title: Disease-associated prion protein oligomers inhibit the 26S proteasome.
abstract: The mechanism of cell death in prion disease is unknown but is associated with the production of a misfolded conformer of the prion protein. We report that disease-associated prion protein specifically inhibits the proteolytic beta subunits of the 26S proteasome. Using reporter substrates, fluorogenic peptides, and an activity probe for the beta subunits, this inhibitory effect was demonstrated in pure 26S proteasome and three different cell lines. By challenge with recombinant prion and other amyloidogenic proteins, we demonstrate that only the prion protein in a nonnative beta sheet conformation inhibits the 26S proteasome at stoichiometric concentrations. Preincubation with an antibody specific for aggregation intermediates abrogates this inhibition, consistent with an oligomeric species mediating this effect. We also present evidence for a direct relationship between prion neuropathology and impairment of the ubiquitin-proteasome system (UPS) in prion-infected UPS-reporter mice. Together, these data suggest a mechanism for intracellular neurotoxicity mediated by oligomers of misfolded prion protein.
authors.affiliation: MRC Prion Unit, Institute of Neurology, University College London, Queen Square, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Kristiansen
authors.forename: Pelagia
authors.initials: P
authors.lastname: Deriziotis
authors.forename: Derek E
authors.initials: DE
authors.lastname: Dimcheff
authors.forename: Graham S
authors.initials: GS
authors.lastname: Jackson
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.forename: Heike
authors.initials: H
authors.lastname: Naumann
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Clarke
authors.forename: Fijs W B
authors.initials: FW
authors.lastname: van Leeuwen
authors.forename: Victoria
authors.initials: V
authors.lastname: Menéndez-Benito
authors.forename: Nico P
authors.initials: NP
authors.lastname: Dantuma
authors.forename: John L
authors.initials: JL
authors.lastname: Portis
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D018620:PrPSc Proteins / Q000737:chemistry / Q000633:toxicity; D017096:Prion Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D011328:Prions / Q000737:chemistry* / Q000633:toxicity*; D011480:Protease Inhibitors / Q000737:chemistry / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors; D011489:Protein Denaturation; D020836:Protein Structure, Quaternary; D021122:Protein Subunits; D011994:Recombinant Proteins / Q000737:chemistry / Q000633:toxicity; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018620:PrPSc Proteins; D011328:Prions; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D011994:Recombinant Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease