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

Abstract

Loss of protein homeostasis is a hazardous situation that jeopardizes cellular functionality and viability. Cells have developed mechanisms that supervise protein integrity and direct misfolded 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 cyclophilins by the drug cyclosporin A (CsA) leads to the accumulation of aggregated PrP and to its deposition in aggresomes. In this study, we asked whether secretion is an alternative strategy that cells adopt to get rid of misfolded PrP molecules and found that, upon treatment with CsA, 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 activated upon CsA treatment to secrete misfolded PrP species from the cell and may underlie the spreading of toxic prions among cells and across tissues.-Pan, I., Roitenberg, N., Cohen, E. Vesicle-mediated secretion of misfolded prion protein molecules from cyclosporin A-treated cells.

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

“…Moreover, it was shown that these exosomal prion proteins retained their infectivity (Arellano-Anaya et al, 2015). Pan et al observed that prion proteins were secreted in exosomes upon inhibition of cyclophillins by the immunosuppressive agent cyclosporine A, which usually leads to an accumulation of aggregated PrP sc and its deposition in aggresomes in N2a and Chinese hamster ovary cells (Pan et al, 2018). The presented studies strongly indicate that different prion protein species are secreted via exosomes and therefore contribute, possibly to a high extent, to the spread of the misfolded, pathogenic protein in prion diseases.…”

The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

“…The highest fold increase is seen in the cyclophilin family of peptidyl-prolyl isomerases PPIA, PPIB and FKBP2. Interestingly, inhibition or deficiency of PPIA results in increased aggregation and faster disease progression in models for prion disease [1,49]. Other, mainly ER resident, protein folding associated proteins maintain normal expression in GVD but decrease in tangle bearing neurons (Fig.…”

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury

“…Specifically, EVs have been linked to important biological functions, such as cell-to-cell signaling pathways associated with inflammatory responses and removal of aggregated and misfolded proteins within the brain (129,143). Moreover, EVs can cross the BBB and their membrane provides protection to proteins and nucleic acids, likely reducing their degradation in the peripheral circulation (163)(164)(165)(166).…”