Neurodegeneration and Unfolded-Protein Response in Mice Expressing a Membrane-Tethered Flexible Tail of PrP

Abstract

The cellular prion protein (PrPC) consists of a flexible N-terminal tail (FT, aa 23–128) hinged to a membrane-anchored globular domain (GD, aa 129–231). Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141–225, or “FTgpi”). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.

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

“…Sonati et al propose that the PrP C globular domain acts as a regulator of the N-terminal “effector” domain, and that toxic anti-PrP ligands somehow disrupt this regulatory ability, resulting in deleterious interactions of the N-terminus and subsequent gain-of-function neurotoxicity. This paradigm is supported by studies showing similar neurotoxicity in transgenic mice expressing a GPI-anchored PrP construct lacking the globular domain, although proper cellular localization is impaired in this mutant (Dametto et al, 2015). …”

The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6

“…pCDNA-PrP C was generated by cloning murine PrP C into pCDNA3.1 vector as described previously 26 . Site-specific mutagenesis kit (Stratagene) was used to induce alanine substitutions of QPSPG and KKRPK domains in PrP C .…”

Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

“…80e82 ER stress and UPR activation have also been observed in prion infection in vivo 83e85 as well as transgenic mice expressing mutant PrP C . 86 Genetic and chemical modulation of different UPR pathways in prion-infected models has revealed intriguing and surprising differences from mutant rhodopsin models in the role of UPR signaling pathways in cellular degeneration. PrP C -to-PrP Sc conversion and neurodegeneration are unchanged in mice deficient in neuronal Xbp1 À/À compared with controls.…”

“…One fundamental difference between these diseases is that prion conversion likely occurs on the cell membrane or in an endolysosomal compartment; thus, PrP Sc escapes the misfolded protein clearance and degradation mechanisms triggered during UPR activation 86 Figure 4 A: Rhodopsin (Rho) is robustly degraded during retinal degeneration. Light micrographs of wild-type and P23H knock-in mouse retinas at postnatal (P) day 15.…”