Oculopharyngeal muscular dystrophy (OPMD) is caused by expansion of a short GCG repeat in the gene that encodes polyadenylate binding protein 2 (Pab2), a ubiquitous protein that has an essential role in the polyadenylation of mRNA. The repeat is translated as a homopolymeric tract of alanines. In OPMD, modest expansions of this tract (10 alanines in normals, 11 to 17 alanines in OPMD) are associated with formation of nuclear inclusions and degeneration of muscle fibers. It is uncertain whether the nuclear inclusions are pathogenic or protective, or whether they may simply be a histologic marker for an underlying tendency of mutant protein to aggregate. Despite recent genetic advances, there are no treatments that reverse or slow the disease progression in OPMD. No animal models are available to study the pathophysiology or treatment of this disorder. The goal of this proposal is to complete the development and initial characterization of a transgenic mouse model of OPMD. An inducible model has been developed for expression of mutant Pab2 in all tissues or specifically in skeletal muscle. The preliminary studies have indicated that induction of Pab2 transgenes can be achieved in mice. Unexpectedly, there is premature mortality in lines that express low levels of mutant Pab2 mRNA (<25% of endogenous Pab2 mRNA) even in the uninduced state.
The specific aims are to: (1) characterize the phenotype in uninduced Pab2(mutant) mice to determine if these transgenic lines are a valid model for OPMD, (2) establish the transgenic lines and conditions that are optimal for studying the chronic induction of mutant and wild-type Pab2, and (3) determine the effects of mutant Pab2 on regulation of poly(A) tail length, formation of nuclear inclusions, and maintenance of muscle fiber integrity. These transgenic lines may provide a useful model for studying the long-term effects of protein misfolding/aggregation on post-mitotic cells. Results from these studies will improve our understanding of the pathogenesis of OPMD and lay the groundwork for developing and testing new therapeutic strategies.
| Mankodi, Ami; Wheeler, Thurman M; Shetty, Reena et al. (2012) Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy. Neurobiol Dis 45:539-46 |
