Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy.

Cécile Ribot,Nicolas Barbezier,Rima Naït-Saïdi,Sandy Al Hayek,Cédric Soler,Martine Simonelig,Aymeric Chartier,Olivier Coux,Bingwei Lu

doi:10.1371/journal.pgen.1010015

Abstract

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.

Highlights

Protein aggregation represents a pathological hallmark in many neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis, among others
Oculopharyngeal muscular dystrophy (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

Summary

Introduction

Protein aggregation represents a pathological hallmark in many neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis, among others. Oculopharyngeal muscular dystrophy (OPMD) is one of these proteinopathies in which the mutant protein accumulates as aggregates in diseased nuclei. OPMD is a rare autosomal dominant muscular dystrophy that starts in the late fifties. It is characterized by progressive weakness of specific muscles, leading to eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness [2,3]. OPMD is due to short expansions of a GCN repeat in the gene encoding poly(A) binding protein nuclear 1 (PABPN1) [4]. Alanine-expanded PABPN1 form nuclear aggregates in muscle fibres, which are a pathological hallmark of the disease [7]

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Discussion

Conclusion