HISTOLOGY AND HISTOPATHOLOGY

Cellular and Molecular Biology

 

Review

Dysfunction of protein homeostasis in myotonic dystrophies

Giovanni Meola1, Karlie Jones2, Christina Wei2 and Lubov T. Timchenko2

1Department of Neurology, University of Milan, IRCCS Policlinico San Donato, San Donato, Milan, Italy and 2Department of Molecular Physiology and Biophysics, One Baylor Plaza, Houston, TX, USA.

Offprint requests to: Prof. Lubov Timchenko, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. e-mail: lubovt@bcm.edu


Summary. Neuromuscular diseases Myotonic Dystrophies type 1 and type 2 (DM1 and DM2) are caused by unstable CTG and CCTG repeat expansions and have highly complex molecular mechanisms. DM1 is caused by the expansion of CTG repeats in the 3’ UTR of the gene coding for Dystrophia Myotonica-Protein Kinase (DMPK). In DM2, intronic CCTG repeats are located in a gene encoding the Zinc Finger Protein 9 (ZNF9, also known as Cellular Nucleic Acid Binding Protein, CNBP). Both expansions cause pathologies through RNA CUG and CCUG repeats, which have toxic effects on the processing of many RNAs in the patients’ tissues. The pathogenic role of CUG and CCUG repeats in the mis-regulation of alternative splicing, mediated by RNA-binding proteins CUGBP1 and MBNL1, has been discussed in a number of excellent reviews. Recent reports suggest that mutant RNA repeats affect several other RNA-binding proteins such as Staufen1 and the DEAD-box RNA helicase p68 (DDX5). Since CUGBP1, Staufen1 and p68 have many functions in cytoplasm, including regulation of protein translation, it is predicted that the alterations of these proteins in DM cells might have a toxic effect on global protein turnover. In this mini-review, we will summarize observations showing the role of RNA-binding proteins, CUGBP1 and ZNF9, in protein turnover in DM1 and in DM2. We will also discuss a possible role of misbalanced protein turnover in the age-dependent progression of DM1 and in a late onset of DM2
. Histol Histopathol 28, 1089-1098 (2013)

Key words: Myotonic Dystrophy, CUGBP1, ZNF9, Translation, Aging

DOI: 10.14670/HH-28.1089