Journal articles: 'Prione, lipid raft'

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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.

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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.

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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.

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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.

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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.

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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.

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Kazlauskaite, Jurate, and Teresa J. T. Pinheiro. "Aggregation and fibrillization of prions in lipid membranes." Biochemical Society Symposia 72 (January 1, 2005): 211–22. http://dx.doi.org/10.1042/bss0720211.

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A key molecular event in prion diseases is the conversion of PrP (prion protein) from its normal cellular form (PrPc) into the disease-specific form (PrPSc). The transition from PrPc to PrPSc involves a major conformational change, resulting in amorphous aggregates and/or fibrillar amyloid deposits. Here, we review several lines of evidence implicating membranes in the conversion of PrP, and summarize recent results from our own work on the role of lipid membranes in conformational transitions of prion proteins. By establishing new correlations between in vivo biological findings with in vitro biophysical results, we propose a role for lipid rafts in prion conversion, which takes into account the structural heterogeneity of PrP in different lipid environments.

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Taylor, David R., and Nigel M. Hooper. "The prion protein and lipid rafts (Review)." Molecular Membrane Biology 23, no. 1 (January 2006): 89–99. http://dx.doi.org/10.1080/09687860500449994.

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Elfrink, Kerstin, Luitgard Nagel-Steger, and Detlev Riesner. "Interaction of the cellular prion protein with raft-like lipid membranes." Biological Chemistry 388, no. 1 (January 1, 2007): 79–89. http://dx.doi.org/10.1515/bc.2007.010.

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Abstract Conversion of the cellular isoform of the prion protein (PrPC) into the disease-associated isoform (PrPSc) plays a key role in the development of prion diseases. Within its cellular pathway, PrPC undergoes several posttranslational modifications, i.e., the attachment of two N-linked glycans and a glycosyl phosphatidyl inositol (GPI) anchor, by which it is linked to the plasma membrane on the exterior cell surface. To study the interaction of PrPC with model membranes, we purified posttranslationally modified PrPC from transgenic Chinese hamster ovary (CHO) cells. The mono-, di- and oligomeric states of PrPC free in solution were analyzed by analytical ultracentrifugation. The interaction of PrPC with model membranes was studied using both lipid vesicles in solution and lipid bilayers bound to a chip surface. The equilibrium and mechanism of PrPC association with the model membranes were analyzed by surface plasmon resonance. Depending on the degree of saturation of binding sites, the concentration of PrPC released from the membrane into aqueous solution was estimated at between 10-9 and 10-7 M. This corresponds to a free energy of the insertion reaction of -48 kJ/mol. Consequences for the conversion of PrPC to PrPSc are discussed.

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Wadia, Jehangir S., Monica Schaller, R. Anthony Williamson, and Steven F. Dowdy. "Pathologic Prion Protein Infects Cells by Lipid-Raft Dependent Macropinocytosis." PLoS ONE 3, no. 10 (October 2, 2008): e3314. http://dx.doi.org/10.1371/journal.pone.0003314.

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Hooper, Nigel M. "Glypican-1 facilitates prion conversion in lipid rafts." Journal of Neurochemistry 116, no. 5 (February 9, 2011): 721–25. http://dx.doi.org/10.1111/j.1471-4159.2010.06936.x.

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Hnasko, Robert, Ana V. Serban, George Carlson, Stanley B. Prusiner, and Larry H. Stanker. "Generation of antisera to purified prions in lipid rafts." Prion 4, no. 2 (April 2010): 94–104. http://dx.doi.org/10.4161/pri.4.2.12622.

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Lewis, Victoria. "The role of lipid rafts in prion protein biology." Frontiers in Bioscience 16, no. 1 (2011): 151. http://dx.doi.org/10.2741/3681.

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Watarai, Masahisa. "Interaction between Brucella abortus and cellular prion protein in lipid raft microdomains." Microbes and Infection 6, no. 1 (January 2004): 93–100. http://dx.doi.org/10.1016/j.micinf.2003.11.002.

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Taylor, David R., Isobel J. Whitehouse, and Nigel M. Hooper. "Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation." PLoS Pathogens 5, no. 11 (November 20, 2009): e1000666. http://dx.doi.org/10.1371/journal.ppat.1000666.

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Agostini, Federica, Carlos G. Dotti, Azucena Pérez-Cañamás, Maria Dolores Ledesma, Federico Benetti, and Giuseppe Legname. "Prion Protein Accumulation in Lipid Rafts of Mouse Aging Brain." PLoS ONE 8, no. 9 (September 10, 2013): e74244. http://dx.doi.org/10.1371/journal.pone.0074244.

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Malchiodi-Albedi, Fiorella, Silvia Paradisi, Andrea Matteucci, Claudio Frank, and Marco Diociaiuti. "Amyloid Oligomer Neurotoxicity, Calcium Dysregulation, and Lipid Rafts." International Journal of Alzheimer's Disease 2011 (2011): 1–17. http://dx.doi.org/10.4061/2011/906964.

