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Sci Adv. 2019 Dec 11;5(12):eaaw7099. doi: 10.1126/sciadv.aaw7099. eCollection 2019 Dec.

Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy.

Author information

1
Wellstone Muscular Dystrophy Program, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
2
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
3
Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Abstract

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.

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