Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways

Uli S Herrmann,Uli Wagner,Agnes Lau,Despina Sanoudou,Bei Li,Jeppe Falsig,Paolo Dametto,Regina R Reimann,Tracy O’Connor,Simone Hornemann,Tiziana Sonati,Silvia Sorce,Adriano Aguzzi,Neil A Mabbott

doi:10.1371/journal.ppat.1004662

Uli S Herrmann, Uli Wagner + Show 12 more

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https://doi.org/10.1371/journal.ppat.1004662

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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.

Highlights

Prion diseases are lethal infectious diseases that propagate through the conversion of the cellular prion protein (PrPC) into a pathological conformer, the scrapie-associated prion protein (PrPSc) [1]
Rapid neurotoxicity is elicited in cerebellar organotypic cultured slices (COCS) and in vivo by several monoclonal antibodies, singlechain variable fragments, and F(ab)1, and F(ab)2 fragments directed against the globular domain of PrPC [15]
We have previously reported that neurodegeneration and prion replication occur in COCS exposed to the three prion strains, RML, 22L, and 139A [13]

Summary

Introduction

Prion diseases are lethal infectious diseases that propagate through the conversion of the cellular prion protein (PrPC) into a pathological conformer, the scrapie-associated prion protein (PrPSc) [1]. Neuronal expression of PrPC is required to mediate the neurotoxicity of PrPSc [2] and possibly of other protein aggregates [3], yet the pathways leading to neurotoxicity are largely unknown. Excessive unfolded protein responses (UPR) in the endoplasmic reticulum (ER) plays a significant role in the pathogenesis of prion and other neurodegenerative diseases [9,10], yet the biochemical events emanating from prion replication and leading to UPR induction are unknown, and it is unclear how extracellular aggregates can trigger pathology in a subcellular compartment to which they have no direct access. Prion-infected COCS replicate all salient biochemical, histological, and pathophysiological events which occur during prion infections in vivo, including PrPC-dependent prion replication [11,12], neuroinflammation with proliferation of microglia and astrogliosis, spongiosis, and neuronal cell loss. In prion-infected COCS, calpain inhibition confers neuroprotection without reducing prion replication, suggesting that calpains are involved in neurotoxicity [13]

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