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Amyloid proteins constitute a chemically heterogeneous group of proteins, which share some biophysical and biological characteristics, the principal of which are the high propensity to acquire an incorrect folding and the tendency to aggregate. A number of diseases are associated with misfolding and aggregation of proteins, although only in some of them—most notably Alzheimer's disease (AD) and transmissible spongiform encephalopathies (TSEs)—a pathogenetic link with misfolded proteins is now widely recognized. Lipid rafts (LRs) have been involved in the pathophysiology of diseases associated with protein misfolding at several levels, including aggregation of misfolded proteins, amyloidogenic processing, and neurotoxicity. Among the pathogenic misfolded proteins, the AD-related protein amyloid β (Aβ) is by far the most studied protein, and a large body of evidence has been gathered on the role played by LRs in Aβ pathogenicity. However, significant amount of data has also been collected for several other amyloid proteins, so that their ability to interact with LRs can be considered an additional, shared feature characterizing the amyloid protein family. In this paper, we will review the evidence on the role of LRs in the neurotoxicity of huntingtin, α-synuclein, prion protein, and calcitonin.

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Martellucci, Stefano, Costantino Santacroce, Francesca Santilli, Luca Piccoli, Simona Delle Monache, Adriano Angelucci, Roberta Misasi, Maurizio Sorice, and Vincenzo Mattei. "Cellular and Molecular Mechanisms Mediated by recPrPC Involved in the Neuronal Differentiation Process of Mesenchymal Stem Cells." International Journal of Molecular Sciences 20, no. 2 (January 16, 2019): 345. http://dx.doi.org/10.3390/ijms20020345.

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Human Dental Pulp Stem Cells (hDPSCs) represent a type of adult mesenchymal stem cells that have the ability to differentiate in vitro in several lineages such as odontoblasts, osteoblasts, chondrocytes, adipocytes and neurons. In the current work, we used hDPSCs as the experimental model to study the role of recombinant prion protein 23–231 (recPrPC) in the neuronal differentiation process, and in the signal pathway activation of ERK 1/2 and Akt. We demonstrated that recPrPC was able to activate an intracellular signal pathway mediated by extracellular-signal-regulated kinase 1 and 2 (ERK 1/2) and protein kinase B (Akt). Moreover, in order to understand whether endogenous prion protein (PrPC) was necessary to mediate the signaling induced by recPrPC, we silenced PrPC, demonstrating that the presence of endogenous PrPC was essential for ERK 1/2 and Akt phosphorylation. Since endogenous PrPC is a well-known lipid rafts component, we evaluated the role of these structures in the signal pathway induced by recPrPC. Our results suggest that lipid rafts integrity play a key role in recPrPC activity. In fact, lipid rafts inhibitors, such as fumonisin B1 and MβCD, significantly prevented ERK 1/2 and Akt phosphorylation induced by recPrPC. In addition, we investigated the capacity of recPrPC to induce hDPSCs neuronal differentiation process after long-term stimulation through the evaluation of typical neuronal markers expression such as B3-Tubulin, neurofilament-H (NFH) and growth associated protein 43 (GAP43). Accordingly, when we silenced endogenous PrPC, we observed the inhibition of neuronal differentiation induced by recPrPC. The combined data suggest that recPrPC plays a key role in the neuronal differentiation process and in the activation of specific intracellular signal pathways in hDPSCs.

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Kawarabayashi, Takeshi, Takashi Nakata, Mikio Shoji, and Yasuhito Wakasaya. "P2-041: Aβ OLIGOMERS AND PRION FORM COMPLEX IN LIPID RAFTS." Alzheimer's & Dementia 10 (July 2014): P484—P485. http://dx.doi.org/10.1016/j.jalz.2014.05.714.

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Walmsley, Adrian R., Fanning Zeng, and Nigel M. Hooper. "The N-terminal Region of the Prion Protein Ectodomain Contains a Lipid Raft Targeting Determinant." Journal of Biological Chemistry 278, no. 39 (July 14, 2003): 37241–48. http://dx.doi.org/10.1074/jbc.m302036200.

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Hooper, Nigel M., David R. Taylor, and Nicole T. Watt. "Mechanism of the metal-mediated endocytosis of the prion protein." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1272–76. http://dx.doi.org/10.1042/bst0361272.

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The cellular form of the prion protein, PrPc, is critically required for the establishment of prion diseases, such as Creutzfeldt–Jakob disease. Within the N-terminal half of PrPc are four octapeptide repeats that bind Cu2+. Exposure of neuronal cells expressing PrPc to Cu2+ results in the rapid endocytosis of the protein. First, PrPc translocates laterally out of detergent-resistant lipid rafts into detergent-soluble regions of the plasma membrane, then it is internalized through clathrin-coated pits. The extreme N-terminal region of PrPc is critically required for its endocytosis, as is the transmembrane LRP1 (low-density lipoprotein receptor-related protein-1). Incubation of cells with a competitive inhibitor of LRP1 ligands, receptor-associated protein, or down-regulation of LRP1 with siRNA (short interfering RNA) reduces the endocytosis of PrPc. Zn2+ also promotes the endocytosis of PrPc, a phenomenon that is also dependent on the octapeptide repeats and requires LRP1.

