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PLoS Pathog. 2015 Feb 24;11(2):e1004662. doi: 10.1371/journal.ppat.1004662. eCollection 2015 Feb.

Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways.

Author information

1
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
2
Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
3
Department of Pharmacology, Medical School, University of Athens, Athens, Greece.

Abstract

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.

PMID:
25710374
PMCID:
PMC4339193
DOI:
10.1371/journal.ppat.1004662
[Indexed for MEDLINE]
Free PMC Article

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