Wellstone Muscular Dystrophy Program, Department of Neurology; Department of Biochemistry and Molecular Pharmacology; Emerson Lab
Amino Acids, Peptides, and Proteins | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Genetics and Genomics | Musculoskeletal Diseases | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics
Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic derepression of the germline/embryonic transcription factor DUX4 in skeletal muscle. However, the etiology of muscle pathology is not fully understood, as DUX4 misexpression is not tightly correlated with disease severity. Using a DUX4-inducible cell model, we show that multiple DUX4-induced molecular pathologies that have been observed in patient-derived disease models are mediated by the signaling molecule hyaluronic acid (HA), which accumulates following DUX4 induction. These pathologies include formation of RNA granules, FUS aggregation, DNA damage, caspase activation, and cell death. We also observe previously unidentified pathologies including mislocalization of mitochondria and the DUX4- and HA-binding protein C1QBP. These pathologies are prevented by 4-methylumbelliferone, an inhibitor of HA biosynthesis. Critically, 4-methylumbelliferone does not disrupt DUX4-C1QBP binding and has only a limited effect on DUX4 transcriptional activity, establishing that HA signaling has a central function in pathology and is a target for FSHD therapeutics.
Facioscapulohumeral muscular dystrophy, FSHD, DUX4
Rights and Permissions
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
DOI of Published Version
Sci Adv. 2019 Dec 11;5(12):eaaw7099. doi: 10.1126/sciadv.aaw7099. eCollection 2019 Dec. Link to article on publisher's site
DeSimone AM, Leszyk JD, Wagner K, Emerson, Jr. CP. (2019). Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy. Open Access Articles. https://doi.org/10.1126/sciadv.aaw7099. Retrieved from https://escholarship.umassmed.edu/oapubs/4105
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Amino Acids, Peptides, and Proteins Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Musculoskeletal Diseases Commons, Nervous System Diseases Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, Therapeutics Commons