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Taylor, David R., and Nigel M. Hooper. "The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein." Biochemical Journal 402, no. 1 (January 25, 2007): 17–23. http://dx.doi.org/10.1042/bj20061736.

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PrPC (cellular prion protein) is located at the surface of neuronal cells in detergent-insoluble lipid rafts, yet is internalized by clathrin-dependent endocytosis. As PrPC is glycosyl-phosphatidylinositol-anchored, it requires a transmembrane adaptor protein to connect it to the clathrin endocytosis machinery. Using receptor-associated protein and small interfering RNA against particular LDL (low-density lipoprotein) family members, in combination with immunofluorescence microscopy and surface biotinylation assays, we show that the transmembrane LRP1 (LDL receptor-related protein 1) is required for the Cu2+-mediated endocytosis of PrPC in neuronal cells. We show also that another LRP1 ligand that can cause neurodegenerative disease, the Alzheimer's amyloid precursor protein, does not modulate the endocytosis of PrPC.

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Russelakis-Carneiro, Milene, Claudio Hetz, Kinsey Maundrell, and Claudio Soto. "Prion Replication Alters the Distribution of Synaptophysin and Caveolin 1 in Neuronal Lipid Rafts." American Journal of Pathology 165, no. 5 (November 2004): 1839–48. http://dx.doi.org/10.1016/s0002-9440(10)63439-6.

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Botto, Laura, Diana Cunati, Silvia Coco, Silvia Sesana, Alessandra Bulbarelli, Emiliano Biasini, Laura Colombo, et al. "Role of Lipid Rafts and GM1 in the Segregation and Processing of Prion Protein." PLoS ONE 9, no. 5 (May 23, 2014): e98344. http://dx.doi.org/10.1371/journal.pone.0098344.

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Alomari, Munther, Dana Almohazey, Sarah Ameen Almofty, Firdos Alam Khan, Mohammad Al hamad, and Deena Ababneh. "Role of Lipid Rafts in Hematopoietic Stem Cells Homing, Mobilization, Hibernation, and Differentiation." Cells 8, no. 6 (June 22, 2019): 630. http://dx.doi.org/10.3390/cells8060630.

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Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells that can differentiate into myeloid or lymphoid cells. The mobilization and differentiation processes are affected by the external environment, such as extracellular matrix and soluble molecules in the niche, where the lipid rafts (LRs) of the HSCs act as the receptors and control platforms for these effectors. LRs are membrane microdomains that are enriched in cholesterol, sphingolipid, and proteins. They are involved in diverse cellular processes including morphogenesis, cytokinesis, signaling, endocytic events, and response to the environment. They are also involved in different types of diseases, such as cancer, Alzheimer’s, and prion disease. LR clustering and disruption contribute directly to the differentiation, homing, hibernation, or mobilization of HSCs. Thus, characterization of LR integrity may provide a promising approach to controlling the fate of stem cells for clinical applications. In this review, we show the critical role of LR modification (clustering, disruption, protein incorporation, and signal responding) in deciding the fate of HSCs, under the effect of soluble cytokines such as stem cell factor (SCF), transforming growth factor- β (TGF-β), hematopoietic-specific phospholipase Cβ2 (PLC-β2), and granulocyte colony-stimulating factor (G-CSF).

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Santuccione, Antonella, Vladimir Sytnyk, Iryna Leshchyns'ka, and Melitta Schachner. "Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth." Journal of Cell Biology 169, no. 2 (April 25, 2005): 341–54. http://dx.doi.org/10.1083/jcb.200409127.

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In spite of advances in understanding the role of the cellular prion protein (PrP) in neural cell interactions, the mechanisms of PrP function remain poorly characterized. We show that PrP interacts directly with the neural cell adhesion molecule (NCAM) and associates with NCAM at the neuronal cell surface. Both cis and trans interactions between NCAM at the neuronal surface and PrP promote recruitment of NCAM to lipid rafts and thereby regulate activation of fyn kinase, an enzyme involved in NCAM-mediated signaling. Cis and trans interactions between NCAM and PrP promote neurite outgrowth. When these interactions are disrupted in NCAM-deficient and PrP-deficient neurons or by PrP antibodies, NCAM/PrP-dependent neurite outgrowth is arrested, indicating that PrP is involved in nervous system development cooperating with NCAM as a signaling receptor.

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Rushworth, Jo V., Heledd H. Griffiths, Nicole T. Watt, and Nigel M. Hooper. "Prion Protein-mediated Toxicity of Amyloid-β Oligomers Requires Lipid Rafts and the Transmembrane LRP1." Journal of Biological Chemistry 288, no. 13 (February 5, 2013): 8935–51. http://dx.doi.org/10.1074/jbc.m112.400358.

