title: Iron content of ferritin modulates its uptake by intestinal epithelium: implications for co-transport of prions.
abstract: The spread of Chronic Wasting Disease (CWD) in the deer and elk population has caused serious public health concerns due to its potential to infect farm animals and humans. Like other prion disorders such a sporadic Creutzfeldt-Jakob-disease of humans and Mad Cow Disease of cattle, CWD is caused by PrP-scrapie (PrPSc), a beta-sheet rich isoform of a normal cell surface glycoprotein, the prion protein (PrPC). Since PrPSc is sufficient to cause infection and neurotoxicity if ingested by a susceptible host, it is important to understand the mechanism by which it crosses the stringent epithelial cell barrier of the small intestine. Possible mechanisms include co-transport with ferritin in ingested food and uptake by dendritic cells. Since ferritin is ubiquitously expressed and shares considerable homology among species, co-transport of PrPSc with ferritin can result in cross-species spread with deleterious consequences. We have used a combination of in vitro and in vivo models of intestinal epithelial cell barrier to understand the role of ferritin in mediating PrPSc uptake and transport. In this report, we demonstrate that PrPSc and ferritin from CWD affected deer and elk brains and scrapie from sheep resist degradation by digestive enzymes, and are transcytosed across a tight monolayer of human epithelial cells with significant efficiency. Likewise, ferritin from hamster brains is taken up by mouse intestinal epithelial cells in vivo, indicating that uptake of ferritin is not limited by species differences as described for prions. More importantly, the iron content of ferritin determines its efficiency of uptake and transport by Caco-2 cells and mouse models, providing insight into the mechanism(s) of ferritin and PrPSc uptake by intestinal epithelial cells.
authors.affiliation: Department of Pathology, Wolstein Research Building, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH- 44106, USA. neena.singh@case.edu.
authors.forename: Solomon Raju
authors.initials: SR
authors.lastname: Bhupanapadu Sunkesula
authors.forename: Xiu
authors.initials: X
authors.lastname: Luo
authors.forename: Dola
authors.initials: D
authors.lastname: Das
authors.forename: Ajay
authors.initials: A
authors.lastname: Singh
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018938:Caco-2 Cells; D002417:Cattle; D004705:Endocytosis; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D004798:Enzymes / Q000378:metabolism; D005293:Ferritins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D021381:Protein Transport; D012756:Sheep; D034081:Wasting Disease, Chronic / Q000378:metabolism
chemical_list: D004798:Enzymes; D018620:PrPSc Proteins; D011328:Prions; D005293:Ferritins; D007501:Iron