Novel structure-guided therapeutic approaches for oculopharyngeal muscular dystrophy (OPMD) and related diseases

Oculopharyngeal muscular dystrophy (OPMD) is a genetic disease associated with muscular weakness and functional impairment involving primarily pharyngeal, facial, and the limb-girdle muscles, and leading to late-onset progressive ptosis, ophtalmoplegia, dysphagia, dysphonia, and limb-girdle weakness with variable degrees of motor impairment. This disease is associated with mutations of the PABPN1 gene. In OPMD patients, the PABPN1 protein produced by the mutant PABPN1 gene, bears an abnormally long chain of the amino acid alanine, called polyalanine (polyA) expansion. This polyA expansion is toxic especially for the cells of certain muscles, thus causing the symptoms of OPMD. Currently, no treatment is available for OPMD that can correct the cause of the disease, or that can abolish the toxicity of the mutant PABPN1 protein. Understanding, the mechanisms by which the mutant PABPN1 protein damages muscle cells is very important for finding effective treatments for OPMD. We have initial evidence that the mutant PABPN1 protein may cause harm to cells through the entangling of polyA expansions to form so called "coiled coils". The PABPN1 proteins become trapped in clumps by the formation of coiled coils, and this may damage the muscle cells. Our research therefore aims at finding drugs that can block the formation of these coiled coils, thus preventing the damage to muscle cells observed in OPMD. These drugs may be then used to treat, and even to prevent, OPMD in people carrying the genetic mutation that causes this debilitating disease.