Vesicle-mediated secretion of misfolded prion protein molecules from cyclosporin A-treated cells

Ieshita Pan, Noa Roitenberg, Ehud Cohen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Loss of protein homeostasis is a hazardous situation that jeopardizes cellular functionality and viability. Cells have developedmechanisms that supervise protein integrity and directmisfolded molecules for degradation. Nevertheless, subsets of aggregation-prone proteins escape degradation and form aggregates that can underlie the development of neurodegenerative disorders. In some cases, cells deposit hazardous protein aggregates in designated sites, like aggresomes, or secrete them with vesicles. The prion protein (PrP) is an aggregation-prone, membrane-anchored glycoprotein, whose aggregation causes familial and sporadic, fatal, neurodegenerative diseases. The proper maturation of PrP is assisted by cyclophilin B, an endoplasmic reticulum-resident foldase. Accordingly, the inhibition of cyclophilinsby the drug cyclosporinA(CsA) leads tothe accumulation of aggregatedPrP and to its deposition in aggresomes. In this study, we asked whether secretion is an alternative strategy that cells adopt to get rid ofmisfolded PrPmolecules and found that, upon treatmentwithCsA, cells secrete PrP by exosomes, a subtype of secretion vesicles, and by additional types of vesicles.CsA-induced, PrP-containing exosomes originate from the endoplasmic reticulum in a Golgi-independent manner. These findings divulge a new cellular response that is activateduponCsAtreatment to secretemisfoldedPrPspecies fromthe cell andmayunderlie the spreading of toxic prions among cells and across tissues.

Original languageAmerican English
Pages (from-to)1479-1492
Number of pages14
JournalFASEB Journal
Volume32
Issue number3
DOIs
StatePublished - Mar 2018

Bibliographical note

Publisher Copyright:
© FASEB.

Keywords

  • Exosome
  • Neurodegeneration
  • PrP
  • Proteotoxicity

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