Transfer of Scrapie Prion Infectivity by Cell Contact in Culture

Kanu, Nnennaya; Imokawa, Yutaka; Drechsel, David; Williamson, R. Anthony; Birkett, Christopher R.; Bostock, Christopher J.; Brockes, Jeremy P.

doi:10.1016/s0960-9822(02)00722-4

Cited by 127 publications

(107 citation statements)

References 28 publications

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“…The presence of PrP C in caveolae and interactions between PrP C and caveolin-1 have been reported earlier (6,22,39). Binding of prion proteins to the HS chains of recycling Gpc-1 (24 -28) could contribute to the observed transfer of scrapie prion infectivity by cell-to-cell contact (40).…”

Section: Discussionsupporting

confidence: 54%

Prion, Amyloid β-derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-dependent Autocleavage of Glypican-1 Heparan Sulfate

Mani

Cheng

Havsmark

et al. 2003

Journal of Biological Chemistry

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Copper are generally bound to proteins, e.g. the prion and the amyloid ␤ proteins. We have previously shown that copper ions are required to nitrosylate thiol groups in the core protein of glypican-1, a heparan sulfate-substituted proteoglycan. When S-nitrosylated glypican-1 is then exposed to an appropriate reducing agent, such as ascorbate, nitric oxide is released and autocatalyzes deaminative cleavage of the glypican-1 heparan sulfate side chains at sites where the glucosamines are N-unsubstituted. These processes take place in a stepwise manner, whereas glypican-1 recycles via a caveolin-1-associated pathway where copper ions could be provided by the prion protein. Here we show, by using both biochemical and microscopic techniques, that (a) the glypican-1 core protein binds copper(II) ions, reduces them to copper(I) when the thiols are nitrosylated and reoxidizes copper(I) to copper(II) when ascorbate releases nitric oxide; (b) maximally S-nitrosylated glypican-1 can cleave its own heparan sulfate chains at all available sites in a nitroxyl ion-dependent reaction; (c) free zinc(II) ions, which are redox inert, also support autocleavage of glypican-1 heparan sulfate, probably via transnitrosation, whereas they inhibit copper(II)-supported degradation; and (d) copper(II)-loaded but not zinc(II)-loaded prion protein or amyloid ␤ peptide support heparan sulfate degradation. As glypican-1 in prion null cells is poorly S-nitrosylated and as ectopic expression of cellular prion protein restores S-nitrosylation of glypican-1 in these cells, we propose that one function of the cellular prion protein is to deliver copper(II) for the S-nitrosylation of recycling glypican-1.

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Section: Discussionsupporting

confidence: 54%

Prion, Amyloid β-derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-dependent Autocleavage of Glypican-1 Heparan Sulfate

Mani

Cheng

Havsmark

et al. 2003

Journal of Biological Chemistry

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“…It has been reported recently that TSE infectivity can spread through infected cell cultures either by direct cell-to-cell contact (43) or via the release of infectivity into the culture medium (44). Whereas a direct correlation between cell-to-cell spread of TSE infectivity and persistence of infection remains to be established, it is possible that impairment of such a mechanism on a cellular level could account for the resistance of some cells to persistent infection.…”

Section: Discussionmentioning

confidence: 99%

Acute Formation of Protease-resistant Prion Protein Does Not Always Lead to Persistent Scrapie Infection in Vitro