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Angelopoulou, Efthalia, Yam Nath Paudel, Mohd Farooq Shaikh, and Christina Piperi. "Flotillin: A Promising Biomarker for Alzheimer’s Disease." Journal of Personalized Medicine 10, no. 2 (March 26, 2020): 20. http://dx.doi.org/10.3390/jpm10020020.

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Alzheimer’s disease (AD) is characterized by the accumulation of beta amyloid (Aβ) in extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein. Although the exact etiology of the disease remains elusive, accumulating evidence highlights the key role of lipid rafts, as well as the endocytic pathways in amyloidogenic amyloid precursor protein (APP) processing and AD pathogenesis. The combination of reduced Aβ42 levels and increased phosphorylated tau protein levels in the cerebrospinal fluid (CSF) is the most well established biomarker, along with Pittsburgh compound B and positron emission tomography (PiB-PET) for amyloid imaging. However, their invasive nature, the cost, and their availability often limit their use. In this context, an easily detectable marker for AD diagnosis even at preclinical stages is highly needed. Flotillins, being hydrophobic proteins located in lipid rafts of intra- and extracellular vesicles, are mainly involved in signal transduction and membrane–protein interactions. Accumulating evidence highlights the emerging implication of flotillins in AD pathogenesis, by affecting APP endocytosis and processing, Ca2+ homeostasis, mitochondrial dysfunction, neuronal apoptosis, Aβ-induced neurotoxicity, and prion-like spreading of Aβ. Importantly, there is also clinical evidence supporting their potential use as biomarker candidates for AD, due to reduced serum and CSF levels that correlate with amyloid burden in AD patients compared with controls. This review focuses on the emerging preclinical and clinical evidence on the role of flotillins in AD pathogenesis, further addressing their potential usage as disease biomarkers.

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Liu, Xi-Lin, Xiao-Li Feng, Guang-Ming Wang, Bin-Bin Gong, Waqas Ahmad, Nan-Nan Liu, Yuan-Yuan Zhang, Li Yang, Hong-Lin Ren, and Shu-Sen Cui. "Exploration of the main sites for the transformation of normal prion protein (PrPC) into pathogenic prion protein (PrPsc)." Journal of Veterinary Research 61, no. 1 (March 1, 2017): 11–22. http://dx.doi.org/10.1515/jvetres-2017-0002.

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Abstract Introduction: The functions and mechanisms of prion proteins (PrPC) are currently unknown, but most experts believe that deformed or pathogenic prion proteins (PrPSc) originate from PrPC, and that there may be plural main sites for the conversion of normal PrPC into PrPSc. In order to better understand the mechanism of PrPC transformation to PrPSc, the most important step is to determine the replacement or substitution site. Material and Methods: BALB/c mice were challenged with prion RML strain and from 90 days post-challenge (dpc) mice were sacrificed weekly until all of them had been at 160 dpc. The ultra-structure and pathological changes of the brain of experimental mice were observed and recorded by transmission electron microscopy. Results: There were a large number of pathogen-like particles aggregated in the myelin sheath of the brain nerves, followed by delamination, hyperplasia, swelling, disintegration, phagocytic vacuolation, and other pathological lesions in the myelin sheath. The aggregated particles did not overflow from the myelin in unstained samples. The phenomenon of particle aggregation persisted all through the disease course, and was the earliest observed pathological change. Conclusion: It was deduced that the myelin sheath and lipid rafts in brain nerves, including axons and dendrites, were the main sites for the conversion of PrPC to PrPSc, and the PrPSc should be formed directly by the conversion of protein conformation without the involvement of nucleic acids.

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Stuermer, Claudia A. O., and Helmut Plattner. "The 'lipid raft' microdomain proteins reggie-1 and reggie-2 (flotillins) are scaffolds for protein interaction and signalling." Biochemical Society Symposia 72 (January 1, 2005): 109–18. http://dx.doi.org/10.1042/bss0720109.

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Reggie-1 and reggie-2 are two evolutionarily highly conserved proteins which are up-regulated in retinal ganglion cells during regeneration of lesioned axons in the goldfish optic nerve. They are located at the cytoplasmic face of the plasma membrane and are considered to be 'lipid raft' constituents due to their insolubility in Triton X-100 and presence in the 'floating fractions'; hence they were independently named flotillins. According to our current view, the reggies subserve functions as protein scaffolds which form microdomains in neurons, lymphocytes and many other cell types across species as distant as flies and humans. These microdomains are of a surprisingly constant size of less than or equal to 0.1 mm in all cell types, whereas the distance between them is variable. The microdomains co-ordinate signal transduction of specific cell-surface proteins and especially of GPI (glycosylphosphatidylinositol)-anchored proteins into the cell, as is demonstrated for PrPc (cellular prion protein) in T-lymphocytes. These cells possess a pre-formed reggie cap scaffold consisting of densely packed reggie microdomains. PrPc is targeted to the lymphocyte reggie cap when activated by antibody cross-linking, and induces a distinct Ca2+ signal. In developing zebrafish, reggies become concentrated in neurons and axon tracts, and their absence, after morpholino antisense RNA-knockdown, results in deformed embryos with reduced brains. Likewise, defects in Drosophila eye morphogenesis occur upon reggie overexpression in mutant flies. The defects observed in the organism, as well as in single cells in culture, indicate a morphogenetic function of the reggies, with emphasis on the nervous system. This complies with their role as scaffolds for the formation of multiprotein complexes involved in signalling across the plasma membrane.

