Myopathy phenotype in transgenic mice expressing mutated PABPN1 as a model of oculopharyngeal muscular dystrophy

Abstract

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized clinically by progressive ptosis, dysphagia and limb weakness, and by unique intranuclear inclusions in the skeletal muscle fibers. The disease is caused by the expansion of a 10-alanine stretch to 12-17 alanine residues in the poly(A)-binding protein, nuclear 1 (PABPN1; PABP2). While PABPN1 is a major component of the inclusions in OPMD, the exact cause of the disease is unknown. To elucidate the molecular mechanism and to construct a useful model for therapeutic trials, we have generated transgenic mice expressing the hPABPN1. Transgenic mice lines expressing a normal hPABPN1 with 10-alanine stretch did not reveal myopathic changes, whereas lines expressing high levels of expanded hPABPN1 with a 13-alanine stretch showed an apparent myopathy phenotype, especially in old age. Pathological studies in the latter mice disclosed intranuclear inclusions consisting of aggregated mutant hPABPN1 product. Furthermore, some TUNEL positive nuclei were shown around degenerating fibers and a cluster of it in the lesion in necrotic muscle fibers. Interestingly, the degree of myopathic changes was more prominent in the eyelid and pharyngeal muscles. Further, muscle weakness in the limbs was apparent as shown by the fatigability test. Nuclear inclusions seemed to develop gradually with aging, at least after 1 week of age, in model mouse muscles. We established the first transgenic mouse model of OPMD by expressing mutated PABPN1, and our model mice appear to have more dramatic alternations in myofiber viability.

Transplantation of Myocyte Precursors Derived from Embryonic Stem Cells Transfected with IGFII Gene in a Mouse Model of Muscle Injury

“…Toluidine blue staining of the myofibers showed uniform pale blue staining and well developed sarcomeres, confirming the differentiation to striated muscle cells (Fig. 6, G and H) (26). Various sizes and irregular shapes of the fibers were seen in the grafted site, and some of them were characterized by centered nuclei.…”

The other trinucleotide repeat: polyalanine expansion disorders

“…In affected areas, the muscle cells show characteristic nuclear inclusions that were shown to contain PABNP1 protein, ubiquitin, proteasome subunits, heat shock proteins, and abundant poly(A)-mRNA [34]. Expressing PABPN1 with a 13-alanine stretch in mice results in muscle weakness and slowly evolving nuclear inclusions [35]. However, PABPN1 intra-nuclear inclusions are also present in normal oxytocin-producing neurons, indicating that polyalanine expansions are not essential to induce PABPN1 aggregation [36].…”

Cystamine Suppresses Polyalanine Toxicity in a Mouse Model of Oculopharyngeal Muscular Dystrophy

“…In unaffected individuals, (GCG) 6 codes for the first six alanines in a homopolymeric stretch of 10 alanines. In most patients, this (GCG) 6 repeat is expanded to (GCG) [8][9][10][11][12][13] , leading to a stretch of 12 to 17 alanines in mutant PABPN1. PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers (2)(3)(4).…”