title: Stimulating the Release of Exosomes Increases the Intercellular Transfer of Prions.
abstract: Exosomes are small extracellular vesicles released by cells and play important roles in intercellular communication and pathogen transfer. Exosomes have been implicated in several neurodegenerative diseases, including prion disease and Alzheimer disease. Prion disease arises upon misfolding of the normal cellular prion protein, PrP(C), into the disease-associated isoform, PrP(Sc). The disease has a unique transmissible etiology, and exosomes represent a novel and efficient method for prion transmission. The precise mechanism by which prions are transmitted from cell to cell remains to be fully elucidated, although three hypotheses have been proposed: direct cell-cell contact, tunneling nanotubes, and exosomes. Given the reported presence of exosomes in biological fluids and in the lipid and nucleic acid contents of exosomes, these vesicles represent an ideal mechanism for encapsulating prions and potential cofactors to facilitate prion transmission. This study investigates the relationship between exosome release and intercellular prion dissemination. Stimulation of exosome release through treatment with an ionophore, monensin, revealed a corresponding increase in intercellular transfer of prion infectivity. Conversely, inhibition of exosome release using GW4869 to target the neutral sphingomyelinase pathway induced a decrease in intercellular prion transmission. Further examination of the effect of monensin on PrP conversion revealed that monensin also alters the conformational stability of PrP(C), leading to increased generation of proteinase K-resistant prion protein. The findings presented here provide support for a positive relationship between exosome release and intercellular transfer of prion infectivity, highlighting an integral role for exosomes in facilitating the unique transmissible nature of prions.
authors.affiliation: From the Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia and.
authors.forename: Belinda B
authors.initials: BB
authors.lastname: Guo
authors.affiliation: From the Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia and.
authors.forename: Shayne A
authors.initials: SA
authors.lastname: Bellingham
authors.affiliation: From the Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia and the Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia andrew.hill@latrobe.edu.au.
authors.forename: Andrew F
authors.identifier: http://orcid.org/0000-0001-5581-2354
authors.initials: AF
authors.lastname: Hill
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008985:Monensin / Q000494:pharmacology; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D011817:Rabbits
chemical_list: D000814:Aniline Compounds; D001597:Benzylidene Compounds; C468773:GW 4869; D011328:Prions; D008985:Monensin
keywords: cell biology; exosome (vesicle); exosomes; extracellular vesicles; monensin; neutral sphingomy; neutral sphingomyelinase; prion; prion disease; transwell