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Chen, Xi, Angela Jen, Alice Warley, M. Jayne Lawrence, Peter J. Quinn, and Roger J. Morris. "Isolation at physiological temperature of detergent-resistant membranes with properties expected of lipid rafts: the influence of buffer composition." Biochemical Journal 417, no. 2 (December 23, 2008): 525–33. http://dx.doi.org/10.1042/bj20081385.

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The failure of most non-ionic detergents to release patches of DRM (detergent-resistant membrane) at 37 °C undermines the claim that DRMs consist of lipid nanodomains that exist in an Lo (liquid ordered) phase on the living cell surface. In the present study, we have shown that inclusion of cations (Mg2+, K+) to mimic the intracellular environment stabilizes membranes during solubilization sufficiently to allow the isolation of DRMs at 37 °C, using either Triton X-100 or Brij 96. These DRMs are sensitive to chelation of cholesterol, maintain outside-out orientation of membrane glycoproteins, have prolonged (18 h) stability at 37 °C, and are vesicles or sheets up to 150–200 nm diameter. DRMs containing GPI (glycosylphosphatidylinositol)-anchored proteins PrP (prion protein) and Thy-1 can be separated by immunoaffinity isolation, in keeping with their separate organization and trafficking on the neuronal surface. Thy-1, but not PrP, DRMs are associated with actin. EM (electron microscopy) immunohistochemistry shows most PrP, and some Thy-1, to be clustered on DRMs, again maintaining their organization on the neuronal surface. For DRMs labelled for either protein, the bulk of the surface of the DRM is not labelled, indicating that the GPI-anchored protein is a minor component of its lipid domain. These 37 °C DRMs thus have properties expected of raft membrane, yet pose more questions about how proteins are organized within these nanodomains.

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Taylor, David R., and Nigel M. Hooper. "Role of lipid rafts in the processing of the pathogenic prion and Alzheimer's amyloid-β proteins." Seminars in Cell & Developmental Biology 18, no. 5 (October 2007): 638–48. http://dx.doi.org/10.1016/j.semcdb.2007.07.008.

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Mantuano, Elisabetta, Pardis Azmoon, Michael A. Banki, Michael S. Lam, Christina J. Sigurdson, and Steven L. Gonias. "A soluble derivative of PrPC activates cell-signaling and regulates cell physiology through LRP1 and the NMDA receptor." Journal of Biological Chemistry 295, no. 41 (August 11, 2020): 14178–88. http://dx.doi.org/10.1074/jbc.ra120.013779.

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Cellular prion protein (PrPC) is a widely expressed glycosylphosphatidylinositol-anchored membrane protein. Scrapie prion protein is a misfolded and aggregated form of PrPC responsible for prion-induced neurodegenerative diseases. Understanding the function of the nonpathogenic PrPC monomer is an important objective. PrPC may be shed from the cell surface to generate soluble derivatives. Herein, we studied a recombinant derivative of PrPC (soluble cellular prion protein, S-PrP) that corresponds closely in sequence to a soluble form of PrPC shed from the cell surface by proteases in the A Disintegrin And Metalloprotease (ADAM) family. S-PrP activated cell-signaling in PC12 and N2a cells. TrkA was transactivated by Src family kinases and extracellular signal–regulated kinase 1/2 was activated downstream of Trk receptors. These cell-signaling events were dependent on the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor-related protein-1 (LRP1), which functioned as a cell-signaling receptor system in lipid rafts. Membrane-anchored PrPC and neural cell adhesion molecule were not required for S-PrP–initiated cell-signaling. S-PrP promoted PC12 cell neurite outgrowth. This response required the NMDA-R, LRP1, Src family kinases, and Trk receptors. In Schwann cells, S-PrP interacted with the LRP1/NMDA-R system to activate extracellular signal–regulated kinase 1/2 and promote cell migration. The effects of S-PrP on PC12 cell neurite outgrowth and Schwann cell migration were similar to those caused by other proteins that engage the LRP1/NMDA-R system, including activated α2-macroglobulin and tissue-type plasminogen activator. Collectively, these results demonstrate that shed forms of PrPC may exhibit important biological activities in the central nervous system and the peripheral nervous system by serving as ligands for the LRP1/NMDA-R system.

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Hooper, N. M. "Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein." Biochemical Society Transactions 33, no. 2 (April 1, 2005): 335–38. http://dx.doi.org/10.1042/bst0330335.

