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Progress in Molecular Biology and Translational Science

Giuseppe Legname, Silvia Vanni
No abstract text is available yet for this article.
2017: Progress in Molecular Biology and Translational Science
Ivana Biljan, Gregor Ilc, Janez Plavec
Prion diseases or transmissible spongiform encephalopathies constitute a group of fatal neurodegenerative diseases that can be of sporadic, genetic, or acquired origin. The central molecular event of prion diseases is the conformational conversion of the physiological cellular prion protein, PrP(C), into a disease-associated form known as prion or PrP(Sc). Spontaneous generation of prions in genetic prion diseases is caused by mutations in the human prion protein gene (PRNP). Understanding of the earliest conformational changes during misfolding of PrP(C) in genetic forms of prion diseases may benefit from detailed structural characterization of various human (Hu) PrP variants...
2017: Progress in Molecular Biology and Translational Science
Daniela Sarnataro, Anna Pepe, Chiara Zurzolo
Cellular prion protein (PrP(C)) is a mammalian glycoprotein which is usually found anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. The precise function of PrP(C) remains elusive but may depend upon its cellular localization. PrP(C) misfolds to a pathogenic isoform PrP(Sc), the causative agent of neurodegenerative prion diseases. Nonetheless some forms of prion disease develop in the apparent absence of infectious PrP(Sc), suggesting that molecular species of PrP distinct from PrP(Sc) may represent the primary neurotoxic culprits...
2017: Progress in Molecular Biology and Translational Science
Edoardo Bistaffa, Martina Rossi, Chiara M G De Luca, Fabio Moda
Prions are the infectious agents that cause devastating and untreatable disorders known as Transmissible Spongiform Encephalopathies (TSEs). The pathologic events and the infectious nature of these transmissible agents are not completely understood yet. Due to the difficulties in inactivating prions, working with them requires specific recommendations and precautions. Moreover, with the advent of innovative technologies, such as the Protein Misfolding Cyclic Amplification (PMCA) and the Real Time Quaking-Induced Conversion (RT-QuIC), prions could be amplified in vitro and the infectious features of the amplified products need to be carefully assessed...
2017: Progress in Molecular Biology and Translational Science
Annachiara Gandini, Maria Laura Bolognesi
Therapy of prion diseases represents an extremely challenging effort for scientists working in the field. These challenges are epitomized by 20 years of failures in clinical trials and preclinical investigations. However, the discovery that misfolded proteins involved in other neurodegenerative diseases show a prion-like mechanism of spreading, is positively impacting the prion drug discovery field. Herein, we describe those efforts that have contributed to strengthen the drug discovery process in prion diseases...
2017: Progress in Molecular Biology and Translational Science
Silvia Vanni
Prion diseases are unique neurodegenerative pathologies that can occur with sporadic, genetic, and acquired etiologies. Human and animal prion diseases can be recapitulated in laboratory animals with good reproducibility providing highly controlled models for studying molecular mechanisms of neurodegeneration. In this chapter the overall area of omics research in prion diseases is described. The term omics includes all fields of studies that employ a comprehensive, unbiased, and high-throughput approach to areas of research such as functional genomics, transcriptomics, and proteomics...
2017: Progress in Molecular Biology and Translational Science
Michele Fiorini, Matilde Bongianni, Salvatore Monaco, Gianluigi Zanusso
Prion disease or transmissible spongiform encephalopathies are characterized by the presence of the abnormal form of the prion protein (PrP(Sc)). The pathological and transmissible properties of PrP(Sc) are enciphered in its secondary and tertiary structures. Since it's well established that different strains of prions are linked to different conformations of PrP(Sc), biochemical characterization of prions seems a preliminary but reliable approach to detect, analyze, and compare prion strains. Experimental biochemical procedures might be helpful in distinguishing PrP(Sc) physicochemical properties and include resistance to proteinase K (PK) digestion, insolubility in nonionic detergents, PK-resistance under denaturing conditions and sedimentation properties in sucrose gradients...
