Efficacy of therapy by MK-28 PERK activation in the Huntington's disease R6/2 mouse model

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Abstract

There is currently no disease-modifying therapy for Huntington's disease (HD). We recently described a small molecule, MK-28, which restored homeostasis in HD models by specifically activating PKR-like ER kinase (PERK). This activation boosts the unfolded protein response (UPR), thereby reducing endoplasmic reticulum (ER) stress, a central cytotoxic mechanism in HD and other neurodegenerative diseases. Here, we have tested the long-term effects of MK-28 in HD model mice. R6/2 CAG (160) mice were treated by lifetime intraperitoneal injections 3 times a week. CatWalk measurements of motor function showed strong improvement compared to untreated mice after only two weeks of MK-28 treatment and continued with time, most significantly at 1 ​mg/kg MK-28, approaching WT values. Seven weeks treatment significantly improved paw grip strength. Body weight recovered and glucose levels, which are elevated in HD mice, were significantly reduced. Treatment with another PERK activator, CCT020312 at 1 ​mg/kg, also caused amelioration, consistent with PERK activation. Lifespan, measured in more resilient R6/2 CAG (120) mice with daily IP injection, was much extended by 16 days (20%) with 0.3 ​mg/kg MK-28, and by 38 days (46%) with 1 ​mg/kg MK-28. No toxicity, measured by weight, blood glucose levels and blood liver function markers, was detectable in WT mice treated for 6 weeks with 6 ​mg/kg MK-28. Boosting of PERK activity by long-term treatment with MK-28 could be a safe and promising therapeutic approach for HD.

Original languageEnglish
Article numbere00335
JournalNeurotherapeutics
Volume21
Issue number2
DOIs
StatePublished - Mar 2024

Keywords

  • ER stress
  • Huntington's disease
  • Motor dysfunction
  • Unfolded protein response
  • eIF2α

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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