Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J Pathol

Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
The Journal of Pathology (Impact Factor: 7.43). 04/2007; 211(5):582-90. DOI: 10.1002/path.2145
Source: PubMed

ABSTRACT Prion diseases are fatal, transmissible neurodegenerative disorders associated with conversion of the host-encoded prion protein (PrP(C)) into an abnormal pathogenic isoform (PrP(Sc)). Following exposure to the infectious agent (PrP(Sc)) in acquired disease, infection is propagated in lymphoid tissues prior to neuroinvasion and spread within the central nervous system. The mechanism of prion dissemination is perplexing due to the lack of plausible PrP(Sc)-containing mobile cells that could account for prion spread between infected and uninfected tissues. Evidence exists to demonstrate that the culture media of prion-infected neuronal cells contain PrP(Sc) and infectivity but the nature of the infectivity remains unknown. In this study we have identified PrP(C) and PrP(Sc) in association with endogenously expressing PrP neuronal cell-derived exosomes. The exosomes from our prion-infected neuronal cell line were efficient initiators of prion propagation in uninfected recipient cells and to non-neuronal cells. Moreover, our neuronal cell line was susceptible to infection by non-neuronal cell-derived exosome PrP(Sc). Importantly, these exosomes produced prion disease when inoculated into mice. Exosome-associated PrP is packaged via a novel processing pathway that involves the N-terminal modification of PrP and selection of distinct PrP glycoforms for incorporation into these vesicles. These data extend our understanding of the relationship between PrP and exosomes by showing that exosomes can establish infection in both neighbouring and distant cell types and highlight the potential contribution of differentially processed forms of PrP in disease distribution. These data suggest that exosomes represent a potent pool of prion infectivity and provide a mechanism for studying prion spread and PrP processing in cells endogenously expressing PrP.

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    • "Depending on the cell or tissue of origin, many different roles and functions have been attributed to exosomes—to name a few: eradication of obsolete molecules, facilitation of the immune response (Théry et al. 2009), antigen presentation, programmed cell death, angiogenesis, inflammation, coagulation , dissemination of oncogenes from tumor cells, and spread of pathogens such as prions and viruses from one cell to another (Vella et al. 2007). Most importantly, exosomes have been shown to deliver macromolecular messages (RNA and protein), enabling cell-to-cell communication and signaling (Vlassov et al. 2012). "
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    ABSTRACT: Exosomes are tiny vesicles (diameter 30-150 nm) secreted by cells in culture and found in all body fluids. These vesicles, loaded with unique RNA and protein cargos, have many biological functions, of which only a small fraction is currently understood-for example, they participate in cell-to-cell communication and signaling within the human body. The spectrum of current scientific interest in exosomes is wide and ranges from understanding their functions and pathways to using them in diagnostics, as biomarkers, and in the development of therapeutics. Here we provide an overview of different strategies for isolation of exosomes from cell-culture media and body fluids. © 2015 Cold Spring Harbor Laboratory Press.
    Cold Spring Harbor Protocols 04/2015; 2015(4):pdb.top074476. DOI:10.1101/pdb.top074476 · 4.63 Impact Factor
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    • "It seems that the exosome-mediated secretion of amyloidassociated proteins is an organized process, as it can be triggered by determinate signaling events, such as calcium release (Emmanouilidou et al., 2010), or platelet activation (Robertson et al., 2006). Of fundamental importance, PrP sc or aSyn oligomers isolated from exosomes retain full toxicity, suggesting that these organelles can indeed serve as infectious vehicles (Fevrier et al., 2004; Vella et al., 2007; Danzer et al., 2012). "
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    ABSTRACT: Many neurodegenerative disorders are linked to irreversible protein aggregation, a process that usually comes along with toxicity and serious cellular damage. However, it is emerging that protein aggregation can also serve for physiological purposes, as impressively shown for prions. While the aggregation of this protein family was initially considered exclusively toxic in mammalians organisms, it is now almost clear that many other proteins adopt prion-like attributes to rationally polymerize into higher order complexes with organized physiologic roles. This implies that cells can tolerate at least in some measure the accumulation of inherently dangerous protein aggregates for functional profit. This review summarizes currently known strategies that living organisms adopt to preserve beneficial aggregation, and to prevent the catastrophic accumulation of toxic aggregates that frequently accompany neurodegeneration.
    Frontiers in Cellular Neuroscience 02/2015; 9. DOI:10.3389/fncel.2015.00045 · 4.29 Impact Factor
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    • "Moreover, exosomes from infected neuronal cells have been described as being more spherical in shape, but diverse in size and internal structure (Coleman et al. 2012), while infected platelets are described as releasing PrP Sc via both microvesicles and exosomes (Robertson et al. 2006). In the case of the neuronal cell line, prion packaging into exosomes is believed to involve N-terminal modifications to a distinct subtype of PrP glycoforms (Vella et al. 2007). "
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    ABSTRACT: Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs-or specific EV cargoes-are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases.
    Biogerontology 06/2014; 16(2). DOI:10.1007/s10522-014-9510-7 · 3.29 Impact Factor
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