Abstract
The muscular dystrophies are a heterogeneous group of disorders for which there are currently no cures. Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset, progressive disease that generally presents in the fifth or sixth decade with dysphagia, ptosis and proximal limb weakness. OPMD is caused by the abnormal expansion of a (GCG)n trinucleotide repeat in the coding region of the poly-(A) binding protein nuclear 1 (PABPN1) gene1. In unaffected individuals, (GCG)6 codes for the first six alanines in a homopolymeric stretch of ten alanines. In most individuals with OPMD this (GCG)6 repeat is expanded to (GCG)8–13, leading to a stretch of 12–17 alanines in mutant PABPN1. PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers2,3,4. We have developed a transgenic mouse model of OPMD that manifests progressive muscle weakness accompanied by intranuclear aggregates and TUNEL-stained nuclei in skeletal muscle fibers. The onset and severity of these abnormalities were substantially delayed and attenuated by doxycycline treatment, which may exert its therapeutic effect by reducing aggregates and by distinct antiapoptotic properties. Doxycycline may represent a safe and feasible therapeutic for this disease.
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Acknowledgements
The authors would like to thank E.Wahle for the kind gift of PABPN1 antibody and PABPN1 constructs, K.E. Davies for the human skeletal muscle actin construct, M. Bobrow for helpful comments and G. Gatward and L. Gilroy for technical assistance. This work was funded by the Wellcome Trust (Senior Fellowship to D.C. Rubinsztein) and a Medical Research Council Programme grant to D.C.R. (with S. Brown).
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Supplementary information
Supplementary Fig. 1
OPMD transgenic construct design, expression, and aggregate characterization. (PDF 131 kb)
Supplementary Fig. 2
Phenotypic assessment of OPMD transgenic mice. (PDF 34 kb)
Supplementary Fig. 3
Effects of doxycycline treatment on mouse and cellular models of OPMD. (PDF 49 kb)
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Davies, J., Wang, L., Garcia-Oroz, L. et al. Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice. Nat Med 11, 672–677 (2005). https://doi.org/10.1038/nm1242
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DOI: https://doi.org/10.1038/nm1242
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