PrP Expression and Replication by Schwann Cells: Implications in Prion Spreading

Follet, Jérôme; Lemaire-Vieille, Catherine; Blanquet-Grossard, Françoise; Podevin-Dimster, Valérie; Lehmann, Sylvain; Chauvin, Jean‐Paul; Decavel, Jean-Pierre; Varea, Ruth; Grassi, Jacques; Fontés, Michel; Cesbron, Jean‐Yves

doi:10.1128/jvi.76.5.2434-2439.2002

Cited by 74 publications

(64 citation statements)

References 32 publications

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“…In cell systems where spread of prion infectivity may require cell to cell contact, 26,27 we propose that the role of GPI anchored PrP-sen is to facilitate the spread of prion infection via a chain of conversion from cell-to-cell, a "domino" type spread of infection that has been previously hypothesized. 35,36 In vivo, such a mechanism might explain why neuroinvasion does not necessarily require axonal transport 32,37,38 and can occur independently of the axonal neurofilament machinery. 39 It would likely vary with cell type 27 and be most important in areas where infectivity is transferred from the periphery to the nervous system as well as in areas where cell division may be limited.…”

Section: Analysis Of Infected and Uninfected Cells Co-expressing Mo3fmentioning

confidence: 99%

The role of the prion protein membrane anchor in prion infection

Priola

McNally

2009

Prion

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Section: Analysis Of Infected and Uninfected Cells Co-expressing Mo3fmentioning

confidence: 99%

The role of the prion protein membrane anchor in prion infection

Priola

McNally

2009

Prion

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“…Immortalized neuronal and neuroglial cell lines persistently infected by prions generally show no overt signs of cytotoxicity, although producing readily detectable amounts of PrP Sc and infectivity (12)(13)(14)(15). Various phenotypical alterations have been reported (16,17), yet it remains uncertain whether similar dysfunctions may affect TSE-injured postmitotic neurons.…”

mentioning

confidence: 99%

Prions can infect primary cultured neurons and astrocytes and promote neuronal cell death

Cronier

Laude

Peyrin

2004

Proc. Natl. Acad. Sci. U.S.A.

139

150

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Transmissible spongiform encephalopathies arise as a consequence of infection of the central nervous system by prions, where neurons and glial cells are regarded as primary targets. Neuronal loss and gliosis, associated with the accumulation of misfolded prion protein (PrP), are hallmarks of prion diseases; yet the mechanisms underlying such disorders remain unclear. Here we introduced a cell system based on primary cerebellar cultures established from transgenic mice expressing ovine PrP and then exposed to sheep scrapie agent. Upon exposure to low doses of infectious agent, such cultures, unlike cultures originating from PrP null mice, were found to accumulate de novo abnormal PrP and infectivity, as assessed by mouse bioassay. Importantly, using astrocyte and neuron͞astrocyte cocultures, both cell types were found capable of sustaining efficient prion propagation independently, leading to the production of proteinase K-resistant PrP of the same electrophoretic profile as in diseased brain. Moreover, contrasting with data obtained in chronically infected cell lines, late-occurring apoptosis was consistently demonstrated in the infected neuronal cultures. Our results provide evidence that primary cultured neural cells, including postmitotic neurons, are permissive to prion replication, thus establishing an approach to study the mechanisms involved in prion-triggered neurodegeneration at a cellular level.T ransmissible spongiform encephalopathies (TSE), which include Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep, are fatal neurodegenerative disorders caused by prions, a class of unconventional agents that targets the CNS in mammals. A hallmark of prion diseases is the accumulation of abnormal prion protein (PrP Sc ), a misfolded form of the cellular PrP (PrP c ). Transmissibility is believed to stem from the ability of the prion isoform to promote the conformational transition from PrP c to PrP Sc . Biologically distinct prion strains can propagate in a same host, presumably through the perpetuation of different specific PrP Sc conformers (1-3).Although it seems clear that neuronal dysfunction must lie at the root of the clinical disorders observed in these diseases, it is still obscure what triggers neurodegeneration and what role nonneuronal cells may play in this process. There is ample evidence to support a primary role of the neurons in prion propagation and neuropathogenesis into the CNS. Intra-or perineuronal PrP Sc deposition, spongiform vacuolation involving cell soma and processes, and neuronal loss are typical histopathological changes observed in TSE-affected brain tissues (4, 5). Transgenic mice with PrP expression specifically targeted to neurons have been obtained that turned out to be fully susceptible to prion disease (6). More recently, it was shown that an acute neuron-targeted depletion of PrP in the brain of mice with ongoing infection is able to prevent neuronal loss and progression to disease and even to reverse early spongiform chang...

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“…In older sheep, the loose connective tissue underlying the respiratory epithelium is rich in GFAP+ fibres and NFH+ fibres have been detected in the lymphoepithelial tissue in proximity to M cells involved in the uptake and transepithelial transport of pathogens (Casteleyn et al 2010). Furthermore, the Schwann cells, revealed by the labelling of GFAP+ nerve fibres, are able to replicate PrPd in vitro and to transmit the disease to mice after intracerebral injection (Follet et al 2002). They might be active in direct nerve infection.…”

Section: Discussionmentioning

confidence: 91%

Neuroimmune connections in ovine pharyngeal tonsil: potential site for prion neuroinvasion

et al. 2012

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Recent studies have established the involvement of nasal-associated lymphoid tissues, mainly the pharyngeal tonsil, in prion pathogenesis. However, the mechanisms of the associated neuroinvasion are still debated. To determine potential sites for prion neuroinvasion inside the ovine pharyngeal tonsil, the topography of heavy (200 kDa) and light (70 kDa) neurofilaments and of glial fibrillar acidic protein has been semi-quantitatively analysed inside the various compartments of the tonsil. The results show that the most innervated areas are the interfollicular area and the connective tissue located beneath the respiratory epithelium. The existence of rare synapses between follicular dendritic cells and nerve fibres inside the germinal centre indicates that this mechanism of neuroinvasion is possible but, since germinal centres of lymphoid follicles are poorly innervated, other routes of neuroinvasion are likely. The host PRNP genotype does not influence the pattern of innervation in these various tonsil compartments, unlike ageing during which an increase of nerve endings occurs in a zone of high trafficking cells beneath the respiratory epithelium. A minimal age-related increase of innervation inside the lymphoid follicles has also been observed. An increase in nerve fibre density around the lymphoid follicles, in an area rich in mobile cells such as macrophages and dendritic cells capable of capturing and conveying pathogen prion protein (PrPd), might ensure more efficient infectivity, not in the early phase but in the advanced phase of lymphoinvasion after the amplification of PrPd; alternatively, this area might even act as a direct site of entry during neuroinvasion.

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PrP Expression and Replication by Schwann Cells: Implications in Prion Spreading

Cited by 74 publications

References 32 publications

The role of the prion protein membrane anchor in prion infection

The role of the prion protein membrane anchor in prion infection

Prions can infect primary cultured neurons and astrocytes and promote neuronal cell death

Neuroimmune connections in ovine pharyngeal tonsil: potential site for prion neuroinvasion

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