title: Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing.
abstract: Tau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type 1. In myotonic dystrophy type 1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the ribonucleic acid level is a major etiological factor responsible for the mis-splicing of several transcripts in myotonic dystrophy type 1. These are probably the consequence of a loss of muscleblind-like 1 (MBNL1) function or gain of CUGBP1 and ETR3-like factor 1 (CELF1) splicing function. Whether these two dysfunctions occur together or separately and whether all mis-splicing events in myotonic dystrophy type 1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of myotonic dystrophy type 1 patients. Two myotonic dystrophy type 1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all myotonic dystrophy type 1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1), CUGBP1 and ETR3-like factor 2 (CELF2), and CUGBP1 and ETR3-like factor 4 (CELF4) or a dominant-negative CUGBP1 and ETR-3 like factor (CELF) factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CUGBP1 and ETR3-like factor 2 (CELF2) whereas it is insensitive to the loss-of-function of muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1) gain-of-function, or a dominant-negative of CUGBP1 and ETR-3 like factor (CELF) factor. Moreover, we observed an increased expression of CUGBP1 and ETR3-like factor 2 (CELF2) only in the brain of myotonic dystrophy type 1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a mis-splicing event in myotonic dystrophy type 1 that is induced neither by a loss of muscleblind-like 1 (MBNL1) function nor by a gain of CUGBP1 and ETR3-like factor 1 (CELF1) function but is rather associated to CUGBP1 and ETR3-like factor 2 (CELF2) gain-of-function.
authors: Inserm, U837-1, Alzheimer & Tauopathies, place de Verdun, F-59045 Lille, France.
authors: C M
authors: CM
authors: Dhaenens
authors: H
authors: H
authors: Tran
authors: M-L
authors: ML
authors: Frandemiche
authors: C
authors: C
authors: Carpentier
authors: S
authors: S
authors: Schraen-Maschke
authors: A
authors: A
authors: Sistiaga
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authors: M
authors: Goicoechea
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authors: S
authors: Eddarkaoui
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authors: E
authors: Van Brussels
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authors: Obriot
authors: A
authors: A
authors: Labudeck
authors: M H
authors: MH
authors: Gevaert
authors: F
authors: F
authors: Fernandez-Gomez
authors: N
authors: N
authors: Charlet-Berguerand
authors: V
authors: V
authors: Deramecourt
authors: C A
authors: CA
authors: Maurage
authors: L
authors: L
authors: Buée
authors: A
authors: A
authors: Lopez de Munain
authors: B
authors: B
authors: Sablonnière
authors: M L
authors: ML
authors: Caillet-Boudin
authors: N
authors: N
authors: Sergeant
mesh_terms: D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D000067878:CELF Proteins; D017931:DNA Primers; D005091:Exons; D020868:Gene Silencing; D006801:Humans; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000067878:CELF Proteins; C117363:CELF2 protein, human; D017931:DNA Primers; C493663:MBNL1 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D016875:tau Proteins