Lubov Timchenko, Ph.D.
Ph.D., Institute of Experimental Medicine, St-Petersburg
Postdoctoral, Baylor College of Medicine
Research Program Description
The Timchenko laboratory investigates molecular bases of Myotonic Dystrophies type 1 and type 2. These diseases are complex and are associated with multiple symptoms in many organs and systems (see diagram). We have discovered that major symptoms of DM1 are mediated by accumulation of un-translated RNA CUG repeats within the mutant DMPK mRNA. Our hypothesis is that expanded CUG repeats interact with specific RNA-binding proteins and interfere with their functions. As the result, RNA metabolism is affected in patients’ tissues. We have identified a CUGBP family of RNA-binding proteins including CUGBP1 and ETR-3. The mutant CUG repeats stabilize CUGBP1 protein. The elevation of CUGBP1 in DM1 tissues, in turn, results in the alterations of processing of RNAs. CUGBP1 regulates three important steps of RNA processing: translation, RNA stability and splicing. The laboratory is focused on the translational function of CUGBP1.
We recently found that CUG repeats alter signal transduction pathways creating stressful environment. As the result of stress, cytoplasm accumulates stress granules that inhibit translation of mRNAs. We are investigating if stress-related inhibition of translation in DM1 is responsible for under-development and dys-function of DM1 muscle. We are also searching for approaches for the correction of the signal transduction pathways in DM1 and for correction of DM1 muscle pathology.
Myotonic Dystrophy type 2 (DM2), which is a second disease, investigated in my lab. DM2 is caused by expansion of CCTG repeats located in intron of ZNF9 gene. We found that CCUG repeats reduce the rate of global protein synthesis through reduction of ZNF9. ZNF9 is an RNA-binding protein that interacts with the 5’ UTRs of TOP (terminal oligopyrimidine tract) mRNAs. TOP mRNAs encode proteins of translational apparatus including human ribosomal protein, RPS17, poly(A)-binding protein, PABP1, and elongation factors, eEF1A and eEF2. The binding activity of ZNF9 toward these TOP-containing 5’ UTRs is reduced in DM2 muscle decreasing proteins of translational apparatus. This decrease of proteins of translational apparatus in DM2 reduces rate of global protein synthesis in DM2 muscle precursors. The lab is investigating the role of reduction of the rate of global protein synthesis in muscle loss using muscle biopsies, cultured myoblasts from DM2 patients and mouse models with the goal to correct muscle weakness in DM2.
The development of approaches to degrade the mutant DMPK mRNA and mutant CCUG repeats is one of the most important directions in my lab. We have identified several CCUG100-binding proteins that alter their activities during accumulation and degradation of CCUG repeats. The role of these proteins in the degradation of the mutant CCUG repeats and DMPK mRNA and correction of DM1/2 symptoms will be studied in mouse models of DM1 and DM2: CTG and CCTG transgenic mice. It is expected that these studies will set the stage for the elimination of CUG and CCUG toxicity in a clinical setting.