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

ArticleinThe Journal of Pathology 211(5):582-90 · April 2007with20 Reads
Impact Factor: 7.43 · DOI: 10.1002/path.2145 · Source: PubMed

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.

    • "Notably, all of these proteins have shown a propensity to assume a prionlike behavior of changing the conformation of other proteins in tissue and propagate disease (Ghidoni et al., 2008; Coleman and Hill, 2015). Accordingly, the injection of exosomes containing prions induced prion propagation in wild-type recipient cells and induced prion disease when inoculated into mice (Fevrier et al., 2004; Vella et al., 2007 Vella et al., , 2008b). Similar EV toxicity was reported for α-synuclein in PD (Emmanouilidou et al., 2010) and for mutant SOD1 (Basso et al., 2013; Grad et al., 2014) and TDP-43 (Ding et al., 2015) in ALS. "
    [Show abstract] [Hide abstract] ABSTRACT: In numerous neurodegenerative diseases, the interplay between neurons and glia modulates the outcome and progression of pathology. One particularly intriguing mode of interaction between neurons, astrocytes, microglia, and oligodendrocytes is characterized by the release of extracellular vesicles that transport proteins, lipids, and nucleotides from one cell to another. Notably, several proteins that cause disease, including the prion protein and mutant SOD1, have been detected in glia-derived extracellular vesicles and observed to fuse with neurons and trigger pathology in vitro. Here we review the structural and functional characterization of such extracellular vesicles in neuron-glia interactions. Furthermore, we discuss possible mechanisms of extracellular vesicle biogenesis and release from activated glia and microglia, and their effects on neurons. Given that exosomes, the smallest type of extracellular vesicles, have been reported to recognize specific cellular populations and act as carriers of very specialized cargo, a thorough analysis of these vesicles may aid in their engineering in vitro and targeted delivery in vivo, opening opportunities for therapeutics.
    Full-text · Article · Mar 2016 · Frontiers in Neuroscience
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    • "The putative spread of these neurotoxic lesions has been proposed to be mediated by exosomes. An increasing number of studies has demonstrated that the propagation of the prion protein that occurs in prion diseases, such as Creutzfeldt-Jakob disease, is via an exosomal pathway [109,110]. The infectious prion protein replicates by recruiting and converting the cellular form of the prion protein (PrP c ) to the abnormal protein isoform (PrP sc ). "
    [Show abstract] [Hide abstract] ABSTRACT: Growing evidence indicates that small extracellular vesicles, called exosomes, are prominent mediators of neurodegenerative diseases such as prion, Alzheimer’s and Parkinson’s disease. Exosomes contain neurodegenerative disease associated proteins such as the prion protein, β-amyloid and α-synuclein. Only demonstrated so far in vivo with prion disease, exosomes are hypothesised to also facilitate the spread of β-amyloid and α-synuclein from their cells of origin to the extracellular environment. In the current review, we will discuss the role of exosomes in Alzheimer’s and Parkinson’s disease including their possible contribution to disease propagation and pathology and highlight their utility as a diagnostic in neurodegenerative disease.
    Full-text · Article · Feb 2016 · International Journal of Molecular Sciences
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    • "Ultrastructural studies confirmed the presence of both PrP C and PrP Sc in MVB, as well as in the late endosome, confirming the involvement of the exosomal pathway [169,170]. Furthermore, it has been reported that PrP Sc and PrP C are secreted in exosomes from a PrP-expressing neuronal cell line, and exosomes can spread PrP Sc in uninfected recipient [162]. Additionally, Fevrier and colleagues have also shown that the inoculation of ovine PrP Sc -positive EVs in the brain of transgenic mice that express ovine PrP induced acute neurological symptoms that eventually led to the death of all animals [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Extracellular vesicles (EVs) are a heterogeneous population of secreted membrane vesicles, with distinct biogenesis routes, biophysical properties and different functions both in physiological conditions and in disease. The release of EVs is a widespread biological process, which is conserved across species. In recent years, numerous studies have demonstrated that several bioactive molecules are trafficked with(in) EVs, such as microRNAs, mRNAs, proteins and lipids. The understanding of their final impact on the biology of specific target cells remains matter of intense debate in the field. Also, EVs have attracted great interest as potential novel cell-free therapeutics. Here we describe the proposed physiological and pathological functions of EVs, with a particular focus on their molecular content. Also, we discuss the advances in the knowledge of the mechanisms regulating the secretion of EV-associated molecules and the specific pathways activated upon interaction with the target cell, highlighting the role of EVs in the context of the immune system and as mediators of the intercellular signalling in the brain.
    Preview · Article · Feb 2016 · International Journal of Molecular Sciences
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