Vorberg¹,

Raines

Priola

2004

Journal of Biological Chemistry

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Transmissible spongiform encephalopathies are accompanied by the accumulation of a pathologic isoform of a host-encoded protein, termed prion protein (PrP). Despite the widespread distribution of the cellular isoform of PrP (protease-sensitive PrP; PrP-sen), the disease-associated isoform (protease-resistant PrP; PrPres) appears to be primarily restricted to cells of the nervous and lymphoreticular systems. In order to study why scrapie infection appears to be restricted to certain cells, we followed acute and persistent PrP-res formation upon exposure of cells to different scrapie agents. We found that, independent of the cell type and scrapie strain, initial PrP-res formation occurred rapidly in cells. However, sustained generation of PrP-res and persistent infection did not necessarily follow acute PrPres formation. Persistent PrP-res formation and scrapie infection was restricted to one cell line inoculated with the mouse scrapie strain 22L. In contrast to cells that did not become scrapie-infected, the level of PrP-res in the 22L-infected cells rapidly increased in the absence of a concomitant increase in the number of PrP-resproducing cells. Furthermore, the protein banding pattern of PrP-res in these cells changed over time as the cells became chronically infected. Thus, our results suggest that the events leading to the initial formation of PrP-res may differ from those required for sustained PrP-res formation and infection. This may, at least in part, explain the observation that not all PrP-sen-expressing cells appear to support transmissible spongiform encephalopathy agent replication.

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“…SMB cells were originally isolated from Chandler strain-infected mouse brain culture [31]. However, Chandler-infected SMB cells can be cured with pentosan sulphate and infected de novo with other mouse-adapted prion strains [13,65]. SN56 is a mouse cholinergic septal neuronal cell line which is permissive to the multiplication of several mouse-adapted prion strains [7].…”

Section: Cell Models Permissive To Experimental Rodent-adapted Scrapmentioning

confidence: 99%

“…infectious brain homogenate) with cultured target cells. However, several independent studies have recently shown that prion transmission is much more efficient when live infected biological material is used as the source of infectivity [39,65,99]. Further investigation into the underlying active biological processes will be necessary to optimise prion transmission to cultured cells.…”

Section: De Novo Infection and Cell-to-cell Dissemination Of Prionsmentioning

confidence: 99%

“…Extracellular forms of PrP Sc can also be detected in infected tissues [62], the diffusion of which could transmit infection to more distant cells [17]. Cell surface abnormal PrP could potentially infect contacting cells as suggested by infection of recipient cells by paraformaldehyde-fixed infected SMB cells [65]. On the contrary, the presence of infectivity in the cell culture media of numerous prion-infected cell lines, including N2a, GT1, HpL3-4, SN56, MovS, and Rov [7,34,46,80,124] raised the possibility that infection can be transmitted, at least among cultured cells, through the release of cell-free forms of prions.…”

Section: De Novo Infection and Cell-to-cell Dissemination Of Prionsmentioning

confidence: 99%

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Cell models of prion infection

Vilette

2007

Vet. Res.

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-Due to recent renewal of interest and concerns in prion diseases, a number of cell systems permissive to prion multiplication have been generated in the last years. These include established cell lines, neuronal stem cells and primary neuronal cultures. While most of these models are permissive to experimental, mouse-adapted strains of prions, the propagation of natural field isolates from sheep scrapie and chronic wasting disease has been recently achieved. These models have improved our knowledge on the molecular and cellular events controlling the conversion of the PrP C protein into abnormal isoforms and on the cell-to-cell spreading of prions. Infected cultured cells will also facilitate investigations on the molecular basis of strain identity and on the mechanisms that lead to neurodegeneration. The ongoing development of new cell models with improved characteristics will certainly be useful for a number of unanswered critical issues in the prion field.

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Transfer of Scrapie Prion Infectivity by Cell Contact in Culture

Abstract: Cell-mediated infection of target cells in this culture system is effective and requires significantly less PrP(Sc) than infection by a prion preparation. Several lines of evidence indicate that it depends on cell contact, in particular, the activity of aldehyde-fixed infected cells.

Cited by 127 publications

References 28 publications

Prion, Amyloid β-derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-dependent Autocleavage of Glypican-1 Heparan Sulfate

Prion, Amyloid β-derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-dependent Autocleavage of Glypican-1 Heparan Sulfate

Acute Formation of Protease-resistant Prion Protein Does Not Always Lead to Persistent Scrapie Infection in Vitro

Cell models of prion infection

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