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Emerging Infectious Diseases Jun 2012
Topics: Animals; Humans; Prion Diseases; Prions; Protein Structure, Quaternary; Protein Structure, Secondary; Terminology as Topic
PubMed: 22607731
DOI: 10.3201/eid1806.120271 -
Viruses Dec 2018Prion diseases display multiple disease phenotypes characterized by diverse clinical symptoms, different brain regions affected by the disease, distinct cell tropism and... (Review)
Review
Prion diseases display multiple disease phenotypes characterized by diverse clinical symptoms, different brain regions affected by the disease, distinct cell tropism and diverse PrP deposition patterns. The diversity of disease phenotypes within the same host is attributed to the ability of PrP to acquire multiple, alternative, conformationally distinct, self-replicating PrP states referred to as prion strains or subtypes. Structural diversity of PrP strains has been well documented, yet the question of how different PrP structures elicit multiple disease phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that carbohydrates in the form of sialylated N-linked glycans, which are a constitutive part of PrP, are important players in defining strain-specific structures and disease phenotypes. This article introduces a new hypothesis, according to which individual strain-specific PrP structures govern selection of PrP sialoglycoforms that form strain-specific patterns of carbohydrate epitopes on PrP surface and contribute to defining the disease phenotype and outcomes.
Topics: Glycosylation; Models, Molecular; N-Acetylneuraminic Acid; Phenotype; Polysaccharides; Prion Diseases; Prions
PubMed: 30567302
DOI: 10.3390/v10120723 -
Uirusu Jun 2002
Review
Topics: Animals; Humans; PrPC Proteins; PrPSc Proteins; Prion Diseases; Prions
PubMed: 12227168
DOI: No ID Found -
Antioxidants & Redox Signaling Jun 2010Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several... (Review)
Review
Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several neurodegenerative conditions, including prion disorders. Whereas some reports attribute this to end-stage disease, others provide evidence for specific mechanisms leading to brain metal dyshomeostasis during disease progression. In prion disorders, imbalance of brain-iron homeostasis is observed before end-stage disease and worsens with disease progression, implicating iron-induced oxidative stress in disease pathogenesis. This is an unexpected observation, because the underlying cause of brain pathology in all prion disorders is PrP-scrapie (PrP(Sc)), a beta-sheet-rich conformation of a normal glycoprotein, the prion protein (PrP(C)). Whether brain-iron dyshomeostasis occurs because of gain of toxic function by PrP(Sc) or loss of normal function of PrP(C) remains unclear. In this review, we summarize available evidence suggesting the involvement of oxidative stress in prion-disease pathogenesis. Subsequently, we review the biology of PrP(C) to highlight its possible role in maintaining brain metal homeostasis during health and the contribution of PrP(Sc) in inducing brain metal imbalance with disease progression. Finally, we discuss possible therapeutic avenues directed at restoring brain metal homeostasis and alleviating metal-induced oxidative stress in prion disorders.
Topics: Animals; Humans; Oxidation-Reduction; Prion Diseases; Prions
PubMed: 19803746
DOI: 10.1089/ars.2009.2628 -
Prion 2010While prions share the ability to propagate strain information with nucleic acid-based pathogens, it is unclear how they mutate and acquire fitness in the absence of... (Review)
Review
While prions share the ability to propagate strain information with nucleic acid-based pathogens, it is unclear how they mutate and acquire fitness in the absence of this informational component. Because prion diseases occur as epidemics, understanding this mechanism is of paramount importance for implementing control strategies to limit their spread and for evaluating their zoonotic potential. Here we review emerging evidence indicating how prion protein primary structures, in concert with PrP(Sc) conformational compatibility, determine prion strain mutation.
Topics: Animals; Humans; Mutation; Nucleic Acids; Prion Diseases; Prions; Species Specificity
PubMed: 20948302
DOI: 10.4161/pri.4.4.13675 -
Cellular & Molecular Biology Letters Jun 2013Prion diseases are a class of fatal neurodegenerative disorders that can be sporadic, genetic or iatrogenic. They are characterized by the unique nature of their... (Review)
Review
Prion diseases are a class of fatal neurodegenerative disorders that can be sporadic, genetic or iatrogenic. They are characterized by the unique nature of their etiologic agent: prions (PrP(Sc)). A prion is an infectious protein with the ability to convert the host-encoded cellular prion protein (PrP(C)) into new prion molecules by acting as a template. Since Stanley B. Prusiner proposed the "protein-only" hypothesis for the first time, considerable effort has been put into defining the role played by PrP(C) in neurons. However, its physiological function remains unclear. This review summarizes the major findings that support the involvement of PrP(C) in signal transduction.
Topics: Animals; Gene Knockout Techniques; Humans; Ligands; Models, Biological; Prions; Protein Kinases; Signal Transduction
PubMed: 23479001
DOI: 10.2478/s11658-013-0085-0 -
Journal of Biochemistry Jul 2023Accumulation of insoluble aggregates of infectious, partially protease-resistant prion protein (PrPD) generated via the misfolding of protease sensitive prion protein...
Accumulation of insoluble aggregates of infectious, partially protease-resistant prion protein (PrPD) generated via the misfolding of protease sensitive prion protein (PrPC) into the same infectious conformer, is a hallmark of prion diseases. Aggregated PrPD is taken up and degraded by cells, a process likely involving changes in aggregate structure that can be monitored by accessibility of the N-terminus of full-length PrPD to cellular proteases. We therefore tracked the protease sensitivity of full-length PrPD before and after cellular uptake for two murine prion strains, 22L and 87V. For both strains, PrPD aggregates were less stable following cellular uptake with increased accessibility of the N-terminus to cellular proteases across most aggregate sizes. However, a limited size range of aggregates was able to better protect the N-termini of full-length PrPD, with the N-terminus of 22L-derived PrPD more protected than that of 87V. Interestingly, changes in aggregate structure were associated with minimal changes to the protease-resistant core of PrPD. Our data show that cells destabilize the aggregate quaternary structure protecting PrPD from proteases in a strain-dependent manner, with structural changes exposing protease sensitive PrPD having little effect on the protease-resistant core, and thus conformation, of aggregated PrPD.
Topics: Animals; Mice; Endopeptidases; Peptide Hydrolases; Prion Diseases; Prion Proteins; Prions; PrPSc Proteins
PubMed: 37099550
DOI: 10.1093/jb/mvad032 -
Cold Spring Harbor Perspectives in... Sep 2016The [Het-s] prion of the fungus Podospora anserina is a well-studied model system to elucidate the action of prions and beyond. The [Het-s] prion works as an activation... (Review)
Review
The [Het-s] prion of the fungus Podospora anserina is a well-studied model system to elucidate the action of prions and beyond. The [Het-s] prion works as an activation trigger of a cell death execution protein termed HET-S. Amyloid transconformation of the prion-forming region of HET-S induces activation of its pore-forming cell death execution HeLo domain. The prion motif functions in a signal transduction process by which a nucleotide-binding oligomerization domain (NOD)-like receptor termed NWD2 controls the HET-S cell death effector. This prion motif thus corresponds to a functional amyloid motif, allowing a conformational crosstalk between homologous motif domains in signal transduction processes that appears to be widespread from the fungal to the mammalian animal kingdoms. This review aims to establish a structure-activity relationship of the HET-S/s prion system and sets it in the context of its wider biological significance.
Topics: Apoptosis; Fungal Proteins; Podospora; Prions; Signal Transduction; Structure-Activity Relationship
PubMed: 27352624
DOI: 10.1101/cshperspect.a023515 -
Cell and Tissue Research Apr 2023Prions are proteinaceous pathogens responsible for a wide range of neurodegenerative diseases in animal and human. Prions are formed from misfolded, ß-sheet rich, and... (Review)
Review
Prions are proteinaceous pathogens responsible for a wide range of neurodegenerative diseases in animal and human. Prions are formed from misfolded, ß-sheet rich, and aggregated conformers (PrP) of the host-encoded prion protein (PrP). Prion replication stems from the capacity of PrP to self-replicate by templating PrP conversion and polymerization. The question then arises about the molecular mechanisms of prion replication, host invasion, and capacity to contaminate other species. Studying these mechanisms has gained in recent years further complexity with evidence that PrP is a pleiomorphic protein. There is indeed compelling evidence for PrP structural heterogeneity at different scales: (i) within prion susceptible host populations with the existence of different strains with specific biological features due to different PrP conformers, (ii) within a single infected host with the co-propagation of different strains, and (iii) within a single strain with evidence for co-propagation of PrP assemblies differing in their secondary to quaternary structure. This review summarizes current knowledge of prion assembly heterogeneity, potential mechanisms of formation during the replication process, and importance when crossing the species barrier.
Topics: Animals; Humans; Prions; Neurodegenerative Diseases; Prion Proteins; Prion Diseases
PubMed: 36399162
DOI: 10.1007/s00441-022-03700-2 -
Current Issues in Molecular Biology 2010Metal induced free radicals are important mediators of neurotoxicity in several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and... (Review)
Review
Metal induced free radicals are important mediators of neurotoxicity in several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Similar evidence is now emerging for prion diseases, a group of neurodegenerative disorders of humans and animals. The main pathogenic agent in all prion disorders is PrP-scrapie (PrP(Sc)), a beta-sheet rich isoform of a normal cell surface glycoprotein known as the prion protein (PrP(C)). Deposits of PrP(Sc) in the brain parenchyma are believed to induce neurotoxicity through poorly understood mechanisms. Recent reports suggest that imbalance of brain metal homeostasis is a significant cause of PrP(Sc)-associated neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information. Proposed hypotheses include a functional role for PrP(C) in metal metabolism, and loss of this function due to aggregation to the disease associated PrP(Sc) form as the cause of brain metal imbalance. Other views suggest gain of toxic function by PrP(Sc) due to sequestration of PrP(C)-associated metals within the aggregates, resulting in the generation of redox-active PrP(Sc) complexes. The physiological implications of some PrP(C)-metal interactions are known, while others are still unclear. The pathological implications of PrP(C)-metal interaction include metal-induced oxidative damage, and in some instances conversion of PrP(C) to a PrP(Sc)-like form. Despite its significance, only limited information is available on PrP-metal interaction and its implications on prion disease pathogenesis. In this review, we summarize the physiological significance and pathological implications of PrP-metal interaction on prion disease pathogenesis.
Topics: Animals; Humans; Metals; Models, Biological; PrPSc Proteins; Prion Diseases; Prions; Protein Binding
PubMed: 19767653
DOI: No ID Found