Τίτλος:
Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS) induced the production of reactive oxygen species (ROS). Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion-infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT) of PrPC reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfolded protein response was activated in both models. Finally, 80% of transcriptionally downregulated genes overlapped between prion-infected and GDL-treated COCS. We conclude that GDL mimic the interaction of PrPSc with PrPC, thereby triggering the downstream events characteristic of prion infection. © 2015 Herrmann et al.
Συγγραφείς:
Herrmann, U.S.
Sonati, T.
Falsig, J.
Reimann, R.R.
Dametto, P.
O’Connor, T.
Li, B.
Lau, A.
Hornemann, S.
Sorce, S.
Wagner, U.
Sanoudou, D.
Aguzzi, A.
Περιοδικό:
PLoS Pathogens
Εκδότης:
Public Library of Science
Λέξεις-κλειδιά:
activating transcription factor 4; prion protein antibody; protein elf2; protein PERK; reactive oxygen metabolite; transcription factor; unclassified drug; antibody; PERK kinase; prion protein; protein kinase R; reactive oxygen metabolite, animal tissue; Article; cell assay; cell viability; controlled study; down regulation; endoplasmic reticulum stress; excitotoxicity; gene expression; gene regulatory network; immunofluorescence; microarray analysis; mouse; nerve degeneration; neurotoxicity; nonhuman; prion disease; protein analysis; protein interaction; scrapie cell assay; signal transduction; transcription regulation; unfolded protein response; animal; chemically induced; drug effects; genetics; immunology; pathology; prion disease; transgenic mouse, Mus, Animals; Antibodies; eIF-2 Kinase; Mice; Mice, Transgenic; Prion Diseases; PrPSc Proteins; Reactive Oxygen Species; Signal Transduction
DOI:
10.1371/journal.ppat.1004662