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In the amyloidogenic pathway, the APP (amyloid precursor protein) is proteolytically processed by the β- and γ-secretases to release the Aβ (amyloid-β) peptide that is neurotoxic and aggregates in the brains of patients suffering from Alzheimer's disease. In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain, precluding deposition of intact Aβ peptide. The cellular form of the PrPC (prion protein) undergoes reactive oxygen species-mediated β-cleavage within the copper-binding octapeptide repeats or, alternatively, α-cleavage within the central hydrophobic neurotoxic domain. In addition, PrPC is shed from the membrane by the action of a zinc metalloprotease. Members of the ADAM (a disintegrin and metalloproteinase) family of zinc metalloproteases, notably ADAM10 and TACE (ADAM17) display α-secretase activity towards APP and appear to be responsible for the α-cleavage of PrPC. The amyloidogenic cleavage of APP by the β- and γ-secretases appears to occur preferentially in cholesterol-rich lipid rafts, while the conversion of PrPC into the infectious form PrPSc also appears to occur in these membrane domains.

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Persad, A., and C. Taghibiglou. "P.111 Plasma ADAM-10 as a novel biomarker for traumatic brain injury and concussion." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 46, s1 (June 2019): S43. http://dx.doi.org/10.1017/cjn.2019.204.

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Background: Cellular prion protein (PrPC) is a lipid raft protein locallizing within CNS tissue. It is reguated by a disiintegrin and metaloproteinase domain containing protein 10 (ADAM10), which induces ectodomain shedding. PrPC has been previousy implicated as a ptentia lbiomarker for TBI, but no prior studies have examined the potential of ADAM10 as a biomarker. Methods: Serum samples from patients admitted for TBI were collected and patient data was recorded. Control serum was acquired from a commercial tissue bank. Patient GCS was recorded during admission. Serum was used for ELISA to assess PrPC and ADAM10 expression. GraphPad was used to conduct ANOVA and regressional analysis. Results: 37 control and 20 TBI samples were collected. Of the TBI patiients, 8 were mild, 3 were moderate, and 9 were severe cilnical grade. Both PrPC and ADAM10 were elevated in TBI patients compared with control (p<0.001). ADAM10 exhibited a dose response, with greter expression in patients with higher clinical grade. There was no significant association of either PrPC or ADAM10 with time after injury. Conclusions: Our results indicate that PrPC and ADAM10 may be useful tools for screening of TBI. ADAM10 is associated closely with clinlcal grade, and may in the future represent a promising prognostic tool.

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Bate, Clive. "Breaking the Cycle, Cholesterol Cycling, and Synapse Damage in Response to Amyloid-β." Journal of Experimental Neuroscience 11 (January 1, 2017): 117906951773309. http://dx.doi.org/10.1177/1179069517733096.

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Soluble amyloid-β (Aβ) oligomers, a key driver of pathogenesis in Alzheimer disease, bind to cellular prion proteins (PrPC) expressed on synaptosomes resulting in increased cholesterol concentrations, movement of cytoplasmic phospholipase A2 (cPLA2) to lipid rafts and activation of cPLA2. The formation of Aβ-PrPC-cPLA2 complexes was controlled by the cholesterol ester cycle. Thus, Aβ activated cholesterol ester hydrolases which released cholesterol from stores of cholesterol esters; the increased cholesterol concentrations stabilised Aβ-PrPC-cPLA2 complexes. Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrPC-cPLA2. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; inhibition of cholesterol ester hydrolases protected neurons, whereas inhibition of cholesterol esterification increased the Aβ-induced synapse damage. Here, I speculate that a failure to deactivate signalling pathways can lead to pathology. Consequently, the esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms and synapse degeneration.

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Hugel, B., M. C. Mart�nez, C. Kunzelmann, T. Bl�ttler, A. Aguzzi, and J. M. Freyssinet. "Modulation of signal transduction through the cellular prion protein is linked to its incorporation in lipid rafts." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2998–3007. http://dx.doi.org/10.1007/s00018-004-4318-2.

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Nah, Jihoon, Jong-Ok Pyo, Sunmin Jung, Seung-Min Yoo, Tae-In Kam, JaeWoong Chang, Jonghee Han, Seong Soo A. An, Takashi Onodera, and Yong-Keun Jung. "BECN1/Beclin 1 is recruited into lipid rafts by prion to activate autophagy in response to amyloid β 42." Autophagy 9, no. 12 (December 5, 2013): 2009–21. http://dx.doi.org/10.4161/auto.26118.

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Sekar, Sathiya, Raja Solomon Viswas, Hajar Miranzadeh Mahabadi, Elahe Alizadeh, Humphrey Fonge, and Changiz Taghibiglou. "Concussion/Mild Traumatic Brain Injury (TBI) Induces Brain Insulin Resistance: A Positron Emission Tomography (PET) Scanning Study." International Journal of Molecular Sciences 22, no. 16 (August 20, 2021): 9005. http://dx.doi.org/10.3390/ijms22169005.

