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Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation

التفاصيل البيبلوغرافية
العنوان: Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation
المؤلفون: Jongkyu Choi, Kirkwood E. Personius, Marino DiFranco, Warunee Dansithong, Carl Yu, Saumya Srivastava, Donald M. Dixon, Darshan B. Bhatt, Lucio Comai, Julio L. Vergara, Sita Reddy
المصدر: EBioMedicine, Vol 2, Iss 9, Pp 1034-1047 (2015)
بيانات النشر: Elsevier, 2015.
سنة النشر: 2015
المجموعة: LCC:Medicine
LCC:Medicine (General)
مصطلحات موضوعية: Muscleblind-like 1, Muscleblind-like 2, Myotonia, Clc-1, RNA translation, Medicine, Medicine (General), R5-920
الوصف: Loss of Muscleblind-like 1 (Mbnl1) is known to alter Clc-1 splicing to result in myotonia. Mbnl1ΔE3/ΔE3/Mbnl3ΔE2 mice, depleted of Mbnl1 and Mbnl3, demonstrate a profound enhancement of myotonia and an increase in the number of muscle fibers with very low Clc-1 currents, where gClmax values approach ~1 mS/cm2, with the absence of a further enhancement in Clc-1 splice errors, alterations in polyA site selection or Clc-1 localization. Significantly, Mbnl1ΔE3/ΔE3/Mbnl3ΔE2 muscles demonstrate an aberrant accumulation of Clc-1 RNA on monosomes and on the first polysomes. Mbnl1 and Mbnl3 bind Clc-1 RNA and both proteins bind Hsp70 and eEF1A, with these associations being reduced in the presence of RNA. Thus binding of Mbnl1 and Mbnl3 to Clc-1 mRNA engaged with ribosomes can facilitate an increase in the local concentration of Hsp70 and eEF1A to assist Clc-1 translation. Dual depletion of Mbnl1 and Mbnl3 therefore initiates both Clc-1 splice errors and translation defects to synergistically enhance myotonia. As the HSALR model for myotonic dystrophy (DM1) shows similar Clc-1 defects, this study demonstrates that both splice errors and translation defects are required for DM1 pathology to manifest. Research in context: Research in context: Myotonic Dystrophy type 1 (DM1) is a dominant disorder resulting from the expression of expanded CUG repeat RNA, which aberrantly sequesters and inactivates the muscleblind-like (MBNL) family of proteins. In mice, inactivation of Mbnl1 is known to alter Clc-1 splicing to result in myotonia. We demonstrate that concurrent depletion of Mbnl1 and Mbnl3 results in a synergistic enhancement of myotonia, with an increase in muscle fibers showing low chloride currents. The observed synergism results from the aberrant accumulation of Clc-1 mRNA on monosomes and the first polysomes. This translation error reflects the ability of Mbnl1 and Mbnl3 to act as adaptors that recruit Hsp70 and eEF1A to the Clc-1 mRNA engaged with ribosomes, to facilitate translation. Thus our study demonstrates that Clc-1 RNA translation defects work coordinately with Clc-1 splice errors to synergistically enhance myotonia in mice lacking Mbnl1 and Mbnl3.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2352-3964
Relation: http://www.sciencedirect.com/science/article/pii/S2352396415300803; https://doaj.org/toc/2352-3964
DOI: 10.1016/j.ebiom.2015.07.028
URL الوصول: https://doaj.org/article/75518b18e54c49019f1c7a530c742778
رقم الأكسشن: edsdoj.75518b18e54c49019f1c7a530c742778
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:23523964
DOI:10.1016/j.ebiom.2015.07.028