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The Journal of Neuroscience, July 15, 2009, 29(28):9042-9049; doi:10.1523/JNEUROSCI.1983-09.2009

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Cellular/Molecular
Reduction of the Rate of Protein Translation in Patients with Myotonic Dystrophy 2

Claudia Huichalaf,¹ Benedikt Schoser,² Christiane Schneider-Gold,³ Bingwen Jin,¹ Partha Sarkar,⁴ and Lubov Timchenko¹

¹Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, ²Friedrich-Baur Institute, Department of Neurology, Ludwig-Maximilians-University, 80336 Munich, Germany, ³Department of Neurology, St. Josef Hospital of the Ruhr–University of Bochum, 44791 Bochum, Germany, and ⁴The University of Texas Medical Branch, Galveston, Texas 77555

Correspondence should be addressed to Dr. Lubov Timchenko, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030. Email: lubovt{at}bcm.tmc.edu

Myotonic dystrophy 2 (DM2) is an autosomal dominant, multisystem disease, which primarily affects skeletal muscle. DM2 is caused by CCTGn expansion in the intron 1 of the ZNF9 gene. Expression of the mutant CCUGn RNA changes RNA processing in patients with DM2; however, the role of ZNF9 protein in DM2 pathology has been not elucidated. ZNF9 has been shown to regulate cap-dependent and cap-independent translation. We have examined a possible role of ZNF9 in the regulation of translation in DM2 patients. We found that ZNF9 interacts with the 5' UTRs of terminal oligopyrimidine (TOP) tract mRNAs encoding human ribosomal protein, RPS17, poly(A)-binding protein 1 (PABP1), and the elongation factors, eEF1A and eEF2. The binding activity of ZNF9 toward these TOP-containing 5' UTRs is reduced in DM2 muscle. Consistent with the reduction of this activity, the levels of RPS17, PABP, eEF1A, and eEF2 proteins are also diminished in DM2 muscle. The reduction of ZNF9 RNA-binding activity in DM2 correlates with a decrease of ZNF9 protein levels in cytoplasm of DM2 muscle cells. We found that the reduction of ZNF9 is caused by expression of the mutant CCUG repeats. This decrease of proteins of translational apparatus in DM2 correlates with a reduction of a rate of protein synthesis in myoblasts from DM2 patients. We found that the ectopic expression of ZNF9 in DM2 myoblasts corrects rate of protein synthesis, suggesting that the alterations in CCUG-ZNF9-TOP mRNAs pathway are responsible for the reduction of the rate of protein translation in DM2 muscle cells.

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Received April 27, 2009; revised June 3, 2009; accepted June 15, 2009.

Correspondence should be addressed to Dr. Lubov Timchenko, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030. Email: lubovt{at}bcm.tmc.edu

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