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Human Molecular Genetics Advance Access published online on May 24, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl137
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received March 20, 2006
Revised May 19, 2006
Accepted May 19, 2006

Article

MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of Myotonic Dystrophy Type 1

María de Haro 1, Ismael Al-Ramahi 1, Beatrice De Gouyon 2, Lubna Ukani 2, Alberto Rosa 3, Nuno André Faustino 4, Tetsuo Ashizawa 5, Thomas A. Cooper 4, and Juan Botas 2 *

1 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Departamento de Biología, Facultad de Ciencias-UAM, Madrid 28049, Spain.
2 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
3 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Laboratorio de Neurogenética, Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra, Córdoba 5016, Argentina.
4 Departments of Pathology and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
5 Department of Neurology, University of Texas Medical Branch, Galveston 77555, TX.

* To whom correspondence should be addressed.
Juan Botas, E-mail: jbotas{at}bcm.tmc.edu


  Abstract

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG expansion in the 3' UTR of the DMPK gene. It has been hypothesized that the pathogenesis in DM1 is triggered by a toxic gain of function of the expanded DMPK RNA. This expanded RNA is retained in nuclear foci where it sequesters and induces alterations in the levels of RNA-binding proteins. To model DM1 and study the implication of RNA-binding proteins in CUG-induced toxicity, we have generated a Drosophila DM1 model expressing a non-coding mRNA containing 480 interrupted CUG repeats; i.e., [(CUG)20CUCGA]24. This (iCUG)480 transcript accumulates in nuclear foci and its expression leads to muscle wasting and degeneration in Drosophila. We also report that altering the levels of two RNA-binding proteins known to be involved in DM1 pathogenesis, MBNL1 and CUGBP1, modify the (iCUG)480 degenerative phenotypes. Expanded CUG-induced toxicity in Drosophila is suppressed when MBNL1 expression levels are increased, and enhanced when MBNL1 levels are reduced. In addition, (iCUG)480 also causes a decrease in the levels of soluble MBNL1, which is sequestered in the CUG-containing nuclear foci. In contrast, increasing the levels of CUGBP1 worsens (iCUG)480-induced degeneration even though CUGBP1 distribution is not altered by expression of the expanded triplet repeat. Our data supports a mechanism for DM1 pathogenesis in which decreased levels of MBNL and increased levels of CUGBP mediate the RNA-induced toxicity observed in DM1. Perhaps more importantly they also provide proof of principle that CUG-induced muscle toxicity can be suppressed.


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