Misregulation of Alternative Splicing Causes Pathogenesis in Myotonic Dystrophy

Kuyumcu-Martinez, N. Muge; Cooper, Thomas A.

doi:10.1007/978-3-540-34449-0_7

Cited by 68 publications

(51 citation statements)

References 165 publications

(242 reference statements)

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“…Loss of MBNL1 function and elevated CUGBP1 protein levels are 2 major molecular events involved in DM1 pathogenesis (6). However, the individual roles of CUGBP1 and/or MBNL1 in the DM1 cardiac phenotype remain undefined.…”

Section: Discussionmentioning

confidence: 99%

“…A major molecular feature of DM1 is misregulation of a subset of alternative splicing events, resulting in the inappropriate expression of embryonic splicing patterns in adult tissues (6). The basis for these splicing transitions is a gain of function for CUGBP1 and a loss of MBNL1 function (1).…”

Section: Figurementioning

confidence: 99%

“…Nuclear accumulation of the DMPK RNA with expanded CUG repeats triggers events that lead to disruption of developmentally regulated alternative splicing (6), which result in some of the disease symptoms such as myotonia and insulin resistance (7)(8)(9). At least 2 families of RNA-binding proteins are implicated in DM1 pathogenesis: CUGBP and ETR3-like proteins (CELF) and muscleblind like (MBNL).…”

Section: Introductionmentioning

confidence: 99%

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PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1

Wang¹,

Kuyumcu‐Martinez²,

Sarma³

et al. 2009

J. Clin. Invest.

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102

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Cardiac complications are a common cause of death in individuals with the inherited multisystemic disease myotonic dystrophy type 1 (DM1). A characteristic molecular feature of DM1 is misregulated alternative splicing due to disrupted functioning of the splicing regulators muscleblind-like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1). CUGBP1 is upregulated in DM1 due to PKC pathway activation and subsequent CUGBP1 protein hyperphosphorylation and stabilization. Here, we blocked PKC activity in a heart-specific DM1 mouse model to determine its pathogenic role in DM1. Animals given PKC inhibitors exhibited substantially increased survival that correlated with reduced phosphorylation and decreased steady-state levels of CUGBP1. Functional studies demonstrated that PKC inhibition ameliorated the cardiac conduction defects and contraction abnormalities found in this mouse model. The inhibitor also reduced misregulation of splicing events regulated by CUGBP1 but not those regulated by MBNL1, suggesting distinct roles for these proteins in DM1 cardiac pathogenesis. The PKC inhibitor did not reduce mortality in transgenic mice with heart-specific CUGBP1 upregulation, indicating that PKC inhibition did not have a general protective effect on PKC-independent CUGBP1 increase. Our results suggest that pharmacological blockade of PKC activity mitigates the DM1 cardiac phenotype and provide strong evidence for a role for the PKC pathway in DM1 pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1

Wang¹,

Kuyumcu‐Martinez²,

Sarma³

et al. 2009

J. Clin. Invest.

Self Cite

102

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show abstract

“…Altered activities of MBNL and CELF proteins mediate the disrupted alternative splicing observed in DM1 (2,31). In addition, altered CUGBP1 cytoplasmic function is proposed to alter regulated translation of key myogenic proteins in skeletal muscle contributing to muscle degeneration (32).…”

Section: Discussionmentioning

confidence: 99%

Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy

et al. 2007

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Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide expansion in the 3′ untranslated region (3′ UTR) of DM protein kinase (DMPK). The key feature of DM1 pathogenesis is nuclear accumulation of RNA, which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of CUG-binding proteins (CUGBPs). Cardiac involvement occurs in more than 80% of individuals with DM1 and is responsible for up to 30% of disease-related deaths. We have generated an inducible and heart-specific DM1 mouse model expressing expanded CUG RNA in the context of DMPK 3′ UTR that recapitulated pathological and molecular features of DM1 including dilated cardiomyopathy, arrhythmias, systolic and diastolic dysfunction, and misregulated alternative splicing. Combined in situ hybridization and immunofluorescent staining for CUGBP1 and CUGBP2, the 2 CUGBP1 and ETR-3 like factor (CELF) proteins expressed in heart, demonstrated elevated protein levels specifically in nuclei containing foci of CUG repeat RNA. A time-course study demonstrated that colocalization of MBNL1 with RNA foci and increased CUGBP1 occurred within hours of induced expression of CUG repeat RNA and coincided with reversion to embryonic splicing patterns. These results indicate that CUGBP1 upregulation is an early and primary response to expression of CUG repeat RNA.

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“…This is thought to be a causative event of DM1. The toxic RNA hypothesis posits that these nuclear foci sequester essential proteins and disrupt their normal function in the cell (Kuyumcu-Martinez and Cooper, 2006;Miller et al, 2000;Nykamp and Swanson, 2004;Ranum and Day, 2004). In support of the toxic RNA hypothesis, a mouse model reproduced key DM1 features by expressing an unrelated mRNA with 250 CUG repeats (Mankodi et al, 2000).…”

Section: Introductionmentioning

confidence: 98%

Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats

Querido

Gallardo

Beaudoin

et al. 2011

Journal of Cell Science

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SummaryTranscripts containing expanded CNG repeats, which are found in several neuromuscular diseases, are not exported from the nucleus and aggregate as ribonuclear inclusions by an unknown mechanism. Using the MS2-GFP system, which tethers fluorescent proteins to a specific mRNA, we followed the dynamics of single CUG-repeat transcripts and RNA aggregation in living cells. Single transcripts with 145 CUG repeats from the dystrophia myotonica-protein kinase (DMPK) gene had reduced diffusion kinetics compared with transcripts containing only five CUG repeats. Fluorescence recovery after photobleaching (FRAP) experiments showed that CUGrepeat RNAs display a stochastic aggregation behaviour, because individual RNA foci formed at different rates and displayed different recoveries. Spontaneous clustering of CUG-repeat RNAs was also observed, confirming the stochastic aggregation revealed by FRAP. The splicing factor Mbnl1 colocalized with individual CUG-repeat transcripts and its aggregation with RNA foci displayed the same stochastic behaviour as CUG-repeat mRNAs. Moreover, depletion of Mbnl1 by RNAi resulted in decreased aggregation of CUG-repeat transcripts after FRAP, supporting a direct role for Mbnl1 in CUG-rich RNA foci formation. Our data reveal that nuclear CUG-repeat RNA aggregates are labile, constantly forming and disaggregating structures, and that the Mbnl1 splicing factor is directly involved in the aggregation process.

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Misregulation of Alternative Splicing Causes Pathogenesis in Myotonic Dystrophy

Cited by 68 publications

References 165 publications

PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1

PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1

Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy

Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats

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