SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA

Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness. The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss. Importantly, muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression, and TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics. These findings point to ERO1A as a biomarker and a viable target for intervention and to TUDCA as a pharmacological treatment for SEPN1-RM. [Display omitted] •SEPN1 interacts with the endoplasmic-reticulum-stress-induced oxidoreductase ERO1A•Upregulation of ERO1A is a hallmark of the SEPN1-RM preclinical models•Targeting ERO1A improves the muscle disease phenotype of SEPN1-RM•TUDCA, a pan ER stress inhibitor, is an effective pharmacological strategy for SEPN1-RM SEPN1-related myopathy (SEPN1-RM) is a congenital muscle disorder with no approved pharmacological treatment. Germani et al. show an interaction between SEPN1 and ERO1A and that targeting ERO1A improves the muscle phenotype of SEPN1-RM. Furthermore, they find that TUDCA, an FDA-approved drug, is an effective pharmacological strategy for SEPN1-RM.