PrP<sup>c</sup> on the road: trafficking of the cellular prion protein

Prado, Marco A. M.; Silva, Juliana Alves da; Magalhães, Ana C.; Prado, Vânia F.; Linden, Rafael; Martins, Vilma R.; Brentani, Ricardo R.

doi:10.1046/j.1471-4159.2003.02199.x

Cited by 83 publications

(67 citation statements)

References 166 publications

(200 reference statements)

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“…Although we have demonstrated that this occurs in conjunction with exposure of the SN56 cells to m(Ch)PrP-res and m(22L)PrP-res, it is unclear where and when within the cells this occurs. In neuroblastoma cells, PrPsen is known to reside in the Golgi apparatus, on the plasma membrane, and in early and recycling endosomes (Borchelt et al, 1990;Shyng et al, 1993;Prado et al, 2004). In scrapie-infected cells, PrP-sen is converted to PrP-res after transport to the cell surface but before degradation in lysosomes Borchelt et al, 1992).…”

Section: Prp-res Uptake Versus Establishing a Sustained Infectionmentioning

confidence: 99%

“…These results raise the possibility that neuronal cells might similarly internalize exogenously derived PrP-res when infected for the first time. The normal protease-sensitive precursor of PrP-res, PrP-sen or PrP C , is also endocytosed from the cell surface in neuroblastoma cells and either recycled to the plasma membrane or degraded (Shyng et al, 1993;Magalhaes et al, 2002;Prado et al, 2004). In PNS and CNS neurons, fast anterograde and retrograde axonal transport of PrP-sen also has been detected (Borchelt et al, 1994;Moya et al, 2004), facilitating movement to and from neural extremities.…”

Section: Introductionmentioning

confidence: 99%

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Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells

Magalhães¹,

Baron²,

Lee³

et al. 2005

J. Neurosci.

140

144

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Invasion of the nervous system and neuronal spread of infection are critical, but poorly understood, steps in the pathogenesis of transmissible spongiform encephalopathies or prion diseases. To characterize pathways for the uptake and intraneuronal trafficking of infectious, protease-resistant prion protein (PrP-res), fluorescent-labeled PrP-res was used to infect a neuronally derived murine cell line (SN56) and adult hamster cortical neurons in primary culture. Concurrent with the establishment of persistent scrapie infection, SN56 cells internalized PrP-res aggregates into vesicles positive for markers for late endosomes and/or lysosomes but not synaptic, early endocytic, or raft-derived vesicles. Internalized PrP-res was then transported along neurites to points of contact with other cells. Similar trafficking was observed with dextran, Alzheimer's A␤1-42 fibrils and noninfectious recombinant PrP fibrils, suggesting that PrP-res is internalized by a relatively nonspecific pinocytosis or transcytosis mechanism. Hamster cortical neurons were also capable of internalizing and disseminating exogenous PrP-res. Similar trafficking of exogenous PrP-res by cortical neurons cultured from the brains of PrP knock-out mice showed that uptake and neuritic transport did not require the presence of endogenous cellular PrP. These experiments visualize and characterize the initial steps associated with prion infection and transport within neuronal cells.

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Section: Prp-res Uptake Versus Establishing a Sustained Infectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells

Magalhães¹,

Baron²,

Lee³

et al. 2005

J. Neurosci.

140

144

View full text Add to dashboard Cite

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“…However, the mechanism of PrP C internalisation is still controversial, as both raft/caveolae-based (Kaneko et al, 1997;Marella et al, 2002;Peters et al, 2003;Vey et al, 1996) and clathrin-dependent processes (Magalhaes et al, 2002;Shyng et al, 1994;Sunyach et al, 2003) have been described (reviewed by Prado et al, 2004). Although other studies have investigated the fate of endocytosed PrP C , the mechanism of its internalisation was not addressed (Brown and Harris, 2003;Hachiya et al, 2004;Lee et al, 2001).…”

Section: Prpmentioning

confidence: 99%

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis

Taylor

Watt

Perera

et al. 2005

Journal of Cell Science

142

148

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The cellular prion protein (PrPC) is essential for the pathogenesis and transmission of prion diseases. Although PrPC is known to be located in detergent-insoluble lipid rafts at the surface of neuronal cells, the mechanism of its internalisation is unclear, with both raft/caveolae-based and clathrin-mediated processes being proposed. We have investigated the mechanism of copper-induced internalisation of PrPC in neuronal cells by immunofluorescence microscopy, surface biotinylation assays and buoyant sucrose density gradient centrifugation in the presence of Triton X-100. Clathrin-mediated endocytosis was selectively blocked with tyrphostin A23, which disrupts the interaction between tyrosine motifs in the cytosolic domains of integral membrane proteins and the adaptor complex AP2, and a dominant-negative mutant of the adaptor protein AP180. Both these agents inhibited the copper-induced endocytosis of PrPC. Copper caused PrPC to move laterally out of detergent-insoluble lipid rafts into detergent-soluble regions of the plasma membrane. Using mutants of PrPC that lack either the octapeptide repeats or the N-terminal polybasic region, and a construct with a transmembrane anchor, we show that copper binding to the octapeptide repeats promotes dissociation of PrPC from lipid rafts, whereas the N-terminal polybasic region mediates its interaction with a transmembrane adaptor protein that engages the clathrin endocytic machinery. Our results provide an experimental basis for reconciling the apparently contradictory observations that the prion protein undergoes clathrin-dependent endocytosis despite being localised in lipid rafts. In addition, we have been able to assign distinct functions in the endocytic process to separate regions of the protein.

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“…Increasing evidence indicates that subtle intracellular cholesterol changes affect the intracellular processing/ trafficking, function and/or activation of raft-resident proteins, including PrPc [2, [5][6][7]. Therefore, a role for cholesterol in the metabolism of PrPc and its conversion into PrPSc has been proposed [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

et al. 2010

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Scrapie is a prion disease for which no means of ante-mortem diagnosis is available. We recently found a relationship between cell susceptibility to scrapie and altered cholesterol homeostasis. In brains and in skin fibroblasts and peripheral blood mononuclear cells from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype, the levels of cholesterol esters were consistently higher than in tissues and cultures derived from animals with a scrapie-resistant genotype. Here we show that intracellular accumulation of cholesterol esters (CE) in fibroblasts derived from scrapie-susceptible sheep was accompanied by parallel alterations in the expression level of acyl-coenzymeA: cholesterol-acyltransferase (ACAT1) and caveolin-1 (Cav-1) that are involved in the pathways leading to intracellular cholesterol esterification and trafficking. Comparative analysis of cellular prion protein (PrPc) mRNA, showed an higher expression level in cells from animals carrying a susceptible genotype, with or without Scrapie. These data suggest that CE accumulation in peripheral cells, together with the altered expression of some proteins implicated in intracellular cholesterol homeostasis, might serve to identify a distinctive lipid metabolic profile associated with increased susceptibility to develop prion disease following infection.

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PrP^c on the road: trafficking of the cellular prion protein

Abstract: The glycosylphosphatidylinositol (GPI)-anchored cellular prion protein (PrP c ) has a fundamental role in prion diseases.

Cited by 83 publications

References 166 publications

Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells

Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

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PrPc on the road: trafficking of the cellular prion protein

Abstract: The glycosylphosphatidylinositol (GPI)-anchored cellular prion protein (PrP c ) has a fundamental role in prion diseases.

Cited by 83 publications

References 166 publications

Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells

Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

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Resources

About

PrP^c on the road: trafficking of the cellular prion protein