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Academic literature on the topic 'Prione, lipid raft'
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Journal articles on the topic "Prione, lipid raft"
1
Fantini, Jacques, Nicolas Garmy, Radhia Mahfoud, and Nouara Yahi. "Lipid rafts: structure, function and role in HIV, Alzheimer's and prion diseases." Expert Reviews in Molecular Medicine 4, no. 27 (December 20, 2002): 1–22. http://dx.doi.org/10.1017/s1462399402005392.
Full textAbstract:
The fluid mosaic model of the plasma membrane has evolved considerably since its original formulation 30 years ago. Membrane lipids do not form a homogeneous phase consisting of glycerophospholipids (GPLs) and cholesterol, but a mosaic of domains with unique biochemical compositions. Among these domains, those containing sphingolipids and cholesterol, referred to as membrane or lipid rafts, have received much attention in the past few years. Lipid rafts have unique physicochemical properties that direct their organisation into liquid-ordered phases floating in a liquid-crystalline ocean of GPLs. These domains are resistant to detergent solubilisation at 4°C and are destabilised by cholesterol- and sphingolipid-depleting agents. Lipid rafts have been morphologically characterised as small membrane patches that are tens of nanometres in diameter. Cellular and/or exogenous proteins that interact with lipid rafts can use them as transport shuttles on the cell surface. Thus, rafts act as molecular sorting machines capable of co-ordinating the spatiotemporal organisation of signal transduction pathways within selected areas (‘signalosomes’) of the plasma membrane. In addition, rafts serve as a portal of entry for various pathogens and toxins, such as human immunodeficiency virus 1 (HIV-1). In the case of HIV-1, raft microdomains mediate the lateral assemblies and the conformational changes required for fusion of HIV-1 with the host cell. Lipid rafts are also preferential sites of formation for pathological forms of the prion protein (PrPSc) and of the β-amyloid peptide associated with Alzheimer's disease. The possibility of modulating raft homeostasis, using statins and synthetic sphingolipid analogues, offers new approaches for therapeutic interventions in raft-associated diseases.
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Rushworth, Jo V., and Nigel M. Hooper. "Lipid Rafts: Linking Alzheimer's Amyloid-βProduction, Aggregation, and Toxicity at Neuronal Membranes." International Journal of Alzheimer's Disease 2011 (2011): 1–14. http://dx.doi.org/10.4061/2011/603052.
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Lipid rafts are membrane microdomains, enriched in cholesterol and sphingolipids, into which specific subsets of proteins and lipids partition, creating cell-signalling platforms that are vital for neuronal functions. Lipid rafts play at least three crucial roles in Alzheimer's Disease (AD), namely, in promoting the generation of the amyloid-β(Aβ) peptide, facilitating its aggregation upon neuronal membranes to form toxic oligomers and hosting specific neuronal receptors through which the AD-related neurotoxicity and memory impairments of the Aβoligomers are transduced. Recent evidence suggests that Aβoligomers may exert their deleterious effects through binding to, and causing the aberrant clustering of, lipid raft proteins including the cellular prion protein and glutamate receptors. The formation of these pathogenic lipid raft-based platforms may be critical for the toxic signalling mechanisms that underlie synaptic dysfunction and neuropathology in AD.
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Loh, Doris, and Russel J. Reiter. "Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance." Molecules 27, no. 3 (January 21, 2022): 705. http://dx.doi.org/10.3390/molecules27030705.
Full textAbstract:
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
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Bozdaganyan, M. E., and K. V. Shaitan. "INVESTIGATION OF STRUCTURE OF THE MEMBRANE RAFTS BY MEANS OF COMPUTER MODELING." Journal of Clinical Practice 7, no. 4 (December 15, 2016): 66–72. http://dx.doi.org/10.17816/clinpract7466-72.
