Tuesday, March 26, 2019

2:00 PM S05-01 Small non-coding RNAs of intron origin in Myotonic Dystrophy type 1: new candidate drivers of splicing defects > B. Baptiste BOGARD 2:15 PM S05-02 Downregulation of Phosphodiesterase 10A mitigates the manifestation of DMD phenotype in zebrafish model > M. Matthias LAMBERT 2:30 PM S05-03 Using Human Pluripotent Stem Cells Derived Motor Neurons to address the Pathogenesis of Spinal Muscular Atrophy > C. Camille JANUEL
Objectives : Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality characterized by the specific degeneration of lower motor neurons (MNs) in the spinal cord, leading to progressive paralysis and muscle atrophy. SMA etiology relates to insufficient amount of SMN protein, which results from mutations in the survival motor neuron 1 (SMN1) gene. Despite the ubiquitous expression of SMN protein, it is still unclear why MNs are one of the most affected cell types. Understanding this specific cellular tropism is critical but requires access to the relevant cell type. MNs from mouse are difficult to isolate and are obviously impossible to access from human. The ability to reprogram somatic cells into human induced pluripotent stem cells (hiPSC) offers a unique opportunity to access normal and pathological bona fide neuronal populations in sufficient quantities for systematic molecular and cellular analysis. In this present study, we demonstrated that the reduced expression of SMN led to a decreased survival of hiPSC-derived motoneurons rather than a defect in their generation, phenotype that can be rescued by the reintroduction of SMN protein. We identified that this phenotype can be rescued by kenpaullone, an inhibitor of several CKDs (cyclin-dependent kinases) as well as GSK-3b, likely through a CDK independent mechanism. By a transcriptomic approach on SMA hiPSC-derived MNs, we identified SMA-specific changes in early MNs that include genes involved in synaptic plasticity. Interestingly, these genetic defects were partially rescued by kenpaullone treatment. These findings suggest that alteration in synaptic organization might be a new therapeutic target for SMA. Altogether, our results demonstrate the potential offered by human pluripotent stem cells to shed light on the cellular and molecular bases of selective motor neuron vulnerability in SMA condition.
2:45 PM S05-04 Genetic control of skeletal muscle fiber type > M. Matthieu DOS SANTOS

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