A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models.
Javier GanzTalya ShachamMaria KramerMarina ShenkmanHagit EigerNitai WeinbergOri IancoviciSomnath RoyLuba SimhaevBenny Da'adooshHamutal EngelNisim PeretsYael BarhumMoshe PortnoyDaniel OffenGerardo Z LederkremerPublished in: Scientific reports (2020)
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.
Keyphrases
- endoplasmic reticulum stress
- induced apoptosis
- endoplasmic reticulum
- small molecule
- oxidative stress
- signaling pathway
- type diabetes
- nuclear factor
- stem cells
- transcription factor
- immune response
- skeletal muscle
- insulin resistance
- cell death
- mesenchymal stem cells
- molecular dynamics simulations
- smoking cessation
- cerebral ischemia
- toll like receptor