TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy
Year: 2014
Type: article
Abstract: Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-κB pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddu617
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, Role of FN14 in RNA Toxicity, NINDS Research Education Program for Residents and Fellows at the University of V, Molecular Mechanisms of the Myotonic Dystrophy Mutation, G4583128878, The University of Rochester Clinical and Translational Science Institute, Inducible Transgenic Mouse Model of RNA Toxicity, G783251046
OpenAlex ID: W2126569475