Dramatic Reduction of PrP<sup>C</sup>Level and Glycosylation in Peripheral Nerves following PrP Knock-Out from Schwann Cells Does Not Prevent Transmissible Spongiform Encephalopathy Neuroinvasion

Bradford, Barry; Tuzi, Nadia L.; Feltri, M. Laura; McCorquodale, C.; Cancellotti, Enrico; Manson, Jean

doi:10.1523/jneurosci.4195-09.2009

Cited by 14 publications

(9 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, acute conversion (not sustained propagation) was repeatedly observed in Rov cultures expressing PrP lacking a GPI anchor, mostly consisting of aglycosylated species, corroborating a recent study on cells that expressed mouse anchorless PrP (36). Various lines of evidence in vivo and in vitro tend to suggest that a glycosylation defect does not necessarily impair, or could even ease, PrP conversion (7,14,30,39,47,54,62). Taken together, these observations lend support to the view that the inability of aglycosylated mutants that satisfied various cell sorting quality controls to convert into PrP Sc might involve conformational dynamics of the mutant molecules, in turn affecting the efficiency of conversion process.…”

Section: Glycosylation and Prpsupporting

confidence: 80%

Prion Propagation in Cells Expressing PrP Glycosylation Mutants

Salamat

Dron

Chapuis

et al. 2011

J Virol

View full text Add to dashboard Cite

Infection by prions involves conversion of a host-encoded cell surface protein (PrP C ) to a disease-related isoform (PrP Sc ). PrP C carries two glycosylation sites variably occupied by complex N-glycans, which have been suggested by previous studies to influence the susceptibility to these diseases and to determine characteristics of prion strains. We used the Rov cell system, which is susceptible to sheep prions, to generate a series of PrP C glycosylation mutants with mutations at one or both attachment sites. We examined their subcellular trafficking and ability to convert into PrP Sc and to sustain stable prion propagation in the absence of wild-type PrP. The susceptibility to infection of mutants monoglycosylated at either site differed dramatically depending on the amino acid substitution. Aglycosylated double mutants showed overaccumulation in the Golgi compartment and failed to be infected. Introduction of an ectopic glycosylation site near the N terminus fully restored cell surface expression of PrP but not convertibility into PrP Sc , while PrP C with three glycosylation sites conferred cell permissiveness to infection similarly to the wild type. In contrast, predominantly aglycosylated molecules with nonmutated N-glycosylation sequons, produced in cells expressing glycosylphosphatidylinositol-anchorless PrP C , were able to form infectious PrP Sc . Together our findings suggest that glycosylation is important for efficient trafficking of anchored PrP to the cell surface and sustained prion propagation. However, properly trafficked glycosylation mutants were not necessarily prone to conversion, thus making it difficult in such studies to discern whether the amino acid changes or glycan chain removal most influences the permissiveness to prion infection.

show abstract

Section: Glycosylation and Prpsupporting

confidence: 80%

Prion Propagation in Cells Expressing PrP Glycosylation Mutants

Salamat

Dron

Chapuis

et al. 2011

J Virol

View full text Add to dashboard Cite

show abstract

“…Importantly, Schwann cells and oligodendrocytes are highly prone to undergo ER stress as demonstrated in many different disease models due to their high demand for protein and lipid synthesis [ 2 , 69 ]. Since the PrP promoter is also active in Schwann cells [ 70 , 71 ], we propose that ERp57 may have a relevant activity in sustaining glial proteostasis as a central component of the CNX-CRT cycle. In this context, ERp57 may contribute to maintain myelin structure or to reduce stress levels in Schwann cells.…”