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Brain injury/concussion is a growing epidemic throughout the world. Although evidence supports association between traumatic brain injury (TBI) and disturbance in brain glucose metabolism, the underlying molecular mechanisms are not well established. Previously, we reported the release of cellular prion protein (PrPc) from the brain to circulation following TBI. The PrPc level was also found to be decreased in insulin-resistant rat brains. In the present study, we investigated the molecular link between PrPc and brain insulin resistance in a single and repeated mild TBI-induced mouse model. Mild TBI was induced in mice by dropping a weight (~95 g at 1 m high) on the right side of the head. The procedure was performed once and thrice (once daily) for single (SI) and repeated induction (RI), respectively. Micro PET/CT imaging revealed that RI mice showed significant reduction in cortical, hippocampal and cerebellum glucose uptake compared to SI and control. Mice that received RI also showed significant motor and cognitive deficits. In co-immunoprecipitation, the interaction between PrPc, flotillin and Cbl-associated protein (CAP) observed in the control mice brains was disrupted by RI. Lipid raft isolation showed decreased levels of PrPc, flotillin and CAP in the RI mice brains. Based on observation, it is clear that PrPc has an interaction with CAP and the dislodgment of PrPc from cell membranes may lead to brain insulin resistance in a mild TBI mouse model. The present study generated a new insight into the pathogenesis of brain injury, which may result in the development of novel therapy.

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Walmsley, Adrian R., Nicole T. Watt, David R. Taylor, W. Sumudhu S. Perera, and Nigel M. Hooper. "α-cleavage of the prion protein occurs in a late compartment of the secretory pathway and is independent of lipid rafts." Molecular and Cellular Neuroscience 40, no. 2 (February 2009): 242–48. http://dx.doi.org/10.1016/j.mcn.2008.10.012.

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GARMY, N., X. GUO, N. TAIEB, C. TOURRES, C. TAMALET, J. FANTINI, and N. YAHI. "Cellular isoform of the prion protein PrPc in human intestinal cell lines: Genetic polymorphism at codon 129, mRNA quantification and protein detection in lipid rafts." Cell Biology International 30, no. 6 (June 2006): 559–67. http://dx.doi.org/10.1016/j.cellbi.2006.03.006.

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Pesapane, Ada, Pia Ragno, Carmine Selleri, and Nunzia Montuori. "Recent Advances in the Function of the 67 kDa Laminin Receptor and its Targeting for Personalized Therapy in Cancer." Current Pharmaceutical Design 23, no. 32 (December 21, 2017): 4745–57. http://dx.doi.org/10.2174/1381612823666170710125332.

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The 67 kDa high affinity laminin receptor (67LR) is a non-integrin cell surface receptor for laminin, the major component of basement membranes. Interactions between 67LR and laminin play a major role in mediating cell adhesion, migration, proliferation and survival. 67LR derives from homo- or hetero-dimerization of a 37 kDa cytosolic precursor (37LRP), most probably by fatty acid acylation. Interestingly, 37LRP, also called p40 or OFA/iLR (oncofetal antigen/immature laminin receptor), is a multifunctional protein with a dual activity in the cytoplasm and in the nucleus. In the cytoplasm, 37LRP it is associated with the 40S subunit of ribosome, playing a critical role in protein translation and ribosome biogenesis while in the nucleus it is tightly associated with nuclear structures, and bound to components of the cytoskeleton, such as tubulin and actin. 67LR is mainly localized in the cell membrane, concentrated in lipid rafts. Acting as a receptor for laminin is not the only function of 67LR; indeed, it also acts as a receptor for viruses, bacteria and prions. 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. The primary function of 67LR in cancer is to promote tumor cell adhesion to basement membranes, the first step in the invasion-metastasis cascade. Thus, 67LR is overexpressed in neoplastic cells as compared to their normal counterparts and its overexpression is considered a molecular marker of metastatic aggressiveness in cancer of many tissues, including breast, lung, ovary, prostate, stomach, thyroid and also in leukemia and lymphoma. Thus, inhibiting 67LR binding to laminin could be a feasible approach to block cancer progression. Here, we review the current understanding of the structure and function of this molecule, highlighting its role in cancer invasion and metastasis and reviewing the various therapeutic options targeting this receptor that could have a promising future application.

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GARMY, N., X. GUO, N. TAIEB, C. TOURRES, C. TAMALET, J. FANTINI, and N. YAHI. "Erratum to: Cellular isoform of the prion protein PrPc in human intestinalcell lines: Genetic polymorphism at codon 129, mRNA quantification and protein detection in lipid rafts [30 (6) 559–567]." Cell Biology International 32, no. 11 (November 2008): 1465. http://dx.doi.org/10.1016/j.cellbi.2008.08.003.

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Hoover, Clare E., Kristen A. Davenport, Davin M. Henderson, Mark D. Zabel, and Edward A. Hoover. "Endogenous Brain Lipids Inhibit Prion Amyloid Formation In Vitro." Journal of Virology 91, no. 9 (February 15, 2017). http://dx.doi.org/10.1128/jvi.02162-16.

