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Journal of Neurochemistry Apr 2020Prions, which cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease, are misfolded and infectious protein aggregates. Currently, there are no... (Review)
Review
Prions, which cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease, are misfolded and infectious protein aggregates. Currently, there are no treatments available to halt or even delay the progression of prion disease in the brain. The infectious nature of prions has resulted in animal paradigms that accurately recapitulate all aspects of prion disease, and these have proven to be instrumental for testing the efficacy of candidate therapeutics. Nonetheless, infection of cultured cells with prions provides a much more powerful system for identifying molecules capable of interfering with prion propagation. Certain lines of cultured cells can be chronically infected with various types of mouse prions, and these models have been used to unearth candidate anti-prion drugs that are at least partially efficacious when administered to prion-infected rodents. However, these studies have also revealed that not all types of prions are equal, and that drugs active against mouse prions are not necessarily effective against prions from other species. Despite some recent progress, the number of cellular models available for studying non-mouse prions remains limited. In particular, human prions have proven to be particularly challenging to propagate in cultured cells, which has severely hindered the discovery of drugs for Creutzfeldt-Jakob disease. In this review, we summarize the cellular models that are presently available for discovering and testing drugs capable of blocking the propagation of prions and highlight challenges that remain on the path towards developing therapies for prion disease.
Topics: Animals; Cells, Cultured; Humans; In Vitro Techniques; Prion Diseases; Prions
PubMed: 31943194
DOI: 10.1111/jnc.14956 -
Prion Jan 2017
Topics: History, 20th Century; History, 21st Century; Humans; Prion Diseases; Prions
PubMed: 28281923
DOI: 10.1080/19336896.2017.1285618 -
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 -
Emerging Topics in Life Sciences Sep 2020Preclinical evidence indicates that prion diseases can respond favorably to passive immunotherapy. However, certain antibodies to the cellular prion protein PrPC can be... (Review)
Review
Preclinical evidence indicates that prion diseases can respond favorably to passive immunotherapy. However, certain antibodies to the cellular prion protein PrPC can be toxic. Comprehensive studies of structure-function relationships have revealed that the flexible amino-terminal tail of PrPC is instrumental for mediating prion toxicity. In a first-in-human study, an anti-prion antibody has been recently administered to patients diagnosed with sporadic Creutzfeldt-Jakob's disease, the most prevalent human prion disease. Moreover, large-scale serosurveys have mapped the prevalence of naturally occurring human anti-prion autoantibodies in health and disease. Here, we provide a perspective on the limitations and opportunities of therapeutic anti-prion antibodies.
Topics: Amino Acid Sequence; Animals; Autoantibodies; Disease Models, Animal; Drug Design; Humans; Immunotherapy; PrPC Proteins; Prion Diseases; Prions; Protein Conformation; Structure-Activity Relationship
PubMed: 32633322
DOI: 10.1042/ETLS20200002 -
Cell and Tissue Research Apr 2023Mammalian prion or PrP is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of the prion protein or PrP. PrP and PrP are... (Review)
Review
Mammalian prion or PrP is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of the prion protein or PrP. PrP and PrP are posttranslationally modified with N-linked glycans, which are sialylated at the terminal positions. More than 30 years have passed since the first characterization of the composition and structural diversity of N-linked glycans associated with the prion protein, yet the role of carbohydrate groups that constitute N-glycans and, in particular, their terminal sialic acid residues in prion disease pathogenesis remains poorly understood. A number of recent studies shed a light on the role of sialylation in the biology of prion diseases. This review article discusses several mechanisms by which terminal sialylation dictates the spread of PrP across brain regions and the outcomes of prion infection in an organism. In particular, relationships between the sialylation status of PrP and important strain-specific features including lymphotropism, neurotropism, and neuroinflammation are discussed. Moreover, emerging evidence pointing out the roles of sialic acid residues in prion replication, cross-species transmission, strain competition, and strain adaptation are reviewed. A hypothesis according to which selective, strain-specified recruitment of PrP sialoglycoforms dictates unique strain-specific disease phenotypes is examined. Finally, the current article proposes that prion strains evolve as a result of a delicate balance between recruiting highly sialylated glycoforms to avoid an "eat-me" response by glia and limiting heavily sialylated glycoforms for enabling rapid prion replication.
Topics: Animals; Prions; Prion Proteins; N-Acetylneuraminic Acid; PrPSc Proteins; Prion Diseases; Polysaccharides; Mammals
PubMed: 35088180
DOI: 10.1007/s00441-022-03584-2 -
Viruses Oct 2022Prions replicate by a self-templating mechanism. Infidelity in the process can lead to the emergence of new infectious structures, referred to as variants or strains....
