Abstract
Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Disease Models, Animal
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Drosophila melanogaster / genetics
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Gene Expression Regulation
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Humans
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Mice
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Mitochondrial Proteins / biosynthesis
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Mitochondrial Proteins / genetics*
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Muscle, Skeletal / pathology
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Muscular Dystrophy, Oculopharyngeal / genetics*
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Muscular Dystrophy, Oculopharyngeal / pathology
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Poly(A)-Binding Protein I / biosynthesis
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Poly(A)-Binding Protein I / genetics*
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Polyadenylation / genetics
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics*
Substances
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Mitochondrial Proteins
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PABPN1 protein, human
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Poly(A)-Binding Protein I
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RNA, Messenger
Associated data
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GEO/GSE26604
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GEO/GSE64094
Grants and funding
This work was funded by: Centre National de la Recherche Scientifique (CNRS) UPR1142, the Agence Nationale pour la Recherche Genopat (ANR-09-GENO-025-01 from GIS-Maladies Rares and Association Française contre les Myopathies (AFM)), the Fondation pour la Recherche Médicale ("Equipe FRM 2007 DEQ20071210560", "Equipe FRM 2013 DEQ20130326534" and "Projets Innovants ING20101221078"), the European Commission (EC:PolyALA LSHM-CT-2005-018675), and the AFM-TELETHON (Research Programs 15123 and 17110) to MS; the University Paris VI Pierre et Marie Curie, the Institut National de la Santé et de la Recherche Médicale, the CNRS, the Fondation de l’avenir (project ET1-622) and the AFM-TELETHON (Research Programs 15123 and 17110) to CT; and the Muscular Dystrophy Ireland, a Hume scholarship from the National University of Ireland, Maynooth, and a Ulysses travel grant from Enterprise Ireland to KO. NB held a salary from the EC (PolyALA LSHM-CT-2005-018675) and ANR-Maladies Rares, LM from the AFM (15123) and SP from the FRM (Projets Innovants). PK held a salary from the Ministère de l'Education Nationale de la Recherche et de la Technologie. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.