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ABSTRACT The normal cellular prion protein (PrPC) resides in detergent-resistant outer membrane lipid rafts in which conversion to the pathogenic misfolded form is believed to occur. Once misfolding occurs, the pathogenic isoform polymerizes into highly stable amyloid fibrils. In vitro assays have demonstrated an intimate association between prion conversion and lipids, specifically phosphatidylethanolamine, which is a critical cofactor in the formation of synthetic infectious prions. In the current work, we demonstrate an alternative inhibitory function of lipids in the prion conversion process as assessed in vitro by real-time quaking-induced conversion (RT-QuIC). Using an alcohol-based extraction technique, we removed the lipid content from chronic wasting disease (CWD)-infected white-tailed deer brain homogenates and found that lipid extraction enabled RT-QuIC detection of CWD prions in a 2-log10-greater concentration of brain sample. Conversely, addition of brain-derived lipid extracts to CWD prion brain or lymph node samples inhibited amyloid formation in a dose-dependent manner. Subsequent lipid analysis demonstrated that this inhibitory function was restricted to the polar lipid fraction in brain. We further investigated three phospholipids commonly found in lipid membranes, phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol, and found all three similarly inhibited RT-QuIC. These results demonstrating polar-lipid, and specifically phospholipid, inhibition of prion-seeded amyloid formation highlight the diverse roles lipid constituents may play in the prion conversion process. IMPORTANCE Prion conversion is likely influenced by lipid interactions, given the location of normal prion protein (PrPC) in lipid rafts and lipid cofactors generating infectious prions in in vitro models. Here, we use real-time quaking-induced conversion (RT-QuIC) to demonstrate that endogenous brain polar lipids can inhibit prion-seeded amyloid formation, suggesting that prion conversion is guided by an environment of proconversion and anticonversion lipids. These experiments also highlight the applicability of RT-QuIC to identify potential therapeutic inhibitors of prion conversion.

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Kim, Yong-Chan, Junbeom Lee, Dae-Weon Lee, and Byung-Hoon Jeong. "Large-scale lipidomic profiling identifies novel potential biomarkers for prion diseases and highlights lipid raft-related pathways." Veterinary Research 52, no. 1 (July 21, 2021). http://dx.doi.org/10.1186/s13567-021-00975-1.

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AbstractPrion diseases are transmissible spongiform encephalopathies induced by the abnormally-folded prion protein (PrPSc), which is derived from the normal prion protein (PrPC). Previous studies have reported that lipid rafts play a pivotal role in the conversion of PrPC into PrPSc, and several therapeutic strategies targeting lipids have led to prolonged survival times in prion diseases. In addition, phosphatidylethanolamine, a glycerophospholipid member, accelerated prion disease progression. Although several studies have shown that prion diseases are significantly associated with lipids, lipidomic analyses of prion diseases have not been reported thus far. We intraperitoneally injected phosphate-buffered saline (PBS) or ME7 mouse prions into mice and sacrificed them at different time points (3 and 7 months) post-injection. To detect PrPSc in the mouse brain, we carried out western blotting analysis of the left hemisphere of the brain. To identify potential novel lipid biomarkers, we performed lipid extraction on the right hemisphere of the brain and liquid chromatography mass spectrometry (LC/MS) to analyze the lipidomic profiling between non-infected mice and prion-infected mice. Finally, we analyzed the altered lipid-related pathways by a lipid pathway enrichment analysis (LIPEA). We identified a total of 43 and 75 novel potential biomarkers at 3 and 7 months in prion-infected mice compared to non-infected mice, respectively. Among these novel potential biomarkers, approximately 75% of total lipids are glycerophospholipids. In addition, altered lipids between the non-infected and prion-infected mice were related to sphingolipid, glycerophospholipid and glycosylphosphatidylinositol (GPI)-anchor-related pathways. In the present study, we found novel potential biomarkers and therapeutic targets of prion disease. To the best of our knowledge, this study reports the first large-scale lipidomic profiling in prion diseases.

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Kawarabayashi, Takeshi, Takumi Nakamura, Kaoru Sato, Yusuke Seino, Sadanobu Ichii, Naoko Nakahata, Masamitsu Takatama, David Westaway, Peter St George-Hyslop, and Mikio Shoji. "Lipid Rafts Act as a Common Platform for Amyloid-β Oligomer-Induced Alzheimer’s Disease Pathology." Journal of Alzheimer's Disease, April 12, 2022, 1–15. http://dx.doi.org/10.3233/jad-215662.

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Background: Amyloid-β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. Objective: We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. Methods: Cellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. Results: Aβ dimers, the cellular prion protein (PrPc), and Aβ dimer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ dimer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice. Conclusion: Lipid rafts act as a common platform for the progression of AD pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.

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Journal articles on the topic 'Prione, lipid raft'

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