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International Journal of Molecular... Oct 2020Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive... (Review)
Review
Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.
Topics: Aging; Brain; Disease Susceptibility; Humans; Immune System; Immunomodulation; Prion Diseases; Prions
PubMed: 33023255
DOI: 10.3390/ijms21197299 -
Expert Opinion on Therapeutic Patents Dec 2021: Prion diseases are a class of rare and fatal neurodegenerative diseases for which no cure is currently available. They are characterized by conformational conversion... (Review)
Review
: Prion diseases are a class of rare and fatal neurodegenerative diseases for which no cure is currently available. They are characterized by conformational conversion of cellular prion protein (PrP) into the disease-associated 'scrapie' isoform (PrP). Under an etiological point of view, prion diseases can be divided into acquired, genetic, and idiopathic form, the latter of which are the most frequent.: Therapeutic approaches targeting prion diseases are based on the use of chemical and nature-based compounds, targeting either PrP or PrP or other putative player in pathogenic mechanism. Other proposed anti-prion treatments include passive and active immunization strategies, peptides, aptamers, and PrP-directed RNA interference techniques. The treatment efficacy has been mainly assessed in cell lines or animal models of the disease testing their ability to reduce prion accumulation.: The assessed strategies focussing on the identification of an efficient anti-prion therapy faced various issues, which go from permeation of the blood brain barrier to immunological tolerance of the host. Indeed, the use of combinatory approaches, which could boost a synergistic anti-prion effect and lower the potential side effects of single treatments and may represent an extreme powerful and feasible way to tackle prion disease.
Topics: Animals; Humans; Patents as Topic; PrPC Proteins; PrPSc Proteins; Prion Diseases
PubMed: 34134584
DOI: 10.1080/13543776.2021.1945033 -
Acta Neuropathologica Communications Dec 2022Atypical Scrapie, which is not linked to epidemics, is assumed to be an idiopathic spontaneous prion disease in small ruminants. Therefore, its occurrence is unlikely to...
Atypical Scrapie, which is not linked to epidemics, is assumed to be an idiopathic spontaneous prion disease in small ruminants. Therefore, its occurrence is unlikely to be controlled through selective breeding or other strategies as it is done for classical scrapie outbreaks. Its spontaneous nature and its sporadic incidence worldwide is reminiscent of the incidence of idiopathic spontaneous prion diseases in humans, which account for more than 85% of the cases in humans. Hence, developing animal models that consistently reproduce this phenomenon of spontaneous PrP misfolding, is of importance to study the pathobiology of idiopathic spontaneous prion disorders. Transgenic mice overexpressing sheep PrP with I112 polymorphism (TgShI112, 1-2 × PrP levels compared to sheep brain) manifest clinical signs of a spongiform encephalopathy spontaneously as early as 380 days of age. The brains of these animals show the neuropathological hallmarks of prion disease and biochemical analyses of the misfolded prion protein show a ladder-like PrP pattern with a predominant 7-10 kDa band. Brain homogenates from spontaneously diseased transgenic mice were inoculated in several models to assess their transmissibility and characterize the prion strain generated: TgShI112 (ovine I112 ARQ PrP), Tg338 (ovine VRQ PrP), Tg501 (ovine ARQ PrP), Tg340 (human M129 PrP), Tg361 (human V129 PrP), TgVole (bank vole I109 PrP), bank vole (I109I PrP), and sheep (AHQ/ARR and AHQ/AHQ churra-tensina breeds). Our analysis of the results of these bioassays concludes that the strain generated in this model is indistinguishable to that causing atypical scrapie (Nor98). Thus, we present the first faithful model for a bona fide, transmissible, ovine, atypical scrapie prion disease.
Topics: Mice; Animals; Sheep; Humans; Scrapie; Rodentia; Prions; Prion Diseases; Mice, Transgenic; Arvicolinae
PubMed: 36514160
DOI: 10.1186/s40478-022-01477-7 -
Neuropathology and Applied Neurobiology Aug 2019A quarter of a century ago, we proposed an innovative approach to study the pathogenesis of prion disease, one of the most intriguing biomedical problems that remains... (Review)
Review
A quarter of a century ago, we proposed an innovative approach to study the pathogenesis of prion disease, one of the most intriguing biomedical problems that remains unresolved. The synthesis of a peptide homologous to residues 106-126 of the human prion protein (PrP106-126), a sequence present in the PrP amyloid protein of Gerstmann-Sträussler-Scheinker syndrome patients, provided a tractable tool for investigating the mechanisms of neurotoxicity. Together with several other discoveries at the beginning of the 1990s, PrP106-126 contributed to underpin the role of amyloid in the pathogenesis of protein-misfolding neurodegenerative disorders. Later, the role of oligomers on one hand and of prion-like spreading of pathology on the other further clarified mechanisms shared by different neurodegenerative conditions. Our original report on PrP106-126 neurotoxicity also highlighted a role for programmed cell death in CNS diseases. In this review, we analyse the prion research context in which PrP106-126 first appeared and the advances in our understanding of prion disease pathogenesis and therapeutic perspectives 25 years later.
