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      Inhibition of cholesterol recycling impairs cellular PrPSc propagation

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          Abstract

          The infectious agent in prion diseases consists of an aberrantly folded isoform of the cellular prion protein (PrP c), termed PrP Sc, which accumulates in brains of affected individuals. Studies on prion-infected cultured cells indicate that cellular cholesterol homeostasis influences PrP Sc propagation. Here, we demonstrate that the cellular PrP Sc content decreases upon accumulation of cholesterol in late endosomes, as induced by NPC-1 knock-down or treatment with U18666A. PrP c trafficking, lipid raft association, and membrane turnover are not significantly altered by such treatments. Cellular PrP Sc formation is not impaired, suggesting that PrP Sc degradation is increased by intracellular cholesterol accumulation. Interestingly, PrP Sc propagation in U18666A-treated cells was partially restored by overexpression of rab 9, which causes redistribution of cholesterol and possibly of PrP Sc to the trans-Golgi network. Surprisingly, rab 9 overexpression itself reduced cellular PrP Sc content, indicating that PrP Sc production is highly sensitive to alterations in dynamics of vesicle trafficking.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00018-009-0158-4) contains supplementary material, which is available to authorized users.

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          Most cited references 61

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          Prions.

           S B Prusiner (1998)
          Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high beta-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrPSc. Transgenetic studies argue that PrPSc acts as a template upon which PrPC is refolded into a nascent PrPSc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrPSc. While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.
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            Rab proteins as membrane organizers.

            Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution and communicate through an elaborate system of vesiculo-tubular transport. Rab proteins and their effectors coordinate consecutive stages of transport, such as vesicle formation, vesicle and organelle motility, and tethering of vesicles to their target compartment. These molecules are highly compartmentalized in organelle membranes, making them excellent candidates for determining transport specificity and organelle identity.
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              Cellular cholesterol trafficking and compartmentalization.

               Elina Ikonen (2008)
              Cholesterol is an essential structural component in the cell membranes of most vertebrates. The biophysical properties of cholesterol and the enzymology of cholesterol metabolism provide the basis for how cells handle cholesterol and exchange it with one another. A tightly controlled--but only partially characterized--network of cellular signalling and lipid transfer systems orchestrates the functional compartmentalization of this lipid within and between organellar membranes. This largely dictates the exchange of cholesterol between tissues at the whole body level. Increased understanding of these processes and their integration at the organ systems level provides fundamental insights into the physiology of cholesterol trafficking.
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                Author and article information

                Contributors
                +49-89-41406820 , +49-89-41406823 , schaetzl@lrz.tum.de
                Journal
                Cell Mol Life Sci
                Cellular and Molecular Life Sciences
                SP Birkhäuser Verlag Basel (Basel )
                1420-682X
                1420-9071
                13 October 2009
                December 2009
                : 66
                : 24
                : 3979-3991
                Affiliations
                Institute of Virology, Prion Research Group, Technische Universität München, Trogerstr. 30, 81675 Munich, Germany
                158
                10.1007/s00018-009-0158-4
                2777232
                19823766
                © The Author(s) 2009
                Categories
                Research Article
                Custom metadata
                © Birkhäuser Verlag, Basel/Switzerland 2009

                Molecular biology

                npc-1, prion, rab 9, cholesterol, prp, recycling

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