2. Academic Validation
  3. A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models

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

  • Sci Rep. 2020 Apr 23;10(1):6875. doi: 10.1038/s41598-020-63899-4.
Javier Ganz  # 1 2,  Talya Shacham  # 2 3,  Maria Kramer 4,  Marina Shenkman 2 3,  Hagit Eiger 2 3,  Nitai Weinberg 1 2,  Ori Iancovici 2 3,  Somnath Roy 2 3,  Luba Simhaev 5,  Benny Da'adoosh 5,  Hamutal Engel 5,  Nisim Perets 1 2,  Yael Barhum 1 2,  Moshe Portnoy 4,  Daniel Offen 1 2,  Gerardo Z Lederkremer 6 7
Affiliations

Affiliations

  • 1 Department of Human Molecular Genetics and Biochemistry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
  • 2 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel.
  • 3 School of Molecular Cell Biology and Biotechnology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
  • 4 School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
  • 5 Blavatnik Center for Drug Discovery, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
  • 6 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel. gerardol@tauex.tau.ac.il.
  • 7 School of Molecular Cell Biology and Biotechnology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel. gerardol@tauex.tau.ac.il.
  • # Contributed equally.
PMID: 32327686 DOI: 10.1038/s41598-020-63899-4
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.

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