PERK activation mitigates tau pathology invitro and invivo.

Julius Bruch,Peer‐Hendrik Kuhn,Günter U Höglinger,Thomas Arzberger,Anderson De Andrade,Thomas W Rösler,Hong Xu,Stefan F Lichtenthaler,Konstanze F Winklhofer,Ulrich Müller

doi:10.15252/emmm.201606664

Abstract

The RNA‐like endoplasmic reticulum kinase (PERK) is genetically associated with the tauopathy progressive supranuclear palsy (PSP). To elucidate the functional mechanisms underlying this association, we explored PERK activity in brains of PSP patients and its function in three tauopathy models (cultured human neurons overexpressing 4‐repeat wild‐type tau or treated with the environmental neurotoxin annonacin, and P301S tau transgenic mice). In vitro, treatment with a pharmacological PERK activator CCT020312 or PERK overexpression reduced tau phosphorylation, tau conformational change and 4‐repeat tau isoforms, and increased cell viability. In vivo, the PERK activator significantly improved memory and locomotor function, reduced tau pathology, and prevented dendritic spine and motoneuron loss in P301S tau mice. Importantly, the PERK substrate EIF2A, mediating some detrimental effects of PERK signaling, was downregulated in PSP brains and tauopathy models, suggesting that the alternative PERK–NRF2 pathway accounts for these beneficial effects in the context of tauopathies. In summary, PERK activation may be a novel strategy to treat PSP and eventually other tauopathies.

Highlights

Tauopathies are neurodegenerative diseases caused by aggregation of the microtubule-associated protein tau, encoded by the gene MAPT
PERK is upregulated in Progressive supranuclear palsy (PSP), but its substrates eukaryotic translation initiation factor 2-alpha (EIF2A) and nuclear factor erythroid 2-related factor 2 (NRF2) behave differently
The ratios of phosphorylated PERK (pPERK)/PERK, pNRF2/NRF2, and phosphorylated EIF2A (pEIF2A)/ EIF2A were not significantly altered. These findings suggest that PERK and NRF2 signaling are increased, and EIF2A signaling is decreased in PSP

Summary

Introduction

Tauopathies are neurodegenerative diseases caused by aggregation of the microtubule-associated protein tau, encoded by the gene MAPT. In a genome-wide association study, we identified common variants of EIF2AK3, encoding the RNA-like endoplasmic reticulum kinase (PERK), to increase risk for PSP (Hoglinger et al, 2011). An overload of misfolded proteins in the endoplasmic reticulum (ER stress) activates PERK which subsequently phosphorylates the eukaryotic translation initiation factor 2-alpha (EIF2A; Schroder & Kaufman, 2005) and the nuclear factor erythroid 2-related factor 2 (NRF2; Cullinan et al, 2003), resulting in global suppression of translation and transcription of cytoprotective factors. PERK, in turn, activates GSK3ß, a tau kinase (Baltzis et al, 2007; Nijholt et al, 2013)

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