sephin1 and Charcot-Marie-Tooth-Disease

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.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cells, Cultured; Charcot-Marie-Tooth Disease; Disease Models, Animal; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Guanabenz; HeLa Cells; Humans; Mice; Mice, Transgenic; Molecular Targeted Therapy; Phosphorylation; Protein Folding; Protein Phosphatase 1; Proteostasis Deficiencies; Signal Transduction