Ribonuclear foci at the neuromuscular junction in myotonic dystrophy type 1

Wheeler, Thurman M.; Krym, Matt; Thornton, Charles A.

doi:10.1016/j.nmd.2006.12.015

Cited by 45 publications

(50 citation statements)

References 35 publications

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“…The presence of foci and the sequestration of muscleblind protein in the nuclei diaphragm NMJs has also been reported in DM1 muscle biopsies and in another DM1 transgenic mouse model (Wheeler et al, 2007). It is well known that the main pathogenic process at the base of DM1 is a toxic RNA gain-of-function effect of mutant DMPK transcripts, which are retained in distinct ribonuclear foci within the cell nuclei.…”

Section: Discussionmentioning

confidence: 57%

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of Myotonic Dystrophy

Panaite¹,

Küntzer²,

Gourdon

et al. 2012

Disease Models &Amp; Mechanisms

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SUMMARYAcute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.

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Section: Discussionmentioning

confidence: 57%

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of Myotonic Dystrophy

Panaite¹,

Küntzer²,

Gourdon

et al. 2012

Disease Models &Amp; Mechanisms

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“…Altered mRNA splicing has been reported in more than 20 genes in DM1 patients (Kalsotra et al, 2008;Lin et al, 2006). In skeletal and heart muscle cells, and neurons of DM1 patients, the recruitment of Mbnl1 into CUGrepeat RNA foci is so extensive that it is depleted from the nucleoplasm (Cardani et al, 2006;Fardaei et al, 2001;Jiang et al, 2004;Mankodi et al, 2005;Mankodi et al, 2003;Miller et al, 2000;Wheeler et al, 2007). In support of the Mbnl1-sequestration hypothesis, disruption of the Mbnl1 gene in mice reproduces both the spliceopathy found in DM1 and the characteristic symptoms of myotonia and myopathy (Kanadia et al, 2003).…”

Section: Introductionmentioning

confidence: 97%

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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“…The expanded-CCUG-containing transcripts are retained in the cell nucleus and accumulate in the form of focal aggregates (Liquori et al , 2001). These aggregates are a biomolecular feature of DMs and have been evidenced in several adult tissues and cell cultures by in situ hybridization (Taneja et al , 1995; Liquori et al , 2001; Mankodi et al , 2003, 2005; Jiang et al , 2004; Schoser et al , 2004; Wheeler et al , 2007; Cardani et al , 2004, 2009). The nuclear foci of mutant mRNA specifically sequester muscleblind-like (MBNL) proteins, i.e.…”

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confidence: 95%

RNA/MBNL1-containing foci in myoblast nuclei from patients affected by myotonic dystrophy type 2: an immunocytochemical study

Perdoni¹,

Malatesta²,

Cardani³

et al. 2009

Eur J Histochem

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Myotonic dystrophy type 2 (DM2) is a dominantly inherited autosomal disease with multi-systemic clinical features and it is caused by expansion of a CCTG tetranucleotide repeat in the first intron of the zinc finger protein 9 (ZNF9) gene in 3q21.The expanded-CCUG-containing transcripts are retained in the cell nucleus and accumulate in the form of focal aggregates which specifically sequester the muscleblind-like 1 (MBNL1) protein, a RNA binding factor involved in the regulation of alternative splicing. The structural organization and composition of the foci are still incompletely known. In this study, the nuclear foci occurring in cultured myoblasts from DM2 patients were characterised at fluorescence and transmission electron microscopy by using a panel of antibodies recognizing transcription and processing factors of pre-mRNAs. MBNL1 proved to co-locate in the nuclear foci with snRNPs and hnRNPs, whereas no co-location was observed with RNA polymerase II, the non-RNP splicing factor SC35, the cleavage factor CStF and the PML protein. At electron microscopy the MBNL1-containing nuclear foci appeared as roundish domains showing a rather homogeneous structure and proved to contain snRNPs and hnRNPs. The sequestration of splicing factors involved in early phases of pre-mRNA processing supports the hypothesis of a general alteration in the maturation of several mRNAs, which could lead to the multiple pathological dysfunctions observed in dystrophic patients.

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Ribonuclear foci at the neuromuscular junction in myotonic dystrophy type 1

Cited by 45 publications

References 35 publications

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of Myotonic Dystrophy

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of Myotonic Dystrophy

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

RNA/MBNL1-containing foci in myoblast nuclei from patients affected by myotonic dystrophy type 2: an immunocytochemical study

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