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MBNL-dependent impaired development connectivity within neuromuscular circuits in myotonic dystrophy type 1
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Edité par CCSD -
International audience. Introduction: Myotonic dystrophy type I (DM1) is one the most frequent muscular dystrophy in adults. Although DM1 has long been considered mainly as a muscle disorder, growing evidence suggests the involvement in peripheral nerves in the pathogenicity of DM1 raising the question whether motoneurons actively contribute to neuromuscular defects in DM1.Methods: By using a micropatterned 96-well plate as a co-culture platform, we generated a functional humanized cellular model combining DM1 hiPSC-derived MNs and healthy skeletal muscle cells.Results: Such approaches led to the identification of pre-synaptic defects which affect development or stability of the neuromuscular junction at an early developmental stage. These neuropathological defects could be reproduced by the loss of RNA-binding MBNL proteins, whose loss of function is associated with muscular defects associated with DM1.Conclusions: These experiments suggested that the functional defects associated to MNs can be directly attributed to the MBNL family proteins. Altogether, these findings hold several new implications for DM1 pathogenesis.
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