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Abstract
Cellular prion protein (PrPc) is a physiological constituent of eukaryotic cells. The cellular pathways underlying prions spread from the sites of prions infection/peripheral replication to the central nervous system are still not elucidated. Membrane-derived microvesicles (MVs) are submicron (0.1–1 µm) particles, that are released by cells during plasma membrane shedding processes. They are usually liberated from different cell types, mainly upon activation as well as apoptosis, in this case, one of their hallmarks is the exposure of phosphatidylserine in the outer leaflet of the membrane. MVs are also characterized by the presence of adhesion molecules, MHC I molecules, as well as of membrane antigens typical of their cell of origin. Evidence exists that MVs shedding provide vehicles to transfer molecules among cells, and that MVs are important modulators of cell-to-cell communication. In this study we therefore analyzed the potential role of membrane-derived MVs in the mechanism(s) of PrPC diffusion and prion infectivity transmission. We first identified PrPC in association with the lipid raft components Fyn, flotillin-2, GM1 and GM3 in MVs from plasma of healthy human donors. Similar findings were found in MVs from cell culture supernatants of murine neuronal cells. Furthermore we demonstrated that PrPSc is released from infected murine neuronal cells in association with plasma membrane-derived MVs and that PrPSc-bearing MVs are infectious both in vitro and in vivo. The data suggest that MVs may contribute both to the intercellular mechanism(s) of PrPC diffusion and signaling as well as to the process of prion spread and neuroinvasion.
Highlights
Prion diseases are a complex group of fatal neurodegenerative disorders that affect humans and a wide variety of animals and are characterized by strong neuronal cell loss, spongiform vacuolation and astrocytic proliferation [1]
Prion diseases are typically initiated by infection of peripheral sites, as in the case of bovine spongiform encephalopathy (BSE), variant Creutzfeldt– Jakob disease, Kuru, and most cases of iatrogenic Creutzfeldt–Jakob disease
To investigate the presence of PrPC in cell membrane-derived MVs from plasma obtained from healthy human peripheral blood donors, MVs were isolated by sequential centrifugations from platelet-free plasma preparations
Summary
Prion diseases are a complex group of fatal neurodegenerative disorders that affect humans and a wide variety of animals and are characterized by strong neuronal cell loss, spongiform vacuolation and astrocytic proliferation [1]. Prions accumulate in the central and peripheral nervous system and in extracerebral compartments, such as secondary lymphoid organs and muscles. The only organ system in which severe histopathological damage can be demonstrated as a consequence of infection with prions is the nervous system. Prion diseases are typically initiated by infection of peripheral sites, as in the case of bovine spongiform encephalopathy (BSE), variant Creutzfeldt– Jakob disease (vCJD), Kuru, and most cases of iatrogenic Creutzfeldt–Jakob disease (iCJD). The mechanisms by which prions spread from the site of peripheral exposure, such as the gastrointestinal tract, to the lymphoreticular system where a first replication phase occurs and subsequently to and within the central nervous system are still not completely elucidated [3,4,5]
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