Full textAbstract:
Understanding the structure of the biological membrane and its role in the cell has evolved significantly since the introduction of the classical fluid mosaic model by Singer and Nicholson. Later fluid mosaic model has been redesigned, expanded and has become considerably complicated. It has been experimentally proved that the membrane consists of so-called rafts, which are functional “islands” with the specific lipid composition with proteins. Lipid rafts play a central role in many cellular processes, including barrier functions, membrane polarization and the cell signaling. Several groups of pathogens, bacteria, prions, viruses, parasites use lipid rafts for their purposes. Rafts always occur on both sides of the membrane opposite to each other, but the nature of the two-layer rafts are still poorly understood. Previously it was theoretically calculated that the shift of the monolayers in raft occurs, which reduces the mechanical energy of the boundaries, and ultimately leads to a bilayer structure of the raft. In this study with the help of computer modeling we study the energy of interaction between two monolayers of the raft in order to test the hypothesis about their relative shift.
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Sarnataro, Daniela, Vincenza Campana, Simona Paladino, Mariano Stornaiuolo, Lucio Nitsch, and Chiara Zurzolo. "PrPCAssociation with Lipid Rafts in the Early Secretory Pathway Stabilizes Its Cellular Conformation." Molecular Biology of the Cell 15, no. 9 (September 2004): 4031–42. http://dx.doi.org/10.1091/mbc.e03-05-0271.
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The pathological conversion of cellular prion protein (PrPC) into the scrapie prion protein (PrPSc) isoform appears to have a central role in the pathogenesis of transmissible spongiform encephalopathies. However, the identity of the intracellular compartment where this conversion occurs is unknown. Several lines of evidence indicate that detergent-resistant membrane domains (DRMs or rafts) could be involved in this process. We have characterized the association of PrPCto rafts during its biosynthesis. We found that PrPCassociates with rafts already as an immature precursor in the endoplasmic reticulum. Interestingly, compared with the mature protein, the immature diglycosylated form has a different susceptibility to cholesterol depletion vs. sphingolipid depletion, suggesting that the two forms associate with different lipid domains. We also found that cholesterol depletion, which affects raft-association of the immature protein, slows down protein maturation and leads to protein misfolding. On the contrary, sphingolipid depletion does not have any effect on the kinetics of protein maturation or on the conformation of the protein. These data indicate that the early association of PrPCwith cholesterol-enriched rafts facilitates its correct folding and reinforce the hypothesis that cholesterol and sphingolipids have different roles in PrP metabolism.
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Bate, Clive, Mourad Tayebi, and Alun Williams. "The glycosylphosphatidylinositol anchor is a major determinant of prion binding and replication." Biochemical Journal 428, no. 1 (April 28, 2010): 95–101. http://dx.doi.org/10.1042/bj20091469.
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The prion diseases occur following the conversion of the cellular prion protein (PrPC) into an alternatively folded, disease-associated isoform (PrPSc). However, the spread of PrPSc from cell to cell is poorly understood. In the present manuscript we report that soluble PrPSc bound to and replicated within both GT1 neuronal cells and primary cortical neurons. The capacity of PrPSc to bind and replicate within cells was significantly reduced by enzymatic modification of its GPI (glycosylphosphatidylinositol) anchor. Thus PrPSc that had been digested with phosphatidylinositol-phospholipase C bound poorly to GT1 cells or cortical neurons and did not result in PrPSc formation in recipient cells. PrPSc that had been digested with phospholipase A2 (PrPSc-G-lyso-PI) bound readily to GT1 cells and cortical neurons but replicated less efficiently than mock-treated PrPSc. Whereas the addition of PrPSc increased cellular cholesterol levels and was predominantly found within lipid raft micro-domains, PrPSc-G-lyso-PI did not alter cholesterol levels and most of it was found outside lipid rafts. We conclude that the nature of the GPI anchor attached to PrPSc affected the binding of PrPSc to neurons, its localization to lipid rafts and its ability to convert endogenous PrPC.
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Caputo, Anna, Daniela Sarnataro, Vincenza Campana, Maddalena Costanzo, Alessandro Negro, M. Catia Sorgato, and Chiara Zurzolo. "Doppel and PrPC co-immunoprecipitate in detergent-resistant membrane domains of epithelial FRT cells." Biochemical Journal 425, no. 2 (December 23, 2009): 341–51. http://dx.doi.org/10.1042/bj20091050.
