Title :

Nuclear poly(A)-binding protein aggregates misplace a pre-mRNA outside of SC35 speckle causing its abnormal splicing.

Author(s) :

Klein, Pierre [Auteur]
Centre de recherche en myologie
Oloko, Martine [Auteur]
Centre de recherche en myologie
Roth, Fanny [Auteur]
Centre de recherche en myologie
Montel, Valérie [Auteur]
Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS]
Malerba, Alberto [Auteur]
University of London [London]
Jarmin, Susan [Auteur]
University of London [London]
Gidaro, Teresa [Auteur]
Centre de recherche en myologie
Popplewell, Linda [Auteur]
University of London [London]
Perie, Sophie [Auteur]
Centre de recherche en myologie
Lacau St Guily, Jean [Auteur]
Centre de recherche en myologie
de la Grange, Pierre [Auteur]
CHU Pitié-Salpêtrière [AP-HP]
Antoniou, Michael N [Auteur]
Guy's Hospital [London]
Dickson, George [Auteur]
University of London [London]
Butler-Browne, Gillian [Auteur]
Centre de recherche en myologie
Bastide, Bruno [Auteur]
Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS]
Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369
Mouly, Vincent [Auteur]
Centre de recherche en myologie
Trollet, Capucine [Auteur]
Centre de recherche en myologie

Journal title :

Nucleic acids research

Abbreviated title :

Nucleic Acids Res

Volume number :

44

Pages :

10929-10945

Publication date :

2016-12

ISSN :

1362-4962

English keyword(s) :

Adult
Aged
Aged
80 and over
Alternative Splicing
Animals
Case-Control Studies
Female
HEK293 Cells
Humans
Male
Mice
Mice
Transgenic
Middle Aged
Muscle
Skeletal
Muscular Dystrophy
Oculopharyngeal
Poly(A)-Binding Protein I
Protein Aggregates
RNA Precursors
RNA Transport
Serine-Arginine Splicing Factors
Troponin T

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Non spécifiée

Administrative institution(s) :

Université de Lille
Univ. Artois
Univ. Littoral Côte d’Opale

Collections :

• Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369

Research team(s) :

Activité Physique, Muscle, Santé (APMS)

Submission date :

2020-07-20T15:19:23Z
2020-08-18T11:51:47Z
2020-08-18T11:53:08Z
2022-02-09T08:38:22Z