title: Nuclear poly(A)-binding protein aggregates misplace a pre-mRNA outside of SC35 speckle causing its abnormal splicing.
abstract: A short abnormal polyalanine expansion in the polyadenylate-binding protein nuclear-1 (PABPN1) protein causes oculopharyngeal muscular dystrophy (OPMD). Mutated PABPN1 proteins accumulate as insoluble intranuclear aggregates in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice have been established, the molecular mechanisms which trigger pathological defects in OPMD and the role of aggregates remain to be determined. Using exon array, for the first time we have identified several splicing defects in OPMD. In particular, we have demonstrated a defect in the splicing regulation of the muscle-specific Troponin T3 (TNNT3) mutually exclusive exons 16 and 17 in OPMD samples compared to controls. This splicing defect is directly linked to the SC35 (SRSF2) splicing factor and to the presence of nuclear aggregates. As reported here, PABPN1 aggregates are able to trap TNNT3 pre-mRNA, driving it outside nuclear speckles, leading to an altered SC35-mediated splicing. This results in a decreased calcium sensitivity of muscle fibers, which could in turn plays a role in muscle pathology. We thus report a novel mechanism of alternative splicing deregulation that may play a role in various other diseases with nuclear inclusions or foci containing an RNA binding protein.
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.
authors: Pierre
authors: P
authors: Klein
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.
authors: Martine
authors: M
authors: Oloko
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.
authors: Fanny
authors: F
authors: Roth
authors: Univ. Lille - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, équipe APMS, F-59000 Lille, France.
authors: Valérie
authors: V
authors: Montel
authors: School of Biological Sciences, Royal Holloway - University of London, Egham, Surrey TW20 0EX, UK.
authors: Alberto
authors: A
authors: Malerba
authors: School of Biological Sciences, Royal Holloway - University of London, Egham, Surrey TW20 0EX, UK.
authors: Susan
authors: S
authors: Jarmin
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.
authors: Teresa
authors: T
authors: Gidaro
authors: School of Biological Sciences, Royal Holloway - University of London, Egham, Surrey TW20 0EX, UK.
authors: Linda
authors: L
authors: Popplewell
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.|Department of Otolaryngology-Head and Neck Surgery, University Pierre-et-Marie-Curie, Paris VI, Tenon Hospital, Assistance Publique des Hopitaux de Paris, Paris, France.
authors: Sophie
authors: S
authors: Perie
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.|Department of Otolaryngology-Head and Neck Surgery, University Pierre-et-Marie-Curie, Paris VI, Tenon Hospital, Assistance Publique des Hopitaux de Paris, Paris, France.
authors: Jean
authors: J
authors: Lacau St Guily
authors: GenoSplice, ICM, Hôpital de la Pitié Salpêtrière, Paris, France.
authors: Pierre
authors: P
authors: de la Grange
authors: King's College London School of Medicine, Gene Expression and Therapy Group, Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.
authors: Michael N
authors: MN
authors: Antoniou
authors: School of Biological Sciences, Royal Holloway - University of London, Egham, Surrey TW20 0EX, UK.
authors: George
authors: G
authors: Dickson
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.
authors: Gillian
authors: G
authors: Butler-Browne
authors: Univ. Lille - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, équipe APMS, F-59000 Lille, France.
authors: Bruno
authors: B
authors: Bastide
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France.
authors: Vincent
authors: V
authors: Mouly
authors: Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, 47 bd de l'Hôpital, 75013 Paris, France capucine.trollet@upmc.fr.
authors: Capucine
authors: C
authors: Trollet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D034443:RNA Transport; D000068103:Serine-Arginine Splicing Factors / Q000378:metabolism; D020107:Troponin T / Q000235:genetics* / Q000378:metabolism
chemical_list: C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D066329:Protein Aggregates; D012322:RNA Precursors; C518660:TNNT3 protein, human; D020107:Troponin T; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors