title: The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication.
abstract: Formation of aberrant protein conformers is a common pathological denominator of different neurodegenerative disorders, such as Alzheimer's disease or prion diseases. Moreover, increasing evidence indicates that soluble oligomers are associated with early pathological alterations and that oligomeric assemblies of different disease-associated proteins may share common structural features. Previous studies revealed that toxic effects of the scrapie prion protein (PrP(Sc)), a β-sheet-rich isoform of the cellular PrP (PrP(C)), are dependent on neuronal expression of PrP(C). In this study, we demonstrate that PrP(C) has a more general effect in mediating neurotoxic signalling by sensitizing cells to toxic effects of various β-sheet-rich (β) conformers of completely different origins, formed by (i) heterologous PrP, (ii) amyloid β-peptide, (iii) yeast prion proteins or (iv) designed β-peptides. Toxic signalling via PrP(C) requires the intrinsically disordered N-terminal domain (N-PrP) and the GPI anchor of PrP. We found that the N-terminal domain is important for mediating the interaction of PrP(C) with β-conformers. Interestingly, a secreted version of N-PrP associated with β-conformers and antagonized their toxic signalling via PrP(C). Moreover, PrP(C)-mediated toxic signalling could be blocked by an NMDA receptor antagonist or an oligomer-specific antibody. Our study indicates that PrP(C) can mediate toxic signalling of various β-sheet-rich conformers independent of infectious prion propagation, suggesting a pathophysiological role of the prion protein beyond of prion diseases.
authors: Department of Metabolic Biochemistry, Neurobiochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University Munich, Munich, Germany.
authors: Ulrike K
authors: UK
authors: Resenberger
authors: Anja
authors: A
authors: Harmeier
authors: Andreas C
authors: AC
authors: Woerner
authors: Jessica L
authors: JL
authors: Goodman
authors: Veronika
authors: V
authors: Müller
authors: Rajaraman
authors: R
authors: Krishnan
authors: R Martin
authors: RM
authors: Vabulas
authors: Hans A
authors: HA
authors: Kretzschmar
authors: Susan
authors: S
authors: Lindquist
authors: F Ulrich
authors: FU
authors: Hartl
authors: Gerd
authors: G
authors: Multhaup
authors: Konstanze F
authors: KF
authors: Winklhofer
authors: Jörg
authors: J
authors: Tatzelt
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D016923:Cell Death; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D017096:Prion Diseases / Q000473:pathology*; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D018621:PrPC Proteins; D029701:Saccharomyces cerevisiae Proteins