Prions replicate by a self-templating mechanism. Infidelity in the process can lead to the emergence of new infectious structures, referred to as variants or strains. The question of whether prions are prone to mis-templating is not completely answered. Our previous experiments with 23 variants of the yeast [] prion do not support broad mutability. However, it became clear recently that the heat shock protein Hsp104 can restrict [] strain variation. This raises the possibility that many transmutable variants of the prion may have been mistaken as faithful-propagating simply because the mutant structure was too sturdy or too frail to take root in the wild-type cell. Here, I alter the strength of Hsp104 in yeast, overexpressing wild-type Hsp104 or expressing the hypo-active Hsp104 mutant, and check if the new environments enable the variants to mutate. Two variants hitherto thought of as faithful-propagating are discovered to generate different structures, which are stabilized with the hypo-active chaperone. In contrast, most transmutable variants discovered in cells overexpressing Hsp104 have been correctly identified as such previously in wild-type cells without the overexpression. The majority of transmutable variants only mis-template the structure of VH, VK, or VL, which are the most frequently observed variants and do not spontaneously mutate. There are four additional variants that never give rise to different structures in all cell conditions tested. Therefore, quite a few [] variants are faithful-propagating, and even the transmutable ones do not freely evolve but can only change to limited structural types.
Topics: Saccharomyces cerevisiae; Prions; Peptide Termination Factors; Saccharomyces cerevisiae Proteins; Heat-Shock Proteins
PubMed: 36366434
DOI: 10.3390/v14112337 -
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 -
Scientific Reports Dec 2022Prion diseases are characterized by the cellular prion protein, PrP, misfolding and aggregating into the infectious prion protein, PrP, which leads to neurodegeneration...
Prion diseases are characterized by the cellular prion protein, PrP, misfolding and aggregating into the infectious prion protein, PrP, which leads to neurodegeneration and death. An early sign of disease is inflammation in the brain and the shift of resting glial cells to reactive astrocytes and activated microglia. Few therapeutics target this stage of disease. Mesenchymal stromal cells produce anti-inflammatory molecules when exposed to inflammatory signals and damaged tissue. Here, we show that adipose-derived mesenchymal stromal cells (AdMSCs) migrate toward prion-infected brain homogenate and produce the anti-inflammatory molecules transforming growth factor β (TGFβ) and tumor necrosis factor-stimulated gene 6 (TSG-6). In an in vitro model of prion exposure of both primary mixed glia and BV2 microglial cell line, co-culturing with AdMSCs led to a significant decrease in inflammatory cytokine mRNA and markers of reactive astrocytes and activated microglia. This protection against in vitro prion-associated inflammatory responses is independent of PrP replication. These data support a role for AdMSCs as a beneficial therapeutic for decreasing the early onset of glial inflammation and reprogramming glial cells to a protective phenotype.
Topics: Humans; Prions; Prion Proteins; Neuroglia; Prion Diseases; Microglia; Mesenchymal Stem Cells; Inflammation
PubMed: 36581683
DOI: 10.1038/s41598-022-26628-7 -
PLoS Pathogens Apr 2023Prion diseases, also known as transmissible spongiform encephalopathies, are rare, progressive, and fatal neurodegenerative disorders, which are caused by the... (Review)
Review
Prion diseases, also known as transmissible spongiform encephalopathies, are rare, progressive, and fatal neurodegenerative disorders, which are caused by the accumulation of the misfolded cellular prion protein (PrPC). The resulting cytotoxic prion species, referred to as the scrapie prion isoform (PrPSc), assemble in aggregates and interfere with neuronal pathways, ultimately rendering neurons dysfunctional. As the prion protein physiologically interacts with redox-active metals, an altered redox balance within the cell can impact these interactions, which may lead to and facilitate further misfolding and aggregation. The initiation of misfolding and the aggregation processes will, in turn, induce microglial activation and neuroinflammation, which leads to an imbalance in cellular redox homeostasis and enhanced redox stress. Potential approaches for therapeutics target redox signalling, and this review illustrates the pathways involved in the above processes.
Topics: Animals; Sheep; Prion Proteins; Prion Diseases; Prions; Scrapie; Oxidation-Reduction
PubMed: 37104170
DOI: 10.1371/journal.ppat.1011309 -
Acta Neuropathologica Jul 2021Prions are novel pathogens that are composed entirely of PrP, the self-templating conformation of the host prion protein, PrP. Prion strains are operationally defined as... (Review)
Review
Prions are novel pathogens that are composed entirely of PrP, the self-templating conformation of the host prion protein, PrP. Prion strains are operationally defined as a heritable phenotype of disease that are encoded by strain-specific conformations of PrP. The factors that influence the relative distribution of strains in a population are only beginning to be understood. For prions with an infectious etiology, environmental factors, such as strain-specific binding to surfaces and resistance to weathering, can influence which strains are available for transmission to a naïve host. Strain-specific differences in efficiency of infection by natural routes of infection can also select for prion strains. The host amino acid sequence of PrP has the greatest effect on dictating the repertoire of prion strains. The relative abundance of PrP, post-translational modifications of PrP and cellular co-factors involved in prion conversion can also provide conditions that favor the prevalence of a subset of prion strains. Additionally, prion strains can interfere with each other, influencing the emergence of a dominant strain. Overall, both environmental and host factors may influence the repertoire and distribution of strains within a population.
Topics: Animals; Biological Evolution; Environment; Humans; PrPC Proteins; PrPSc Proteins; Prion Diseases; Prions
PubMed: 33899132
DOI: 10.1007/s00401-021-02310-6