2017: Progress in Molecular Biology and Translational Science
Byron Caughey, Christina D Orru, Bradley R Groveman, Andrew G Hughson, Matteo Manca, Lynne D Raymond, Gregory J Raymond, Brent Race, Eri Saijo, Allison Kraus
Among the most sensitive, specific and practical of methods for detecting prions are the real-time quaking-induced conversion (RT-QuIC) assays. These assays exploit the fundamental self-propagating activity of prions to amplify the presence of prion seeds by as much as a trillion-fold. The reactions can detect most of the known mammalian prion diseases, often with sensitivities greater than those of animal bioassays. RT-QuIC assays are performed in multiwell plates with fluorescence detection and have now reached the sensitivity and practicality required for routine prion disease diagnostics...
2017: Progress in Molecular Biology and Translational Science
Fabio Moda
Transmissible spongiform encephalopathies, or prion diseases, are a group of incurable disorders caused by the accumulation of an abnormally folded prion protein (PrP(Sc)) in the brain. According to the "protein-only" hypothesis, PrP(Sc) is the infectious agent able to propagate the disease by acting as a template for the conversion of the correctly folded prion protein (PrP(C)) into the pathological isoform. Recently, the mechanism of PrP(C) conversion has been mimicked in vitro using an innovative technique named protein misfolding cyclic amplification (PMCA)...
2017: Progress in Molecular Biology and Translational Science
Eric G B Evans, Glenn L Millhauser
The function of the cellular prion protein (PrP(C)), while still poorly understood, is increasingly linked to its ability to bind physiological metal ions at the cell surface. PrP(C) binds divalent forms of both copper and zinc through its unstructured N-terminal domain, modulating interactions between PrP(C) and various receptors at the cell surface and ultimately tuning downstream cellular processes. In this chapter, we briefly discuss the molecular features of copper and zinc uptake by PrP(C) and summarize evidence implicating these metal ions in PrP-mediated physiology...
2017: Progress in Molecular Biology and Translational Science
Jesús R Requena, Holger Wille
The prion diseases, which include Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids (i.e., deer, elk, moose, and reindeer), bovine spongiform encephalopathy in cattle, as well as sheep and goat scrapie, are caused by the conversion of the cellular prion protein (PrP(C)) into a disease-causing conformer (PrP(Sc)). PrP(C) is a regular, GPI-anchored protein that is expressed on the cell surface of neurons and many other cell types. The structure of PrP(C) is well studied, based on analyses of recombinant PrP, which is thought to mimic the structure of native PrP(C)...
2017: Progress in Molecular Biology and Translational Science
Diane L Ritchie, James W Ironside
The human prion diseases comprise sporadic, genetic, and acquired disorders. These are rare conditions with a heterogeneous clinicopathologic phenotype, which can make diagnosis challenging. A combined clinical, genetic, neuropathologic and biochemical approach to diagnosis is therefore essential. Since prion infectivity is the highest in tissues from the central nervous system, special laboratory precautions are required for the safe handling of these tissues. Neuropathologic assessment is generally performed following autopsy, when the fixed brain should be adequately sampled and studied by conventional stains and immunohistochemistry for the abnormal form of the prion protein...
2017: Progress in Molecular Biology and Translational Science
Richard Knight
Prion diseases are progressive fatal encephalopathies characterized by a neurodegenerative pathology, the tissue deposition of abnormally folded prion protein and, in general, potential transmissibility. Creutzfeldt-Jakob disease (CJD) is the commonest human prion disease and occurs in three principal forms: sporadic (idiopathic), acquired (infectious), and inherited (genetic). This chapter concerns the sporadic and acquired forms. Sporadic CJD occurs worldwide and affects mainly the middle aged and elderly...
2017: Progress in Molecular Biology and Translational Science
Candace K Mathiason
Transmissible spongiform encephalopathies (TSEs), or prions, are neurodegenerative diseases that affect a variety of animal species, including humans. Cruetzfeldt-Jakob disease (CJD) in humans, sheep and goat scrapie, chronic wasting disease (CWD) of cervids, and transmissible mink encephalopathy (TME) of mink are classified as TSEs. According to the "protein-only" hypothesis (Prusiner, 1982),(1) prions are devoid of nucleic acids and consist of assemblies of misfolded host-encoded normal protein, the prion protein (PrP(C))...