Topics: Animals; Humans; Peptide Fragments; Prion Diseases; Prions
PubMed: 30635947
DOI: 10.1111/nan.12538 -
Current Issues in Molecular Biology 2020Incidences of iatrogenic Creutzfeldt-Jakob disease (iCJD) are caused by transplantation of prion-contaminated hormones, cornea and dura mater as well as contact with...
Incidences of iatrogenic Creutzfeldt-Jakob disease (iCJD) are caused by transplantation of prion-contaminated hormones, cornea and dura mater as well as contact with prion- contaminated medical devices, such as stereotactic electrodes, used in neurosurgery. Because prions are highly resistant and difficult to inactivate, prion contamination is a severe risk when medical instruments are reused after surgical procedures involving suspicious and confirmed cases of patients with prion diseases. Therefore, when high-risk procedures such as cerebral surgery, craniotomy surgery, orthopaedic spinal surgery and ophthalmic surgery are performed for high-risk patients or individuals with prion diseases, it is neces- sary to appropriately treat the medical devices using scientifically proven prion inactivation methods. In this chapter, we introduce fundamental aspects of prion inactivation methods, looking specifically at the practical issues involved in their implementation.
Topics: Animals; Detergents; Humans; Prion Diseases; Prions; Risk Factors; Surgical Equipment
PubMed: 31507270
DOI: 10.21775/cimb.036.023 -
Medicina (Kaunas, Lithuania) Mar 2022Prion diseases are progressive and irreversible neurodegenerative disorders with a low incidence (1.5-2 cases per million per year). Genetic (10-15%), acquired... (Review)
Review
Prion diseases are progressive and irreversible neurodegenerative disorders with a low incidence (1.5-2 cases per million per year). Genetic (10-15%), acquired (anecdotal) and sporadic (85%) forms of the disease have been described. The clinical spectrum of prion diseases is very varied, although the most common symptoms are rapidly progressive dementia, cerebellar ataxia and myoclonus. Mean life expectancy from the onset of symptoms is 6 months. There are currently diagnostic criteria based on clinical phenotype, as well as neuroimaging biomarkers (magnetic resonance imaging), neurophysiological tests (electroencephalogram and polysomnogram), and cerebrospinal fluid biomarkers (14-3-3 protein and real-time quaking-induced conversion (RT-QuIC)). The sensitivity and specificity of some of these tests (electroencephalogram and 14-3-3 protein) is under debate and the applicability of other tests, such as RT-QuIC, is not universal. However, the usefulness of these biomarkers beyond the most frequent prion disease, sporadic Creutzfeldt-Jakob disease, remains unclear. Therefore, research is being carried out on new, more efficient cerebrospinal fluid biomarkers (total tau, ratio total tau/phosphorylated tau and neurofilament light chain) and potential blood biomarkers (neurofilament light chain, among others) to try to universalize access to early diagnosis in the case of prion diseases.
Topics: 14-3-3 Proteins; Biomarkers; Creutzfeldt-Jakob Syndrome; Humans; Prion Diseases; Sensitivity and Specificity
PubMed: 35454316
DOI: 10.3390/medicina58040473 -
Viruses Aug 2022Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of... (Review)
Review
Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of misfolded recPrP conformers have been generated, but despite their seeding capability, many of them have failed to elicit a fatal neurodegenerative disorder in wild-type animals like a naturally occurring prion. The application of the protein misfolding cyclic amplification technique and the inclusion of non-protein cofactors in the reaction mixture have led to the generation of authentic recombinant prions that fully recapitulate the characteristics of native prions. Together, these studies reveal that recPrP can stably exist in a variety of misfolded conformations and when inoculated into wild-type animals, misfolded recPrP conformers cause a wide range of outcomes, from being completely innocuous to lethal. Since all these recPrP conformers possess seeding capabilities, these results clearly suggest that seeding activity alone is not equivalent to prion activity. Instead, authentic prions are those PrP conformers that are not only heritable (the ability to seed the conversion of normal PrP) but also pathogenic (the ability to cause fatal neurodegeneration). The knowledge gained from the studies of the recombinant prion is important for us to understand the pathogenesis of prion disease and the roles of misfolded proteins in other neurodegenerative disorders.