Section: Discussionmentioning

confidence: 99%

Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration

et al. 2015

View full text Add to dashboard Cite

ERp57 (also known as grp58 and PDIA3) is a protein disulfide isomerase that catalyzes disulfide bonds formation of glycoproteins as part of the calnexin and calreticulin cycle. ERp57 is markedly upregulated in most common neurodegenerative diseases downstream of the endoplasmic reticulum (ER) stress response. Despite accumulating correlative evidence supporting a neuroprotective role of ERp57, the contribution of this foldase to the physiology of the nervous system remains unknown. Here we developed a transgenic mouse model that overexpresses ERp57 in the nervous system under the control of the prion promoter. We analyzed the susceptibility of ERp57 transgenic mice to undergo neurodegeneration. Unexpectedly, ERp57 overexpression did not affect dopaminergic neuron loss and striatal denervation after injection of a Parkinson’s disease-inducing neurotoxin. In sharp contrast, ERp57 transgenic animals presented enhanced locomotor recovery after mechanical injury to the sciatic nerve. These protective effects were associated with enhanced myelin removal, macrophage infiltration and axonal regeneration. Our results suggest that ERp57 specifically contributes to peripheral nerve regeneration, whereas its activity is dispensable for the survival of a specific neuronal population of the central nervous system. These results demonstrate for the first time a functional role of a component of the ER proteostasis network in peripheral nerve regeneration.

show abstract

“…As ME7 prions are lymphoinvasive, we examined the reasons for impaired replication and found very little if any PrP C expression in the spleen tissue of the uninfected or infected animals by immunoblot (data not shown). Incidentally, this impaired replication in the spleen is likely to have minimized haematogenous, PNS-independent prion spread to the CNS (Aucouturier et al, 2001), at variance with Bradford et al (2009). Taken together, these results argue against a major role of MSC-PrP C in prion spreading through the PNS.…”

Section: Inoculation Route Volume Inoculated* (Ml)mentioning

confidence: 95%

“…The presence of PrP Sc deposits in Schwann cells ensheathing axons from scrapie-infected sheep and mice peripheral nerves and the sustained prion replication observable in immortalized cultured Schwann-like cells experimentally infected with scrapie prions (Archer et al , 2004; Follet et al , 2002) suggested a possible role for this cell type. Transgenic mice with reduced PrP C expression in Schwann cells did not show any deceleration in the transfer of orally or intraperitoneally injected prions to the CNS (Bradford et al , 2009). These routes of prion exposure may not be optimal if the assumption that the myelin protein zero (P 0 ) promoter used in this study is active in both myelinating (MSCs) and non-myelinating Schwann cells (NMSCs) does not hold true.…”

Section: Full Textmentioning

confidence: 99%

Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

Halliez

Chesnais

Mallucci

et al. 2013

Journal of General Virology

View full text Add to dashboard Cite

Chantier qualité GAIn naturally acquired transmissible spongiform encephalopathies, the pathogenic agents or prions spread from the sites of initial peripheral uptake or replication to the brain where they cause progressive and fatal neurodegeneration. Routing via the peripheral nervous system is considered to be one of the main pathways to the central nervous system. Replication of prions in Schwann cells is viewed as a potentially important mechanism for efficient prion spread along nerves. Here we used a Cre-loxP mouse transgenetic approach to disrupt host-encoded prion protein (PrP(C)) specifically in myelinating Schwann cells. Despite the use of infection routes targeting highly myelinated nerves, there was no alteration in mouse prion pathogenesis, suggesting that conversion-dependent, centripetal spread of prions does not crucially rely on PrP(C) expressed by myelinating Schwann cells

show abstract

Dramatic Reduction of PrP^CLevel and Glycosylation in Peripheral Nerves following PrP Knock-Out from Schwann Cells Does Not Prevent Transmissible Spongiform Encephalopathy Neuroinvasion

Cited by 14 publications

References 47 publications

Prion Propagation in Cells Expressing PrP Glycosylation Mutants

Prion Propagation in Cells Expressing PrP Glycosylation Mutants

Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration

Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

Contact Info

Product

Resources

About

Dramatic Reduction of PrPCLevel and Glycosylation in Peripheral Nerves following PrP Knock-Out from Schwann Cells Does Not Prevent Transmissible Spongiform Encephalopathy Neuroinvasion

Cited by 14 publications

References 47 publications

Prion Propagation in Cells Expressing PrP Glycosylation Mutants

Prion Propagation in Cells Expressing PrP Glycosylation Mutants

Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration

Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

Contact Info

Product

Resources

About

Dramatic Reduction of PrP^CLevel and Glycosylation in Peripheral Nerves following PrP Knock-Out from Schwann Cells Does Not Prevent Transmissible Spongiform Encephalopathy Neuroinvasion