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
  • 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. [email protected].
  • 7. School of Molecular Cell Biology and Biotechnology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel. [email protected].
  • # 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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