Topics: Animals; Mammals; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions; Protein Folding; Recombinant Proteins
PubMed: 36146746
DOI: 10.3390/v14091940 -
Bio Systems Dec 2021Prions or PrP (prion protein, Scrapie isoform) are proteins with an aberrant three-dimensional conformation that present the ability to alter the three-dimensional...
Prions or PrP (prion protein, Scrapie isoform) are proteins with an aberrant three-dimensional conformation that present the ability to alter the three-dimensional structure of natively folded PrP (prion protein, cellular isoform) inducing its abnormal folding, giving raise to neurological diseases known as Transmissible spongiforms encephalopathies (TSEs) or prion diseases. In this work, through a biosemiotic study, we will analyze the molecular code of meanings that are known in the molecular pathway of PrP and how it is altered in prion diseases. This biosemiotic code presents a socio-semiotic correlate in organisms that could be unraveled with the ultimate goal of understanding the code of signs that mediates the process. Finally, we will study recent works that indicate possible relationships in the code between prion proteins and other proteins such as the tau protein and alpha-synuclein to evaluate if it is possible that there is a semiotic expansion of the PrP code and prion diseases in the meaning recently expounded by Prusiner, winner of the Nobel Prize for describing these unusual pathological processes.
Topics: Animals; Genetic Code; Humans; Prion Diseases; Prion Proteins; Proteostasis Deficiencies
PubMed: 34517077
DOI: 10.1016/j.biosystems.2021.104542 -
Experimental Eye Research Oct 2020Prion diseases are invariably fatal neurodegenerative disorders that have gained much publicity due to their transmissible nature. Sporadic Creutzfeldt-Jakob disease... (Review)
Review
Prion diseases are invariably fatal neurodegenerative disorders that have gained much publicity due to their transmissible nature. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common human prion disorder, with an incidence of 1 in a million. Inherited prion disorders are relatively rare, and associated with mutations in the prion protein gene. More than 50 different point mutations, deletions, and insertions have been identified so far. Most are autosomal dominant and fully penetrant. Prion disorders also occur in animals, and are of major concern because of the potential for spreading to humans. The principal pathogenic event underlying all prion disorders is a change in the conformation of prion protein (PrP) from a mainly α-helical to a β-sheet rich isoform, PrP-scrapie (PrP). Accumulation of PrP in the brain parenchyma is the major cause of neuronal degeneration. The mechanism by which PrP is transmitted, propagates, and causes neurodegenerative changes has been investigated over the years, and several clues have emerged. Efforts are also ongoing for identifying specific and sensitive diagnostic tests for sCJD and animal prion disorders, but success has been limited. The eye is suitable for these evaluations because it shares several anatomical and physiological features with the brain, and can be observed in vivo during disease progression. The retina, considered an extension of the central nervous system, is involved extensively in prion disorders. Accordingly, Optical Coherence Tomography and electroretinogram have shown some promise as pre-mortem diagnostic tests for human and animal prion disorders. However, a complete understanding of the physiology of PrP and pathobiology of PrP in the eye is essential for developing specific and sensitive tests. Below, we summarize recent progress in ocular physiology and pathology in prion disorders, and the eye as an anatomically accessible site to diagnose, monitor disease progression, and test therapeutic options.
Topics: Animals; Anterior Eye Segment; Gene Expression Regulation; Homeostasis; Humans; Prion Diseases; Prions; Protein Conformation
PubMed: 32858007
DOI: 10.1016/j.exer.2020.108200 -
Current Opinion in Neurobiology Jun 2024The concept of 'prion-like' behavior has emerged in the study of diseases involving protein misfolding where fibrillar structures, called amyloids, self-propagate and... (Review)
Review
The concept of 'prion-like' behavior has emerged in the study of diseases involving protein misfolding where fibrillar structures, called amyloids, self-propagate and induce disease in a fashion similar to prions. From a biological standpoint, in order to be considered 'prion-like,' a protein must traverse cells and tissues and further propagate via a templated conformational change. Since 2017, cryo-electron microscopy structures from patient-derived 'prion-like' amyloids, in particular tau, have been presented and revealed structural similarities shared across amyloids. Since 2021, cryo-EM structures from prions of known infectivity have been added to the ex vivo amyloid structure family. In this review, we discuss current proposals for the 'prion-like' mechanisms of spread for tau and prion protein as well as discuss different influencers on structures of aggregates from tauopathies and prion diseases. Lastly, we discuss some of the current hypotheses for what may distinguish structures that are 'prion-like' from transmissible prion structures.
Topics: Humans; tau Proteins; Animals; Prion Proteins; Prion Diseases; Tauopathies; Prions; Amyloid
PubMed: 38489865
DOI: 10.1016/j.conb.2024.102857