Myotonic Dystrophy type 1 (DM1) is a complex disease affecting many organs including skeletal muscle and the Central Nervous System (CNS). The majority of mechanistic studies in the DM1 field have been focused on muscle and very little is known about the molecular pathogenesis of CNS dysfunction in DM1. DM1 is caused by the expanded CUG repeats which misregulate RNA-binding proteins of two families, MBNL and CUGBP (CELF). Proteins of both families are expressed in many tissues, including the CNS. CUGBP1 activity is regulated by GSK3-cyclin D3-CDK4 dependent phosphorylation. In DM1, CUG repeats reduce phosphorylation of CUGBP1 at S302 via increase of GSK3 kinase, thereby converting active CUGBP1 into inactive un-pS302-CUGBP1 (termed CUGBP1 repressor or CUGBP1REP) because it blocks translation of mRNAs in Stress Granules. We found that GSK3 is increased in the brains of congenital DM1 (CDM1) mice (DMSXL model). CUGBP1REP is also elevated in the brains of DMSXL mice. The prenatal treatment of DMSXL mice with the inhibitor of GSK3, tideglusib (TG), increases survival rate of underdeveloped DMSXL mice, improves their growth and strength and reduces their anxiety. These findings suggest that the inhibitors of GSK3 are good candidate drugs to reduce CNS defects in CDM1 via correction of GSK3-CUGBP1REP pathway in brain. In support of this hypothesis, recent Phase IIa clinical trial for adult CDM1 showed that TG has beneficial effect on cognitive function in patients with CDM1. Since GSK3? has many substrates in brain, the inhibitors of GSK3 might affect many pathways. This project will determine the contribution of the GSK3-CUGBP1REP pathway in CNS pathogenesis of CDM1 (Aim 1). We will address this question by analysis of DMSXL mice crossed with a new mouse model in which the GSK3-cyclin D3-CDK4 site of CUGBP1 (S302) is mutated (S302A knock in model). The molecular pathways disrupted by the mutant DMPK mRNA in the brains of DMSXL mice will be compared to those disrupted by CUGBP1REP in the brains of S302A mice. We found that the inhibitor of GSK3, TG, reduces the mutant DMPK mRNA in skeletal muscle cell precursors from patients with CDM1, correcting splicing events in myoblasts. To determine if TG has the same function in CNS of CDM1, we will test if TG reduces the mutant DMPK mRNA in the brains of DMSXL mice, normalizing splicing of brain-specific mRNAs (Aim 2). Positive long-term effect of the prenatal treatment of DMSXL mice with TG suggests that early correction of GSK3? in CDM1 is critical for the improved development of CDM1 patients.
Aim 3 of the project will test if short postnatal treatments with TG have a long-term positive effect on phenotype of DMSXL mice. The therapeutic effect of TG will be also examined in DMSXL mice, treated at young age and in adulthood. The knowledge generated is critical for the development of the GSK3 based therapies of CNS dysfunction in CDM1.

Public Health Relevance

Myotonic Dystrophy type 1 is a complex disease characterized by CNS dysfunction. Patients with the severe congenital DM1 (CDM1) are intellectually challenged. There is no cure for CNS dysfunction in DM1. We propose to apply new mouse model to determine the cause of CNS dysfunction in CDM1. The development of drug for the reduction of CNS pathology in CDM1 will be performed in mouse model of CDM1. The obtained knowledge will be used for the developing clinical trial for pediatric patients with CDM1.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Nuckolls, Glen H
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Cincinnati Children's Hospital Medical Center
United States
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