title: 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.
abstract: 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.
authors: Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8194, Université Paris Descartes, F-75270 Paris, France.
authors: Julien
authors: J
authors: Branchu
authors: Olivier
authors: O
authors: Biondi
authors: Farah
authors: F
authors: Chali
authors: Thibault
authors: T
authors: Collin
authors: Felix
authors: F
authors: Leroy
authors: Kamel
authors: K
authors: Mamchaoui
authors: Joelle
authors: J
authors: Makoukji
authors: Claude
authors: C
authors: Pariset
authors: Philippe
authors: P
authors: Lopes
authors: Charbel
authors: C
authors: Massaad
authors: Christophe
authors: C
authors: Chanoine
authors: Frédéric
authors: F
authors: Charbonnier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018920:Coculture Techniques / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000473:pathology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D055540:Survival of Motor Neuron 2 Protein / Q000172:deficiency
chemical_list: D002070:Butadienes; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D009570:Nitriles; D055540:Survival of Motor Neuron 2 Protein; C113580:U 0126; D016202:N-Methylaspartate; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium