PromISR-6, a Guanabenz Analogue, Improves Cellular Survival in an Experimental Model of Huntington's Disease.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Sundaram, JR; Wu, Y; Lee, IC; George, SE; Hota, M; Ghosh, S; Kesavapany, S; Ahmed, M; Tan, E-K; Shenolikar, S

Published Date

  • August 21, 2019

Published In

Volume / Issue

  • 10 / 8

Start / End Page

  • 3575 - 3589

PubMed ID

  • 31313908

Pubmed Central ID

  • 31313908

Electronic International Standard Serial Number (EISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/acschemneuro.9b00185

Language

  • eng

Conference Location

  • United States