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The role of the ESCRT pathway in prion disease

Prion diseases are infectious neurodegenerative disorders caused by PrPSc, a misfolded and aggregated isoform of the cellular prion protein, PrPC. During late disease stages, PrPSc spreads through the CNS, causing neurodegeneration, gliosis, and ultimately death, however the mechanisms of prion cell to cell transport remain poorly defined. Here we investigated the role of exosomes in the intercellular spread of prions. Exosomes are extracellular nanovesicles that originate from the endosomal pathway and are important for intercellular communication, transporting proteins and mRNA to nearby cells. Exosomes harbor infectious prions isolated immortalized cell lines and mice, and these exosomes efficiently cause prion disease in mice. Exosomes are produced by the ESCRT pathway, an endosomal pathway consisting of four protein complexes functioning sequentially. Previous research has shown that knocking down components of this pathway reduce prion conversion and release in vitro. We hypothesize that prions exploit the exosome pathway as the primary mechanism of prion spread within the CNS. We have manipulated the ESCRT pathway in neuronal cells to understand its role in both prion conversion and spread in vitro. We have discovered that inhibiting the initial stages of prion entry into endosomes severely impacts both prion generation as well as autophagic degradation pathways.