PERK activation mitigates tau pathology in vitro and in vivo

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

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


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.

Original languageEnglish
Pages (from-to)371-384
Number of pages14
JournalEMBO Molecular Medicine
Issue number3
StatePublished - 1 Mar 2017


  • EIF2A
  • NRF2
  • PERK
  • progressive supranuclear palsy
  • tauopathy


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