PrPSc Incorporation to Cells Requires Endogenous Glycosaminoglycan Expression

Hijazi, Nuha; Kariv-Inbal, Zehavit; Gasset, Marı́a; Gabizon, Ruth

doi:10.1074/jbc.m411314200

Cited by 79 publications

(84 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The enzymatic removal of cell surface heparan sulphates [58], the inhibition of their sulphation by chlorate [58] or competition with heparan mimetics [58,126] all prevented the binding and the uptake of detergent-extracted, aggregated forms of abnormal PrP in N2a, GT1, and CHO cells. A similar observation was reported for PrP Sc from brain homogenate in CHO cells [55]. Finally, Paquet et al demonstrated an efficient entry of abnormal PrP in permissive Rov cells by mechanisms that apparently did not rely on cellular heparan sulphates [98].…”

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

confidence: 71%

“…Other studies used infected brain tissues homogenised in physiological buffers, arguing that PK-digested, highly aggregated forms have poor biological relevance. Despite varying experimental conditions which may hinder comparisons among them, all of these studies have shown that PrP Sc is internalised by a process that does not require the presence of PrP C at the cell surface [55,81,98]. The identification of putative cellular receptors for PrP Sc led to a different outcome.…”

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

confidence: 99%

See 1 more Smart Citation

Cell models of prion infection

Vilette

2007

Vet. Res.

View full text Add to dashboard Cite

-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.

show abstract

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

confidence: 71%

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

confidence: 99%

Cell models of prion infection

Vilette

2007

Vet. Res.

View full text Add to dashboard Cite

show abstract

“…In vitro, GAG facilitates the conversion of PrP C to PrP Sc (35). Cell surface GAG is a ''receptor'' for PrP Sc (32,33). were approximately four times higher than in Tg(PG14).…”

Section: Discussionmentioning

confidence: 96%

“…Several lines of in vitro and in vivo evidences suggest that binding of PrP to GAG is important in the conversion process, and thus critical for pathogenesis (30)(31)(32)(33). PrP Sc in vivo contains GAG (34).…”

Section: Discussionmentioning

confidence: 99%

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans

Yin

Pham

et al. 2007

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

View full text Add to dashboard Cite

Mutation in the prion gene PRNP accounts for 10 -15% of human prion diseases. However, little is known about the mechanisms by which mutant prion proteins (PrPs) cause disease. Here we investigated the effects of 10 different pathogenic mutations on the conformation and ligand-binding activity of recombinant human PrP (rPrP). We found that mutant rPrPs react more strongly with N terminus-specific antibodies, indicative of a more exposed N terminus. The N terminus of PrP contains a glycosaminoglycan (GAG)-binding motif. Binding of GAG is important in prion disease. Accordingly, all mutant rPrPs bind more GAG, and GAG promotes the aggregation of mutant rPrPs more efficiently than wild-type recombinant normal cellular PrP (rPrP C ). Furthermore, point mutations in PRNP also cause conformational changes in the region between residues 109 and 136, resulting in the exposure of a second, normally buried, GAG-binding motif. Importantly, brainderived PrP from transgenic mice, which express a pathogenic mutant with nine extra octapeptide repeats, also binds more strongly to GAG than wild-type PrP C . Thus, several rPrPs with distinct pathogenic mutations have common conformational changes, which enhance binding to GAG. These changes may contribute to the pathogenesis of inherited prion diseases.genetics ͉ structure

show abstract

“…In epithelial cells, PrP-res appears to be cotransported with ferritin by a receptor-or transporter-mediated pathway (Mishra et al, 2004). Other recent work shows that heparan sulfate molecules are in-volved but not always essential for PrP-res uptake by several cell types (Hijazi et al, 2005;Horonchik et al, 2005).…”

Section: Introductionmentioning

confidence: 96%

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

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.

show abstract

PrPSc Incorporation to Cells Requires Endogenous Glycosaminoglycan Expression

Cited by 79 publications

References 33 publications

Cell models of prion infection

Cell models of prion infection

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans

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

Contact Info

Product

Resources

About