Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways

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.

Interaction between Prion Protein's Copper-Bound Octarepeat Domain and a Charged C-Terminal Pocket Suggests a Mechanism for N-Terminal Regulation

“…This is consistent with the observation that Cu 2+ and Zn 2+ , both of which promote interdomain structure, strongly inhibit the in vitro amplification of scrapie-induced, protease-resistant PrP (Orem et al, 2006). Furthermore, the neurotoxic pathways induced by POM1 and other globular domain ligands are similar to those observed in prion-infected cultured cerebellar brain slices, suggesting that PrP Sc and the toxic antibodies have similar mechanisms of neurotoxicity (Herrmann et al, 2015). …”

A neuroprotective role for microglia in prion diseases

“…Not only did we confirm our previous study that depletion of microglia in COCS leads to enhanced PrP Sc deposition, but we also detected a dramatic acceleration in prion-induced neurodegeneration of the cerebellar granule layer. Notably, microglia ablation does not affect antiprion antibody-induced neurotoxicity (Sonati et al, 2013), suggesting that microglia exert neuroprotection by reducing the prion load rather than by acting on downstream events shared by prion infections and antiprion antibody treatment (Herrmann et al, 2015). The notion that microglia protects the brain against prion-induced neurotoxicity was confirmed in vivo using CD11b-HSV TK transgenic mice.…”

Protein Quality Control in Health and Disease

“…The observation that the PERK pathway is activated in mice that express aggregationprone PrP species directly links PrP toxicity and the UPR ER (Herrmann et al 2015). A fourth UPR ER pathway that is activated when the canonical mechanisms are blocked was identified in the nematode Caenorhabditis elegans (Urano et al 2002).…”