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Science. 2015 Apr 10;348(6231):239-42. doi: 10.1126/science.aaa4484.

Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit.

Author information

1
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
2
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
3
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. aberto@mrc-lmb.cam.ac.uk.

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.

PMID:
25859045
PMCID:
PMC4490275
DOI:
10.1126/science.aaa4484
[Indexed for MEDLINE]
Free PMC Article

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