PromISR-6, a Guanabenz Analogue, Improves Cellular Survival in an Experimental Model of Huntington’s Disease
| Autor: | Shirish Shenolikar, Mahmood Ahmed, Simi Elizabeth George, Jeyapriya Rajameenakshi Sundaram, Sujoy Ghosh, Yilong Wu, Irene Chengjie Lee, Sashi Kesavapany, Monalisa Hota, Eng-King Tan |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
Huntingtin Cell Survival Physiology medicine.drug_class Cognitive Neuroscience Eukaryotic Initiation Factor-2 Biochemistry Mice Protein Aggregates 03 medical and health sciences 0302 clinical medicine Adrenergic alpha-2 Receptor Agonists medicine Animals Integrated stress response Phosphorylation Mode of action 030304 developmental biology 0303 health sciences Guanabenz Chemistry Cell Biology General Medicine Fibroblasts ISRIB Cell biology Huntington Disease Cellular model 030217 neurology & neurosurgery Intracellular medicine.drug |
| Zdroj: | ACS Chemical Neuroscience. 10:3575-3589 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.9b00185 |
| Popis: | Guanabenz (GBZ), an α2-adrenergic agonist, demonstrated off-target effects that restored protein homeostasis and ameliorated pathobiology in experimental models of neurodegenerative disease. However, GBZ did not directly activate the integrated stress response (ISR), and its proposed mode of action remains controversial. Utilizing an iterative in silico screen of over 10,000 GBZ analogues, we analyzed 432 representative compounds for cytotoxicity in Wild-type, PPP1R15A-/-, and PPP1R15B-/- mouse embryonic fibroblasts. Nine compounds clustering into three functional groups were studied in detail using cell biological and biochemical assays. Our studies demonstrated that PromISR-6 is a potent GBZ analogue that selectively activated ISR, eliciting sustained eIF2α phosphorylation. ISRIB, an ISR inhibitor, counteracted PromISR-6-mediated translational inhibition and reduction in intracellular mutant Huntingtin aggregates. Reduced protein synthesis combined with PromISR-6-stimulated autophagic clearance made PromISR-6 the most efficacious GBZ analogue to reduce Huntingtin aggregates and promote survival in a cellular model of Huntington's disease. |
| Databáze: | OpenAIRE |
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