title: Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit.
abstract: Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases.
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors: Indrajit
authors: I
authors: Das
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors: Agnieszka
authors: A
authors: Krzyzosiak
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors: Kim
authors: K
authors: Schneider
authors: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors: Lawrence
authors: L
authors: Wrabetz
authors: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors: Maurizio
authors: M
authors: D'Antonio
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors: Nicholas
authors: N
authors: Barry
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors: Anna
authors: A
authors: Sigurdardottir
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. aberto@mrc-lmb.cam.ac.uk.
authors: Anne
authors: A
authors: Bertolotti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006143:Guanabenz / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D017510:Protein Folding; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000517:prevention & control*; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; C000597020:sephin1; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; D006143:Guanabenz