Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Dhaenens, C. M.²  Tran, H.²  Frandemiche, M-L.²  Carpentier, C.²  Schraen-Maschke, S.²  Sistiaga, A.^3,4,7  Goicoechea, M.^3,4,7  Eddarkaoui, S.²  Van Brussels, E.²  Obriot, H.²  Labudeck, A.⁵  Gevaert, M. H.⁵  Fernandez-Gomez, F.²  Charlet-Berguerand, N.⁶  Maurage, C. A.²  Buee, L.²  Lopez de Munain, A.^3,4,7  Sablonniere, B.²  Caillet-Boudin, M. L.²  Sergeant, N.^1,2 

[1] Univ Lille Nord France, INSERM, Alzheimer & Tauopathies U837 1, USDL,IMPRT, F-59045 Lille, France

[2] Univ Lille Nord France, UDSL, Fac Med, Inst Predict Med & Therapeut Res,Jean Pierre Aube, F-59045 Lille, France

[3] Donostia Hosp, Expt Unit, San Sebastian 20014, Spain

[4] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 528031, Spain

[5] CHU Lille, Dept Neuropathol, Reg Univ Hosp Ctr, F-59037 Lille, France

[6] IGBMC, INSERM, AVENIR Grp, F-67404 Illkirch Graffenstaden, France

[7] Donostia Hosp, Neurol Unit, San Sebastian 20014, Spain

关键词: Myotonic dystrophy;    Triplet expansion disease;    Microtubule-associated protein Tau;    Splicing;    CELF splicing factor family;    MBNL1;   

DOI  :  10.1016/j.bbadis.2011.03.010

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier B.V. All rights reserved.

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