2017: Progress in Molecular Biology and Translational Science
Cristiano Corona, Elena Vallino Costassa, Barbara Iulini, Maria Caramelli, Elena Bozzetta, Maria Mazza, Rosanna Desiato, Giuseppe Ru, Cristina Casalone
After thirty years, bovine spongiform encephalopathy (BSE) still represents the biggest crisis in the field of food safety. Initially detected in the United Kingdom in 1986, BSE spread to many other countries all over the world, involving approximately 200,000 cattle. The origin of BSE is uncertain, but epidemiological studies suggest that the source was cattle feed prepared from prion-infected animal tissues. The implementation of the drastic measures, including the ban of meat and bone meal from livestock feed and the removal of specified risk material from the food chain, has eventually resulted in a significant decline of the epidemic...
2017: Progress in Molecular Biology and Translational Science
Neil A Mabbott
Many natural prion diseases are acquired peripherally, such as following the oral consumption of contaminated food or pasture. After peripheral exposure many prion isolates initially accumulate to high levels within the host's secondary lymphoid tissues. The replication of prions within these tissues is essential for their efficient spread to the brain where they ultimately cause neurodegeneration. This chapter describes our current understanding of the critical tissues, cells, and molecules which the prions exploit to mediate their efficient propagation from the site of exposure (such as the intestine) to the brain...
2017: Progress in Molecular Biology and Translational Science
Alba Marín-Moreno, Natalia Fernández-Borges, Juan C Espinosa, Olivier Andréoletti, Juan M Torres
Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal diseases that affect the nervous system of many mammals including humans. The key molecular event in the pathogenesis of TSEs is the conversion of the cellular prion protein PrP(C) into a disease-associated isoform PrP(Sc). The "protein-only hypothesis" argues that PrP(Sc) itself is the infectious agent. In effect, PrP(Sc) can adopt several structures that represent different prion strains. The interspecies transmission of TSEs is difficult because of differences between the host and donor primary PrP sequence...
2017: Progress in Molecular Biology and Translational Science
Abigail B Diack, James D Alibhai, Jean C Manson
The production of transgenic mice expressing different forms of the prion protein (PrP) or devoid of PrP has enabled researchers to study the role of PrP in the infectious process of a prion disease and its normal function in the healthy individual. A wide range of transgenic models have been produced ranging from PrP null mice, normal expression levels to overexpression models, models expressing different species of the Prnp gene and different mutations and polymorphisms within the gene. Using this range of transgenic models has allowed us to define the influence of PrP expression on disease susceptibility and transmission, assess zoonotic potential, define strains of human prion diseases, elucidate the function of PrP, and start to unravel the mechanisms involved in chronic neurodegeneration...
2017: Progress in Molecular Biology and Translational Science
Giuseppe Legname, Fabio Moda
Transmissible spongiform encephalopathies or prion diseases are a group of fatal neurodegenerative diseases caused by unconventional infectious agents, known as prions (PrP(Sc)). Prions derive from a conformational conversion of the normally folded prion protein (PrP(C)), which acquires pathological and infectious features. Moreover, PrP(Sc) is able to transmit the pathological conformation to PrP(C) through a mechanism that is still not well understood. The generation of synthetic prions, which behave like natural prions, is of fundamental importance to study the process of PrP(C) conversion and to assess the efficacy of therapeutic strategies to interfere with this process...
2017: Progress in Molecular Biology and Translational Science
George A Carlson
Early genetic studies on scrapie, an infectious neurodegenerative disease of sheep that was adapted to mice, provided evidence in support of the hypothesis that the agent was a slow virus with a nucleic acid genome independent of the host. Particularly compelling support for an independent genome came from the existence of strains of scrapie agent, some of which were true breeding, while others appeared to mutate under selective pressure. Kuru, a neurodegenerative disease in the remote highlands of Papua New Guinea, had pathological changes similar to those in scrapie and also proved to be transmissible...
2017: Progress in Molecular Biology and Translational Science
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