Shift from Extracellular Signal-Regulated Kinase to AKT/cAMP Response Element-Binding Protein Pathway Increases Survival-Motor-Neuron Expression in Spinal-Muscular-Atrophy-Like Mice and Patient Cells

Centre d'Étude de la Sensorimotricité, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8194, Laboratoire de Physiologie Cérébrale, CNRS UMR 8118, and Neurophysique et Physiologie du Système Moteur, CNRS UMR 8119, Université Paris Descartes, Unité de Formation et de Recherche Biomédicale, F-75270 Paris, France, Thérapie des Maladies du Muscle Strié/Institut de Myologie, Unité Mixte de Recherche en Santé 974-Université Pierre et Marie Curie, Université Paris 6/Institut National de la Santé et de la Recherche Médicale Unité 974/CNRS UMR 7215, Groupe Hospitalier Pitié-Salpêtrière-Bâtiment Babinski, F-75651 Paris, France, and Université d'Evry-val-d'Essonne, F-91000 Evry, France.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2013; 33(10):4280-4294. DOI: 10.1523/JNEUROSCI.2728-12.2013
Source: PubMed


Spinal muscular atrophy (SMA), a recessive neurodegenerative disease, is characterized by the selective loss of spinal motor neurons. No available therapy exists for SMA, which represents one of the leading genetic causes of death in childhood. SMA is caused by a mutation of the survival-of-motor-neuron 1 (SMN1) gene, leading to a quantitative defect in the survival-motor-neuron (SMN) protein expression. All patients retain one or more copies of the SMN2 gene, which modulates the disease severity by producing a small amount of stable SMN protein. We reported recently that NMDA receptor activation, directly in the spinal cord, significantly enhanced the transcription rate of the SMN2 genes in a mouse model of very severe SMA (referred as type 1) by a mechanism that involved AKT/CREB pathway activation. Here, we provide the first compelling evidence for a competition between the MEK/ERK/Elk-1 and the phosphatidylinositol 3-kinase/AKT/CREB signaling pathways for SMN2 gene regulation in the spinal cord of type 1 SMA-like mice. The inhibition of the MEK/ERK/Elk-1 pathway promotes the AKT/CREB pathway activation, leading to (1) an enhanced SMN expression in the spinal cord of SMA-like mice and in human SMA myotubes and (2) a 2.8-fold lifespan extension in SMA-like mice. Furthermore, we identified a crosstalk between ERK and AKT signaling pathways that involves the calcium-dependent modulation of CaMKII activity. Together, all these data open new perspectives to the therapeutic strategy for SMA patients.

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Available from: Philippe Lopes, Sep 24, 2014
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