Chaperonin-mediated de novo generation of prion protein aggregates

Stöckel, J; Fu, Hartl

doi:10.1006/jmbi.2001.5085

Cited by 51 publications

(36 citation statements)

References 50 publications

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“…According to Watarai's hypothesis that host PrP binds to bacterial GroEL, in line with our previous results (16) also obtained by others (10,33), a direct interaction between bacterial chaperone and prion protein could be postulated. We considered that our negative result could be explained by the absence of GroEL on the surface of B. suis.…”

Section: Discussionsupporting

confidence: 92%

Absence of Evidence for the Participation of the Macrophage Cellular Prion Protein in Infection with Brucella suis

et al. 2005

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Brucella spp. are stealthy bacteria that enter host cells without major perturbation. The molecular mechanism involved is still poorly understood, although numerous studies have been published on this subject. Recently, it was reported that Brucella abortus utilizes cellular prion protein (PrP C ) to enter the cells and to reach its replicative niche. The molecular mechanisms involved were not clearly defined, prompting us to analyze this process using blocking antibodies against PrP C . However, the behavior of Brucella during cellular infection under these conditions was not modified. In a next step, the behavior of Brucella in macrophages lacking the prion gene and the infection of mice knocked out for the prion gene were studied. We observed no difference from results obtained with the wild-type control. Although some contacts between PrP C and Brucella were observed on the surface of the cells by using confocal microscopy, we could not show that Brucella specifically bound recombinant PrP C . Therefore, we concluded from our results that prion protein (PrP C ) was not involved in Brucella infection.

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Section: Discussionsupporting

confidence: 92%

Absence of Evidence for the Participation of the Macrophage Cellular Prion Protein in Infection with Brucella suis

et al. 2005

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“…Finally, because ERAD-PrP does not convert into a scrapie-like conformation in all cells, it is possible that some cytosolic factors allow or prevent PrP conversion. Chaperones GroEL, a close homolog of mammalian Hsp60, and Hsp104 promote the conversion of PrP into PrP Sc -like protein in vitro (25)(26)(27). Cytosolically Located PrP Is Not Toxic in All Neuronal Cell Types-Our results show that ERAD-PrP is not toxic to human primary neurons even when WtPrP or mutant PrPD178N, known to increase trafficking through the ERAD pathway, are overexpressed (5).…”

Section: Conversion Of Cytosolically Located Prp Into a Prp Sc -Like mentioning

confidence: 99%

Cytosolic Prion Protein Is Not Toxic and Protects against Bax-mediated Cell Death in Human Primary Neurons

Roucou

Guo

Zhang

et al. 2003

Journal of Biological Chemistry

157

155

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Recently, it was observed that reverse-translocated cytosolic PrP and PrP expressed in the cytosol induce rapid death in neurons (Ma, J., Wollmann, R., and Lindquist, S. (2002) Science 298, 1781-1785). In this study, we investigated whether accumulation of prion protein (PrP) in the cytosol is toxic to human neurons in primary culture. We show that in these neurons, a single PrP isoform lacking signal peptide accumulates in the cytosol of neurons treated with epoxomicin, a specific proteasome inhibitor. Therefore, endogenously expressed PrP is subject to the endoplasmic reticulumassociated degradation (ERAD) pathway and is degraded by the proteasome in human primary neurons. In contrast to its toxicity in N2a cells, reverse-translocated PrP (ERAD-PrP) is not toxic even when neurons are microinjected with cDNA constructs to overexpress either wild-type PrP or mutant PrPD178N. We found that ERAD-PrP in human neurons remains detergentsoluble and proteinase K-sensitive, in contrast to its detergent-insoluble and proteinase K-resistant state in N2a cells. Furthermore, not only is microinjection of a cDNA construct expressing CyPrP not toxic, it protects these neurons against Bax-mediated cell death. We conclude that in human neurons, ERAD-PrP is not converted naturally into a form reminiscent of scrapie PrP and that PrP located in the cytosol retains its protective function against Bax. Thus, it is unlikely that simple accumulation of PrP in the cytosol can cause neurodegeneration in prion diseases.

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“…However, application of the receptor concept for prion protein may be too restrictive, in view of the complexity of PrP c trafficking and conversion [85] Intracellular vesicles -Signalling a Pint1 [85] Unknown -Signalling a Caveolin-1 [87] Caveolae raft Signalling -b Plasminogen [76] Raft Plasminogen activator -b Plasminogen [75] Extracellular Unknown Unknown a CK2 [88] Caveolae raft CK2 activity modulator -a STI1 [80,81] Cell surface Neuroprotection and -signalling a Bcl-2 [91] Unknown Unknown Unknown c P75 [86] Caveolae raft Apoptosis -a Laminin [72,73] Cell surface Neurite outgrowth and -maintenance a GAG [68,69] Cell surface Unknown Unknown a N-CAM [77] Caveolae-like domain Unknown Unknown a,b GFAP [90] Unknown Unknown Unknown a,b Bip [89] Endoplasmic reticulum -Chaperoning a Hsp60 [64,65] Unknown -PrP aggregation a Nrf2 [78] Unknown Unknown Unknown a Aplp1 [78] Cell surface Unknown Unknown a Laminin receptor [71] Cell surface Internalisation -a Nucleic acid [66,67] Unknown -Chaperoning …”

Section: Scmentioning

confidence: 99%

Towards cellular receptors for prions

Lee

Linden

Prado

et al. 2003

Reviews in Medical Virology

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Transmissible spongiform encephalopathies (TSE) are attributed to the conversion of the cellular prion protein (PrP(c)) into an abnormal isoform (PrP(sc)). This can be caused by the invasion of living organisms by infectious particles, or be inherited due to mutations on the PrP(c) gene. One of the most intriguing problems of prion biology is the inability to generate the infectious agent in vitro. This argues strongly that other cellular proteins besides those added in test tubes or found in cellular preparations are necessary for infection. Despite recent progress in the understanding of prion pathology, the subcellular compartments in which the interaction and conversion of PrP(c) into PrP(sc) take place are still controversial. PrP(c) interacts with various macromolecules at the cell membrane, in endocytic compartments and in the secretory pathway, all of which may play specific roles in the internalisation of PrP(sc) and conversion of PrP(c). A specific interacting protein required for the propagation of prions was originally proposed as a prion receptor, and later referred to as a ligand, a cofactor, protein X, or a partner. However, current studies indicate that PrP(c) associates with multi-molecular complexes, which mediate a variety of functions in distinct cellular compartments. It is proposed that a deeper understanding of the mechanics of such interactions, coupled to a better knowledge of the corresponding signalling pathways and ensuing cellular responses, will have a major impact on the prevention and treatment of TSE.

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Chaperonin-mediated de novo generation of prion protein aggregates

Cited by 51 publications

References 50 publications

Absence of Evidence for the Participation of the Macrophage Cellular Prion Protein in Infection with Brucella suis

Absence of Evidence for the Participation of the Macrophage Cellular Prion Protein in Infection with Brucella suis

Cytosolic Prion Protein Is Not Toxic and Protects against Bax-mediated Cell Death in Human Primary Neurons

Towards cellular receptors for prions

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