspects and the diagnostic workup of RPD. Particular focus is given to both CJD and the potentially treatable inflammatory conditions that may cause a similar presentation. Furthermore, a standardized stepwise approach is outlined for patients presenting with RPD.
CONCLUSIONS
Neurologists should adopt a standardized approach to the rapidly presenting disease processes that may mimic CJD in their clinical and radiologic features.
Topics: Brain Diseases; Creutzfeldt-Jakob Syndrome; Dementia; Disease Progression; Electroencephalography; Encephalitis; Hashimoto Disease; Humans; Limbic Encephalitis; Neurodegenerative Diseases; Neurologic Examination; Prion Diseases; Prognosis
PubMed: 21364356
DOI: 10.1097/NRL.0b013e31820ba5e3 -
Current Issues in Molecular Biology 2020Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurological diseases that include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in... (Review)
Review
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurological diseases that include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, camel spongiform encephalopathy (CSE) in camels and chronic wasting disease (CWD) in cervids. A key event in prion diseases is the conversion of the cellular, host-encoded prion protein (PrPC) to its abnormal isoform (PrPSc) predominantly in the central nervous system of the infected host (Aguzzi et al., 2004). These diseases are transmissible under some circumstances, but unlike other transmissible disorders, prion diseases can also be caused by mutations in the host gene. The mechanism of prion spread among sheep and goats that develop natural scrapie is unknown. CWD, transmissible mink encephalopathy (TME), BSE, feline spongiform encephalopathy (FSE), and exotic ungulate encephalopathy (EUE) are all thought to occur after the consumption of prion-infected material. Most cases of human prion disease occur from unknown reasons, and greater than 20 mutations in the prion protein (PrP) gene may lead to inherited prion disease. In other instances, prion diseases are contracted by exposure to prion infectivity. These considerations raise the question of how a mere protein aggregate can bypass mucosal barriers, circumvent innate and adoptive immunity, and traverse the blood-brain barrier to give rise to brain disease. Here, we will briefly introduce a few topics in current prion studies.
Topics: Alzheimer Disease; Animals; Food Safety; Humans; Huntington Disease; Inflammation; Parkinson Disease; Prion Diseases; Prions; Proteostasis Deficiencies; Risk Factors; Transfusion Reaction
PubMed: 31559970
DOI: 10.21775/cimb.036.063 -
Acta Neurobiologiae Experimentalis 2004Prion diseases are widely recognized for their transmissibility, and it is this feature that has been studied most extensively. In recent years, public health concerns... (Review)
Review
Prion diseases are widely recognized for their transmissibility, and it is this feature that has been studied most extensively. In recent years, public health concerns over the transmission of animal forms of prion disease, such as bovine spongiform encephalopathy and chronic wasting disease, to humans has only augmented the notion that prion diseases are primarily infectious. Yet within the spectrum of human prion diseases, often overlooked is the fact that the overwhelming majority of cases are age-dependent sporadic, or inherited processes. Closer examination of the pathophysiological processes involved in prion disease further indicates a neurodegenerative, rather than infectious disease. Indeed, the age requirement, the numerous kindreds carrying point mutations in an amyloidogenic protein, the copper binding properties of the amyloidogenic protein, the evidence of free radical damage, the presence of polymorphisms that influence disease susceptibility, the formation of amyloid plaques, and in some cases the presence of neurofibrillary pathology, are features common to both prion disease and Alzheimer's disease. Therefore, while transmissibility will continue to be a major subject of prion disease research, we suspect that further characterization of its pathophysiological mechanisms will only substantiate the notion that prion disease is fundamentally a neurodegenerative process.
Topics: Alzheimer Disease; Humans; Prion Diseases
PubMed: 15190676
DOI: 10.55782/ane-2004-1487 -
Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain.Glia Nov 2022Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia...
Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia accelerates central nervous system (CNS) prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1r mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally and show none of the deficits reported in other microglia-deficient models. Csf1r mice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease. Although Csf1r mice succumbed to CNS prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced phagocytosis of neuronal contents and unfolded protein responses. Our data suggest that rather than simply phagocytosing and destroying prions, the microglia instead provide host-protection during CNS prion disease and restrict the harmful activities of reactive astrocytes.
Topics: Animals; Astrocytes; Brain; Mice; Microglia; Prion Diseases; Prions
PubMed: 35852018
DOI: 10.1002/glia.24244 -
Annual Review of Pathology 2008Prion diseases are infectious neurodegenerative diseases occurring in humans and animals with an invariably lethal outcome. One fundamental mechanistic event in prion... (Review)
Review
Prion diseases are infectious neurodegenerative diseases occurring in humans and animals with an invariably lethal outcome. One fundamental mechanistic event in prion diseases is the aggregation of aberrantly folded prion protein into large amyloid plaques and fibrous structures associated with neurodegeneration. The cellular prion protein (PrPC) is absolutely required for disease development, and prion knockout mice are not susceptible to prion disease. Prions accumulate not only in the central nervous system but also in lymphoid organs, as shown for new variant and sporadic Creutzfeldt-Jakob patients and for some animals. To date it is largely accepted that prions consist primarily of PrPSc, a misfolded and aggregated beta-sheet-rich isoform of PrPC. However, PrPSc may or may not be completely congruent with the infectious moiety. Here, we discuss the molecular mechanisms leading to neurodegeneration, the role of the immune system in prion pathogenesis, and the existence of prion strains that appear to have different tropisms and biochemical characteristics.
Topics: Animals; Cattle; Central Nervous System; Disease Models, Animal; Gene Silencing; Humans; Mice; Mice, Knockout; Molecular Biology; Nerve Degeneration; PrPSc Proteins; Prion Diseases; Prions
PubMed: 18233951
DOI: 10.1146/annurev.pathmechdis.3.121806.154326