TY - JOUR
T1 - PERK activation mitigates tau pathology in vitro and in vivo
AU - Bruch, Julius
AU - Xu, Hong
AU - Rösler, Thomas W.
AU - De Andrade, Anderson
AU - Kuhn, Peer Hendrik
AU - Lichtenthaler, Stefan F.
AU - Arzberger, Thomas
AU - Winklhofer, Konstanze F.
AU - Müller, Ulrich
AU - Höglinger, Günter U.
N1 - Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - EIF2A
KW - NRF2
KW - PERK
KW - progressive supranuclear palsy
KW - tauopathy
UR - http://www.scopus.com/inward/record.url?scp=85011333352&partnerID=8YFLogxK
U2 - 10.15252/emmm.201606664
DO - 10.15252/emmm.201606664
M3 - Article
C2 - 28148553
AN - SCOPUS:85011333352
SN - 1757-4676
VL - 9
SP - 371
EP - 384
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 3
ER -