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Dpl (doppel) is a paralogue of the PrPC (cellular prion protein), whose misfolded conformer (the scrapie prion protein, PrPSc) is responsible for the onset of TSEs (transmissible spongiform encephalopathies) or prion diseases. It has been shown that the ectopic expression of Dpl in the brains of some lines of PrP-knockout mice provokes cerebellar ataxia, which can be rescued by the reintroduction of the PrP gene, suggesting a functional interaction between the two proteins. It is, however, still unclear where, and under which conditions, this event may occur. In the present study we addressed this issue by analysing the intracellular localization and the interaction between Dpl and PrPC in FRT (Fischer rat thyroid) cells stably expressing the two proteins separately or together. We show that both proteins localize prevalently on the basolateral surface of FRT cells, in both singly and doubly transfected clones. Interestingly we found that they associate with DRMs (detergent-resistant membranes) or lipid rafts, from where they can be co-immunoprecipitated in a cholesterol-dependent fashion. Although the interaction between Dpl and PrPC has been suggested before, our results provide the first clear evidence that this interaction occurs in rafts and is dependent on the integrity of these membrane microdomains. Furthermore, both Dpl and PrPC could be immunoprecipitated with flotillin-2, a raft protein involved in endocytosis and cell signalling events, suggesting that they share the same lipid environment.
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PARKIN, Edward T., Anthony J. TURNER, and Nigel M. HOOPER. "Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein." Biochemical Journal 344, no. 1 (November 8, 1999): 23–30. http://dx.doi.org/10.1042/bj3440023.
Full textAbstract:
Lipid rafts are regions of the plasma membrane that are enriched in cholesterol, glycosphingolipids and acylated proteins, and which have been proposed as sites for the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Lipid rafts can be isolated on the basis of their insolubility in Triton X-100 at 4 °C, with the resulting low-density, detergent-insoluble glycolipid-enriched fraction (DIG) being isolated by flotation through a sucrose density gradient. The detergent-insolubility of APP in mouse cerebral cortex relative to a variety of DIG marker proteins (alkaline phosphatase, flotillin, F3 protein and prion protein) and non-DIG proteins (alkaline phosphodiesterase I, aminopeptidase A and clathrin) has been examined. Alkaline phosphatase, flotillin, F3 protein and the prion protein were present exclusively in the DIG region of the sucrose gradient over a range of protein/detergent ratios used to solubilize the membranes and displayed a characteristic enrichment in the low-density fraction as the protein/detergent ratio was decreased. In contrast, most of the APP, alkaline phosphodiesterase I, aminopeptidase A and clathrin was effectively solubilized at all of the protein/detergent ratios examined. However, a minor proportion of these latter proteins was detected in DIGs at levels which remained constant irrespective of the protein/detergent ratio. When DIGs were isolated from the sucrose gradients and treated with excess Triton X-100, both the DIG marker proteins and APP, alkaline phosphodiesterase I and clathrin were predominantly resistant to detergent extraction at 37 °C. These results show that, although a minor proportion of APP is present in DIGs, where it is detergent-insoluble even at 37 °C, it behaves as an atypical lipid raft protein and raises questions as to whether lipid rafts are a site for its proteolytic processing.
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Martellucci, Stefano, Costantino Santacroce, Francesca Santilli, Valeria Manganelli, Maurizio Sorice, and Vincenzo Mattei. "Prion Protein in Stem Cells: A Lipid Raft Component Involved in the Cellular Differentiation Process." International Journal of Molecular Sciences 21, no. 11 (June 11, 2020): 4168. http://dx.doi.org/10.3390/ijms21114168.
Full textAbstract:
The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its discovery, this lipid raft component has been involved in several functions, although most of the publications focused on the pathological role of the protein. Recent studies report a key role of cellular prion protein (PrPC) in physiological processes, including cellular differentiation. Indeed, the PrPC, whose expression is modulated according to the cell differentiation degree, appears to be part of the multimolecular signaling pathways of the neuronal differentiation process. In this review, we aim to summarize the main findings that report the link between PrPC and stem cells.
