Protease-Resistant Human Prion Protein and Ferritin Are Cotransported across Caco-2 Epithelial Cells: Implications for Species Barrier in Prion Uptake from the Intestine

Mishra, Ravi Shankar; Basu, Subhabrata; Gu, Yixuan; Luo, Xiaohua; Zou, Wen; Mishra, Richa; Li, Ruliang; Chen, Shu G.; Gambetti, Pierluigi; Fujioka, Hisashi; Singh, Neena

doi:10.1523/jneurosci.2864-04.2004

Cited by 95 publications

(91 citation statements)

References 41 publications

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“…Ferritin has recently been shown to be prominently cotransported with protease-resistant PrP [23]. Iron, while always found associated with amyloid-b deposits in AD, is also in PrP in GSS and vCJD, independent of concomitant amyloid-b deposition.…”

Section: Discussionmentioning

confidence: 99%

Redox metals and oxidative abnormalities in human prion diseases

et al. 2005

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Prion diseases are characterized by the accumulation of diffuse and aggregated plaques of proteaseresistant prion protein (PrP) in the brains of affected individuals and animals. Whereas prion diseases in animals appear to be almost exclusively transmitted by infection, human prion diseases most often occur sporadically and, to a lesser extent, by inheritance or infection. In the sporadic cases (sporadic CreutzfeldJakob disease, sCJD), PrP-containing plaques are infrequent, whereas in transmitted (variant CJD) and inherited (Gerstmann-Straussler-Scheinker Syndrome) cases, plaques are a usual feature. In the current study, representative cases from each of the classes of human prion disease were analyzed for the presence of markers of oxidative damage that have been found in other neurodegenerative diseases. Interestingly, we found that the pattern of deposition of PrP, amyloid-b, and redox active metals was distinct for the various prion diseases. Whereas 8-hydroxyguanosine has been shown to be increased in sCJD, and inducible NOS is increased in scrapie-infected mice, well-studied markers of oxidative damage that accumulate in the lesions of other neurodegenerative diseases (such as Alzheimer's disease, progressive supranuclear palsy, and Parkinson's disease), such as heme oxygenase-1 and lipid peroxidation, were not found around PrP deposits or in vulnerable neurons. These findings suggest an important distinction in prionrelated oxidative stress, indicating that different neurodegenerative pathways are involved in different prion diseases.

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Section: Discussionmentioning

confidence: 99%

Redox metals and oxidative abnormalities in human prion diseases

et al. 2005

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“…Digestive enzymes can break down the infectious agent into smaller molecules of PrP Sc or even into the protease resistant core of PrP Sc . Such smaller fragments can then form complexes with other proteins like ferritin and get endocytosed in vesicular structures by a ferritin dependent mechanism [44]. A third possible route could be through direct uptake by dendritic cells that can open up the tight junctions between epithelial cells and capture antigens by inserting their dendritic processes into the gut lumen [54,55].…”

Section: Crossing the Mucosal Barriermentioning

confidence: 99%

TSE pathogenesis in cattle and sheep

2008

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-Many studies have been undertaken in rodents to study the pathogenesis of transmissible spongiform encephalopathies (TSE). Only a few studies have focused on the pathogenesis of bovine spongiform encephalopathy (BSE) and scrapie in their natural hosts. In this review, we summarize the most recent insights into the pathogenesis of BSE and scrapie starting from the initial uptake of TSE agents and crossing of the gut epithelium. Following replication in the gut-associated lymphoid tissues (GALT), TSE agents spread to the enteric nervous system (ENS) of the gut. Infection is then carried through the efferent fibers of the post-ganglionic neurons of the parasympathetic and sympathetic nervous system to the pre-ganglionic neurons in the medulla oblongata of the brain and the thoracic segments of the spinal cord. The differences between the pathogenesis of BSE in cattle and scrapie in sheep are discussed as well as the possible existence of additional pathogenetic routes.

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“…However, PrP-sen differs dramatically from PrP-res in its biophysical properties, turnover, and subcellular distribution and might not be trafficked by neurons in the same way. 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: 99%

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

Magalhães¹,

Baron²,

Lee³

et al. 2005

J. Neurosci.

139

144

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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.

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Protease-Resistant Human Prion Protein and Ferritin Are Cotransported across Caco-2 Epithelial Cells: Implications for Species Barrier in Prion Uptake from the Intestine

Cited by 95 publications

References 41 publications

Redox metals and oxidative abnormalities in human prion diseases

Redox metals and oxidative abnormalities in human prion diseases

TSE pathogenesis in cattle and sheep

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

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