title: Recognition of lumenal prion protein aggregates by post-ER quality control mechanisms is mediated by the preoctarepeat region of PrP.
abstract: Prion diseases are fatal transmissible neurodegenerative disorders linked to an aberrant conformation of the cellular prion protein (PrP(c)). We have shown previously that the chemical compound suramin induced aggregation of fully matured PrP(c) in post-ER compartments, thereby, activating a post-ER quality control mechanism and preventing cell surface localization of PrP by intracellular re-routing of aggregated PrP from the Golgi/TGN directly to lysosomes. Of note, drug-induced PrP aggregates were not toxic and could easily be degraded by neuronal cells. Here, we focused on determining the PrP domains mediating these effects. Using PrP deletion mutants we show that intracellular re-routing but not aggregation depends on the N-terminal PrP (aa 23-90) and, more precisely, on the preoctarepeat domain (aa 23-50). Fusion of the PrP N-terminus to the GPI-anchored protein Thy-1 did not cause aggregation or re-routing of the chimeric protein, indicating that the N-terminus is only active in re-routing when prion protein aggregation occurs. Insertion of a region with a comparable primary structure contained in the PrP paralogue prnd/doppel (aa 27-50) into N-terminally deleted PrP re-established the re-routing phenotype. Our data reveal an important role for the conserved preoctarepeat region of PrP, namely controlling the intracellular trafficking of misfolded PrP.
authors.affiliation: Institute of Virology, Prion Research Group, Technical University of Munich, Biedersteiner Str. 29, D-80802 Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gilch
authors.forename: Max
authors.initials: M
authors.lastname: Nunziante
authors.forename: Alexa
authors.initials: A
authors.lastname: Ertmer
authors.forename: Franziska
authors.initials: F
authors.lastname: Wopfner
authors.forename: Lajos
authors.initials: L
authors.lastname: Laszlo
authors.forename: Hermann M
authors.initials: HM
authors.lastname: Schätzl
mesh_terms: D000818:Animals; D002417:Cattle; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D011328:Prions / Q000378:metabolism*; D017510:Protein Folding; D021381:Protein Transport / Q000502:physiology
chemical_list: D011328:Prions