A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models

Javier Ganz, Talya Shacham, Maria Kramer, Marina Shenkman, Hagit Eiger, Nitai Weinberg, Ori Iancovici, Somnath Roy, Luba Simhaev, Benny Da’adoosh, Hamutal Engel, Nisim Perets, Yael Barhum, Moshe Portnoy, Daniel Offen, Gerardo Z. Lederkremer

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

One of the pathways of the unfolded protein response, initiated by PKR-like endoplasmic reticulum kinase (PERK), is key to neuronal homeostasis in neurodegenerative diseases. PERK pathway activation is usually accomplished by inhibiting eIF2α-P dephosphorylation, after its phosphorylation by PERK. Less tried is an approach involving direct PERK activation without compromising long-term recovery of eIF2α function by dephosphorylation. Here we show major improvement in cellular (STHdhQ111/111) and mouse (R6/2) Huntington's disease (HD) models using a potent small molecule PERK activator that we developed, MK-28. MK-28 showed PERK selectivity in vitro on a 391-kinase panel and rescued cells (but not PERK−/− cells) from ER stress-induced apoptosis. Cells were also rescued by the commercial PERK activator CCT020312 but MK-28 was significantly more potent. Computational docking suggested MK-28 interaction with the PERK activation loop. MK-28 exhibited remarkable pharmacokinetic properties and high BBB penetration in mice. Transient subcutaneous delivery of MK-28 significantly improved motor and executive functions and delayed death onset in R6/2 mice, showing no toxicity. Therefore, PERK activation can treat a most aggressive HD model, suggesting a possible approach for HD therapy and worth exploring for other neurodegenerative disorders.

Original languageEnglish
Article number6875
JournalScientific Reports
Volume10
Issue number1
DOIs
StatePublished - 23 Apr 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

We are very grateful to D. Ron and D. Frenkel for reagents. Work was supported by Teva Pharmaceuticals National Network in Neuroscience (NNE) program (J.G.), KAMIN program (grant 57748) from the Israel authority for Technology Innovation (G.L.), the Recanati Medical Fund (G.L.) and the Israel Science Foundation Legacy Heritage Fund (2394/17) (G.L.).

FundersFunder number
Israel Science Foundation Legacy Heritage Fund2394/17
Israel authority for Technology Innovation
NNE57748
Recanati Medical Fund
Teva Pharmaceuticals National Network in Neuroscience
Teva Pharmaceutical Industries

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