Myotonic dystrophy Type 1 (DM-1) is caused by abnormal expansion of a (CTG) repeat located in the DM protein kinase gene. Respiratory problems have long been recognized to be a major feature of this disorder. Because respiratory failure can be associated with dysfunction of phrenic nerves and diaphragm muscle, we examined the diaphragm and respiratory neural network in transgenic mice carrying the human genomic DM-1 region with expanded repeats of more than 300 CTG, a valid model of the human disease. Morphologic and morphometric analyses revealed distal denervation of diaphragm neuromuscular junctions in DM-1 transgenic mice indicated by a decrease in the size and shape complexity of end-plates and a reduction in the concentration of acetyl choline receptors on the postsynaptic membrane. More importantly, there was a significant reduction in numbers of unmyelinated, but not of myelinated, fibers in DM-1 phrenic nerves; no morphologic alternations of the nerves or loss of neuronal cells were detected in medullary respiratory centers or cervical phrenic motor neurons. Because neuromuscular junctions are involved in action potential transmission and the afferent phrenic unmyelinated fibers control the inspiratory activity, our results suggest that the respiratory impairment associated with DM-1 may be partially due to pathologic alterations in neuromuscular junctions and phrenic nerves.
"We previously generated transgenic mice expressing DMPK transcripts in multiple tissues under the control of the human DMPK gene promoter, within the environment of the human myotonic dystrophy type 1 locus. In contrast with control DM20 lines (mice overexpressing short 20 CTG tracts), homozygous mice from two independent DM300 expansion lines (carrying 500–600 CTG), expressing sufficient toxic DMPK transcripts, showed wide RNA foci accumulation in a variety of tissues and developed a multisystemic phenotype (Seznec et al., 2001; Guiraud-Dogan et al., 2007; Panaite et al., 2008). Dramatic intergenerational instability in DM300 mice generated DMSXL animals carrying 41000 CTG, who develop a more severe phenotype (Gomes-Pereira et al., 2007; Huguet et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.
"Trinucleotide repeat expansion requires DNA synthesis, either during DNA replication or repair. The effects of replication origin proximity, replication polarity, and replication inhibition support replication-based models of TNR instability in mitotic cells [2-9]. Hairpin formation by DNA polymerase slippage is a likely mechanism for changes in TNR repeat length [10-12]. "
[Show abstract][Hide abstract] ABSTRACT: Expansion of (CTG)n•(CAG)n trinucleotide repeat (TNR) microsatellite sequences is the cause of more than a dozen human neurodegenerative diseases. (CTG)n and (CAG)n repeats form imperfectly base paired hairpins that tend to expand in vivo in a length-dependent manner. Yeast, mouse and human models confirm that (CTG)n•(CAG)n instability increases with repeat number, and implicate both DNA replication and DNA damage response mechanisms in (CTG)n•(CAG)n TNR expansion and contraction. Mutation and knockdown models that abrogate the expression of individual genes might also mask more subtle, cumulative effects of multiple additional pathways on (CTG)n•(CAG)n instability in whole animals. The identification of second site genetic modifiers may help to explain the variability of (CTG)n•(CAG)n TNR instability patterns between tissues and individuals, and offer opportunities for prognosis and treatment.
Cell and Bioscience 02/2012; 2(1):7. DOI:10.1186/2045-3701-2-7 · 3.63 Impact Factor
"Ribonuclear aggregates of mutated DMPK RNA have been observed in the spinal motoneurons of patients (Wheeler et al., 2007). In neuromuscular junctions , synaptic hyperproliferation (Nagao et al., 2003), demyelinated nerve fibers (Panaite et al., 2008), and abnormal morphological motor nerve terminals (Pachter and Eberstein, 1986; Panaite et al., 2008; Stranock and Davis, 1978) have been described in DM1 patients and animal models of the disease. Our results are consistent with these observations and indicate that functional defects in neuritogenesis and synaptogenesis at the neuromuscular junction may be associated with DM1 at an early developmental stage. "
[Show abstract][Hide abstract] ABSTRACT: Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting a variety of organs, including the central nervous system. By using neuronal progeny derived from human embryonic stem cells carrying the causal DM1 mutation, we have identified an early developmental defect in genes involved in neurite formation and the establishment of neuromuscular connections. Differential gene expression profiling and quantitative RT-PCR revealed decreased expression of two members of the SLITRK family in DM1 neural cells and in DM1 brain biopsies. In addition, DM1 motoneuron/muscle cell cocultures showed alterations that are consistent with the known role of SLITRK genes in neurite outgrowth, neuritogenesis, and synaptogenesis. Rescue and knockdown experiments suggested that the functional defects can be directly attributed to SLITRK misexpression. These neuropathological mechanisms may be clinically significant for the functional changes in neuromuscular connections associated with DM1.
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