title: Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.
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.
authors: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
authors: Aymeric
authors: A
authors: Chartier
authors: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Paris, France.
authors: Pierre
authors: P
authors: Klein
authors: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
authors: Stéphanie
authors: S
authors: Pierson
authors: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
authors: Nicolas
authors: N
authors: Barbezier
authors: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Paris, France.
authors: Teresa
authors: T
authors: Gidaro
authors: INRA, UMR 866 Différenciation cellulaire et croissance, Montpellier, France.
authors: François
authors: F
authors: Casas
authors: Department of Biology, National University of Ireland, Maynooth, Ireland.
authors: Steven
authors: S
authors: Carberry
authors: Department of Biology, National University of Ireland, Maynooth, Ireland.
authors: Paul
authors: P
authors: Dowling
authors: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
authors: Laurie
authors: L
authors: Maynadier
authors: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
authors: Maëlle
authors: M
authors: Bellec
authors: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Paris, France.
authors: Martine
authors: M
authors: Oloko
authors: Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, INSERM U1016, Institut Cochin, CNRS UMR 8104, AP-HP, GHU Pitié-Salpêtrière, Paris, France.
authors: Claude
authors: C
authors: Jardel
authors: Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors: Bodo
authors: B
authors: Moritz
authors: School of Biological Sciences, Royal Holloway - University of London, Egham, Surrey, United Kingdom.
authors: George
authors: G
authors: Dickson
authors: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Paris, France.
authors: Vincent
authors: V
authors: Mouly
authors: Department of Biology, National University of Ireland, Maynooth, Ireland.
authors: Kay
authors: K
authors: Ohlendieck
authors: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Paris, France.
authors: Gillian
authors: G
authors: Butler-Browne
authors: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Paris, France.
authors: Capucine
authors: C
authors: Trollet
authors: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
authors: Martine
authors: M
authors: Simonelig
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics* / Q000473:pathology; D039122:Poly(A)-Binding Protein I / Q000096:biosynthesis / Q000235:genetics*; D026723:Polyadenylation / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D012333:RNA, Messenger