부산대학교 도서관

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD. Author summary: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disease characterized by progressive weakness of specific muscles, leading to swallowing difficulties (dysphagia), eyelid drooping (ptosis) and walking difficulties at later stages. No drug treatments are currently available. OPMD is due to mutations in a nuclear protein called poly(A) binding protein nuclear 1 (PABPN1) that is involved in processing of different classes of RNAs in the nucleus. We have used an animal model of OPMD that we have developed in the fly Drosophila to investigate the role in OPMD of the ubiquitin-proteasome system, a pathway specialized in protein degradation. We report an increased activity of the ubiquitin-proteasome system that is associated with degradation of muscular proteins in the OPMD Drosophila model. We propose that higher activity of the ubiquitin-proteasome system leads to muscle atrophy in OPMD. Importantly, oral treatment of this OPMD animal model with an inhibitor of proteasome activity reduces muscle defects. A number of proteasome inhibitors are approved drugs used in clinic against cancers, therefore our results provide a proof-of-concept that inhibitors of proteasome might be of interest in future treatments of OPMD. [ABSTRACT FROM AUTHOR]