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

• Published in: Scientific reports Vol. 10; no. 1; p. 6875
• Main Authors: Ganz, Javier, Shacham, Talya, Kramer, Maria, Shenkman, Marina, Eiger, Hagit, Weinberg, Nitai, Iancovici, Ori, Roy, Somnath, Simhaev, Luba, Da’adoosh, Benny, Engel, Hamutal, Perets, Nisim, Barhum, Yael, Portnoy, Moshe, Offen, Daniel, Lederkremer, Gerardo Z.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.04.2020; Nature Publishing Group
• Subjects: 13; 13/106; 13/51; 631/378/1689/1558; 631/80/304; 64; 64/110; 64/60; 82; Animals; Apoptosis; Apoptosis - drug effects; Dephosphorylation; Disease Models, Animal; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Enzyme Activators - chemistry; Enzyme Activators - pharmacology; Eukaryotic Initiation Factor-2 - metabolism; Homeostasis; Humanities and Social Sciences; Huntingtin Protein - metabolism; Huntington Disease - enzymology; Huntington Disease - pathology; Huntington Disease - physiopathology; Huntington's disease; Huntingtons disease; Kinases; Mice; Models, Biological; multidisciplinary; Neostriatum - pathology; Neurodegenerative diseases; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Pharmacokinetics; Phosphorylation; Phosphorylation - drug effects; Protein folding; Science; Science (multidisciplinary); Signal Transduction - drug effects; Survival Analysis; Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-63899-4

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 (ST Hdh Q111/111 ) 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.