title: Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates.
abstract: Extracellular vesicles (EVs) are actively secreted, membrane-bound communication vehicles that exchange biomolecules between cells. EVs also serve as dissemination vehicles for pathogens, including prions, proteinaceous infectious agents that cause transmissible spongiform encephalopathies (TSEs) in mammals. Increasing evidence accumulates that diverse protein aggregates associated with common neurodegenerative diseases are packaged into EVs as well. Vesicle-mediated intercellular transmission of protein aggregates can induce aggregation of homotypic proteins in acceptor cells and might thereby contribute to disease progression. Our knowledge of how protein aggregates are sorted into EVs and how these vesicles adhere to and fuse with target cells is limited. Here we review how TSE prions exploit EVs for intercellular transmission and compare this to the transmission behavior of self-templating cytosolic protein aggregates derived from the yeast prion domain Sup 35 NM. Artificial NM prions are non-toxic to mammalian cell cultures and do not cause loss-of-function phenotypes. Importantly, NM particles are also secreted in association with exosomes that horizontally transmit the prion phenotype to naive bystander cells, a process that can be monitored with high accuracy by automated high throughput confocal microscopy. The high abundance of mammalian proteins with amino acid stretches compositionally similar to yeast prion domains makes the NM cell model an attractive model to study self-templating and dissemination properties of proteins with prion-like domains in the mammalian context.
authors.affiliation: a German Center for Neurodegenerative Diseases (DZNE e.V.) , Bonn , Germany.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.affiliation: a German Center for Neurodegenerative Diseases (DZNE e.V.) , Bonn , Germany.
authors.forename: André
authors.initials: A
authors.lastname: Hossinger
authors.affiliation: a German Center for Neurodegenerative Diseases (DZNE e.V.) , Bonn , Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Göbbels
authors.affiliation: a German Center for Neurodegenerative Diseases (DZNE e.V.) , Bonn , Germany.|b Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn , Germany.
authors.forename: Ina M
authors.initials: IM
authors.lastname: Vorberg
mesh_terms: D000818:Animals; D000067128:Extracellular Vesicles / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D010454:Peptide Termination Factors / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology*; D011328:Prions / Q000378:metabolism* / Q000472:pathogenicity*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D010454:Peptide Termination Factors; D011328:Prions; D066329:Protein Aggregates; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins
keywords: exosome; extracellular vesicles; prion; spreading