Although myotonic dystrophy (DM) is a multi-systemic neuromuscular disorder, previous mechanistic studies have emphasized disease-associated heart and skeletal muscle abnormalities. However, the DM brain is also profoundly affected with abnormal behavior and cognition, progressive memory loss and cerebral atrophy. The long-term objective of the proposed research is to elucidate the molecular basis for CMS pathology in DM. DM is an RNA-mediated disease caused by the expansion of CTG and CCTG microsatellites in two different genes. Following transcription, mutant CUG and CCUG expansions accumulate in the nucleus and inhibit the RNA alternative splicing activity of the muscleblind-like (MBNL) proteins. During normal postnatal development, MBNL proteins promote skipping of specific fetal exons during RNA splicing by antagonizing the CUGBP1 and ETR-3-like splicing factor (CELF) proteins. Thus, DM is caused by retention of fetal protein isoforms in the adult. While this model explains specific aspects of muscle pathology, including myotonia, it is unclear if a similar pathogenesis mechanism occurs in the brain. This proposal is divided into three specific aims designed to pursue the hypothesis that specific defects in gene expression and RNA splicing induced by expansion RNAs results in the CNS phenotype associated with DM. First, we determine if loss of Mbnh gene, or poly(CCUG) transgene, expression results in similar DM-relevant alterations in the expression and splicing patterns of specific gene transcripts in several different regions of the developing and postnatal brain. Second, we will test the hypothesis that conditional loss of MbnM and/or Mbnl2 gene expression in the brain results in postnatal neurological deficits while MbnIS expression is essential for normal embryonic brain development. Third, recombinant adeno-associated virus (rAAV)-mediated transduction of neurons will be used to test the possibility that abnormal RNA splicing and expression patterns in transgenic poly(CCUG) mouse models for DM1 and DM2 can be modulated by overexpression of Celf and Mbnl proteins in vivo. These studies should elucidate the molecular events underlying DM pathogenesis in the CNS and identify molecular targets for future therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
United States
Zip Code
Pattamatta, Amrutha; Cleary, John D; Ranum, Laura P W (2018) All in the Family: Repeats and ALS/FTD. Trends Neurosci 41:247-250
Sznajder, ?ukasz J; Thomas, James D; Carrell, Ellie M et al. (2018) Intron retention induced by microsatellite expansions as a disease biomarker. Proc Natl Acad Sci U S A 115:4234-4239
Chen, Gang; Carter, Russell E; Cleary, John D et al. (2018) Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy. Neurobiol Dis 112:35-48
Cleary, John Douglas; Pattamatta, Amrutha; Ranum, Laura P W (2018) Repeat-associated non-ATG (RAN) translation. J Biol Chem 293:16127-16141
Grima, Jonathan C; Daigle, J Gavin; Arbez, Nicolas et al. (2017) Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron 94:93-107.e6
Nakamori, Masayuki; Hamanaka, Kohei; Thomas, James D et al. (2017) Aberrant Myokine Signaling in Congenital Myotonic Dystrophy. Cell Rep 21:1240-1252
Zu, Tao; Cleary, John D; Liu, Yuanjing et al. (2017) RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. Neuron 95:1292-1305.e5
Thomas, James D; Sznajder, ?ukasz J; Bardhi, Olgert et al. (2017) Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy. Genes Dev 31:1122-1133
Cleary, John Douglas; Ranum, Laura Pw (2017) New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev 44:125-134
Moloney, Christina; Rayaprolu, Sruti; Howard, John et al. (2016) Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype. Acta Neuropathol Commun 4:122

Showing the most recent 10 out of 57 publications