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’s disease. Prion disease arises upon misfolding of the normal cellular prion protein, PrPC, into the disease-associated isoform, PrPSc. The disease has a unique transmissible aetiology and exosomes represent a novel and efficient method for prion transmission. The precise mechanism by which prions are transmitted from cell to cell remains yet to be fully elucidated, although three hypotheses have been proposed: direct cell-cell contact, tunnelling nanotubes and exosomes. Given the reported presence of exosomes in biological fluids as well as the lipid and nucleic acid contents of exosomes, these vesicles represent an ideal mechanism for encapsulating prions and potential cofactors to facilitate prion transmission.
A recent study by researchers at the University of Melbourne investigated 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 PrPC leading to increased generation of PK-resistant PrP.
Successful intercellular transmission of prions across transwell membranes.
(A) A schematic diagram depicting the set up for a transwell assay with a non-infected population of cells (recipient; blue) separated from a prion-infected population (donor; red) by a membrane with 0.4 μm pores. (B) Cell blot assay confirming presence of PrPSc and transmission of prion infection to recipient cells via the transwell assay.
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.