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Brouckova, Adela, and Karel Holada. "Cellular prion protein in blood platelets associates with both lipid rafts and the cytoskeleton." Thrombosis and Haemostasis 102, no. 11 (2009): 966–74. http://dx.doi.org/10.1160/th09-02-0074.
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SummaryThe recently shown transmissibility of variant Creutzfeldt-Jakob disease (vCJD) by blood transfusion emphasises the need for better understanding of the cellular prion protein (PrPc) in blood. A substantial amount of cell-associated PrPc in blood resides in platelets. Platelet activation leads to up-regulation of PrPc on the platelet surface and its release on exosomes and microparticles. The sub-cellular localisation and function of platelet PrPc, however, is poorly understood. In the present study, we investigated the association of PrPc with platelet lipid rafts and the platelet cytoskeleton. Immuno-fluorescence microscopy showed that the signals of PrPc and P-selectin, both of which occupy intracellular alpha granules, were separated on the membrane, suggesting organisation in different membrane domains. A flotation assay of platelet lysates demonstrated that a relatively small portion of platelet PrPc floats with lipid rafts, regardless of platelet activation status. This was reversed by depolymerisation of the platelet cytoskeleton, which led to flotation of most platelet PrPc, suggesting that interactions with the cytoskeleton prevent flotation of PrPc rafts. This association of PrPc with the platelet cytoskeleton was confirmed by its presence in both the isolated membrane skeleton and actin cytoskeleton. Platelet activation significantly increased the amount of PrPc associated with the cytoskeleton. Our results indicate that the localisation of PrPc in platelets is complex, with the majority of PrPc present within platelet lipid rafts linked to the platelet cytoskeleton. This localisation places PrPc in a position where it can interact with proteins involved in platelet signalling and eventually with vCJD prions.
Dissertations / Theses on the topic "Prione, lipid raft"
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CUNATI, DIANA. "Ruolo dei lipid raft nel metabolismo della proteina prionica." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/27001.
Full textAbstract:
The prion protein (PrP) is a GPI-anchored protein primarily concentrated in neuronal cells. Under certain conditions, the innocuous cellular form of this protein, PrPC, can convert into the lethal scrapie isoform, PrPSc, which can aggregate with other PrP molecules and exert its neurotoxic activity.
The structure of PrPC consists of two domains: an N-terminal, glycosylated, flexible disordered domain which is capable of binding copper and a C-terminal α-helical domain.
In contrast, PrPSc is enriched in β-sheet structures and characterized by its poor solubility in non-denaturing detergents, propensity for aggregation, partial resistance to proteinase K digestion.
The conversion of PrPC into PrPSc occurs in particular regions of the cell membrane, enriched with cholesterol and glycosphingolipid, called lipid rafts; these microdomains are thought to play a crucial role both in physiological functions and in the alternative folding of the prion protein.
In addition, it’s known that:
-PrPC can be cleaved at the 110/111 peptidyl bond to produce a C-terminal fragment, C1, which remains membrane bound and a N-terminal fragment, N1, released in the extracellular space. C1 fragments can’t be converted to the scrapie isoform;
- in cell cultures, ADAM10 and ADAM17 were shown to be responsible for this processing and their activation seems PKC-dependent.
The aim of our project is to establish if the alteration of cell lipid composition can modify the membrane distribution of the prion protein within rafts or non-raft regions and promote the activity of disintegrins such as ADAM10/17 upon the prion protein.
For this reason, granule cells, from the cerebella of 8-day-old rats, were incubated after 8 days in culture with GM1 or GD1a or GT1b for 4 hours at 37°C or with GM1 for 4 hours at 4°C. Detergent resistant fractions, containing lipid rafts, were isolated and proteins in all gradient fractions were separated and analyzed by EF/WB with specific antibodies.
After cell treatments with exogenous gangliosides, a good percentage of them was found in lipid rafts; immunoblotting analysis with specific antibodies showed a significant reduction in the amount of proteins, normally localized in lipid rafts, after incubation with GT1b.
The incorporation of this ganglioside, characterized by a remarkable steric encumbrance, might be responsible for lipid rafts destabilization and proteins redistribution toward non-raft regions.
