Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy
UMass Chan AffiliationsEmerson Lab
Department of Biochemistry and Molecular Pharmacology
Wellstone Muscular Dystrophy Program, Department of Neurology
KeywordsFacioscapulohumeral muscular dystrophy
Amino Acids, Peptides, and Proteins
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Genetics and Genomics
Nervous System Diseases
Nucleic Acids, Nucleotides, and Nucleosides
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AbstractFacioscapulohumeral 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.
Sci Adv. 2019 Dec 11;5(12):eaaw7099. doi: 10.1126/sciadv.aaw7099. eCollection 2019 Dec. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41320
RightsCopyright © 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).
Except where otherwise noted, this item's license is described as 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).