Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice

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) gene. 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 fibers. 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.

Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies

“…Over the last few years, our group and others have generated several of models for OPMD ranging from mammalian cell models to transgenic mouse models in order to test various hypotheses, resulting in a better understanding of the molecular basis of the disease [1,3,18,36,39,40]. This work has provided a foundation of knowledge permitting us to develop treatment strategies that target OPMD pathological mechanisms.…”

“…Using a variety of available resources including transgenic OPMD models [36] and OPMD patient fibroblasts, we are currently investigating the potential of CRIS-PR-Cas9-mediated genome editing approach for correcting the mutation in OPMD as a third strategy for therapy. The primary objective is to correct the genetic defect in the PABPN1 gene of OPMD mice by CRISPR/Cas9-mediated genome editing.…”

Modeling Oculopharyngeal Muscular Dystrophy in Myotube Cultures Reveals Reduced Accumulation of Soluble Mutant PABPN1 Protein

“…[17][18][19][20] In these animal model systems, anti-aggregation treatments reduced muscle symptoms and INI formation 19,21,22 ; how-ever, the molecular mechanisms by which expPABPN1 is toxic to cells have not been fully elucidated. Increased frequency of cell death is found in animal and cellular models with expPABPN1 overexpression, 9 but cell death and overexpression of expPABPN1 have not been reported in heterozygous patients with OPMD.…”

Doxycycline Treatment Decreases Morbidity and Mortality of Murine Neurocysticercosis

“…Doxycycline is known to reduce the susceptibility of cells to pro-apoptotic insult by restricting the release of cytochrome c and the activation of caspases 3 and 9. 38 In addition, MMP inhibition in a mouse model of cerebral ischemia resulted in lower levels of apoptosis and decreased morbidity. This protection was associated with a reduction of cytochrome c release and ␣-spectrin proteolysis.…”