Another possibility is that GT1b incorporation reduces the number of lipid rafts on the cell membrane.
Immunoblotting analysis with three different anti-PrP antibodies showed that this protein is not selectively located in lipid rafts but it is also distributed in several intracellular compartments.
Cell treatments with GM1 or GD1a at 37°C for 4 hours were not able to promote PrPC cleavage at the 110/111 peptidyl bond; cell incubation with GM1 seemed able to induce a conformational change of the prion protein toward a “simil-scrapie” isoform, partially resistant to classical denaturation protocols. Further studies are in progress to fully demonstrate that GM1-PrP interaction results in this conformational change.
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Gyllberg, Hanna. "Prion-infection and Cellular Signaling : Influence of scrapie-infection on lipid raft-associated proteins." Doctoral thesis, Stockholm : Department of Biochemistry and Biophysics, Stockholm university, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-7115.
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CORDA, ERICA. "TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSES): EXPERIMENTAL APPROACHES TO PATHOGENESIS, THERAPY AND PREVENTION IN ANIMAL MODELS." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/169556.
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Prion diseases are perhaps the most mysterious and peculiar diseases in nature. These diseases do not rely on the general dogmas of modern biology, seen in other infectious diseases caused by conventional pathogens, such as viruses and bacteria. On the contrary, their infectious agent is an unconventional proteinaceous pathogen, termed prion, that lacks functional nucleic acids. Prion diseases are also known as Transmissible Spongiform Encephalopathies (TSEs), since the diseases are transmissible from one host to another and manifest a spongiform appearance as result of the destruction of brain tissue during a long incubation period. Prion diseases include Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (BSE, “mad cow disease”) in ruminants, scrapie in sheep and goats and chronic wasting disease in deer and elks. As demonstrated in the BSE outbreak and its transmission to humans, the onset of diseases is not limited to a certain species but can be transmissible from one host species to another. Such a striking nature of prions has generated huge concerns in public health and attracted serious attention in the scientific communities.
To date, the potential transmission of prions to human has not been alleviated and TSEs still have no reliable preclinical screening tests and effective treatments.
This doctoral thesis deals widely with the prion diseases, from epidemiology to pathogenesis, from diagnosis to therapy and prevention. Moreover it describes in detail three experimental projects aimed to clarify different aspects of TSEs. In all of them wild-type mouse bioassays are used, as they are the gold standard for assessing the biological properties of prions.
The goal of the first study was to assess the therapeutic and/or preventive activity on TSEs of the chronic administration of a new γ-secretase modulator. The second research investigated the ability to identify BSE in presence of scrapie. The third project was aimed to study the effects induced by chronic administration of lipid enriched/depleted specific diets on the pathogenesis of prion diseases.
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Broučková, Adéla. "Charakterizace buněčného prionového proteinu krevních destiček." Doctoral thesis, 2011. http://www.nusl.cz/ntk/nusl-311391.
Full textAbstract:
The conformational conversion of the cellular prion protein (PrPc) to the misfolded isoform (PrPsc) is the central pathogenic event in the transmissible neurodegenerative prion diseases. The recently shown transmissibility of variant Creutzfeldt-Jakob disease by blood transfusion emphasizes the need for better understanding of the PrPc in blood. In the current thesis, we focused on blood platelet PrPc, which has not been very well described so far. In the first part of the thesis, platelet PrPc was characterized as glycosylphosphatidylinositol- anchored glycoprotein with dominant diglycosylated form. Platelet PrPc was shown to be sensitive to cleavage with proteinase K, which is a feature discriminating between cellular and pathological prion protein. We have confirmed that platelet PrPc binds copper ions by its N- terminal octapeptide repeat region. Regarding quantity of PrPc molecules expressed on blood elements we have proved that both platelets and red blood cells express considerable amount of PrPc and thus can not be neglected in the problematic of prions transmission by blood transfusion. The detailed study regarding PrPc localization in blood platelets is presented in the second part of the thesis. PrPc was shown to be expressed in -granules as well as on the cytoplasmic membrane of...