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: 6.75). 03/2013; 33(10):4280-4294. DOI: 10.1523/JNEUROSCI.2728-12.2013
Source: PubMed

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.

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    ABSTRACT: Background genetic background and pathogenesis of motor neuron diseases (MNDs) have been increasingly elucidated over recent years. Aims to give an overview about publications during the last year concerning the genetic background and phenotypic manifestations of MNDs, such as familial or sporadic amyotrophic lateral sclerosis (fALS, sALS), spinal muscular atrophies (SMA), bulbospinal muscular atrophy (BSMA), and unclassified MNDs. Methods Pubmed search for literature about ALS, SMA, and BSMA for the period 10/2012 to 9/2013. Results an increasing number of mutated genes is recognised in fALS but also sALS patients. Genes mutated in sALS include C9orf72, SOD1, TARDBP, FUS, UBQL2, SQSTM1, DCTN1, and UNC13A. Juvenile (onset <20y) and adult ALS (early onset 20-60y, late onset >60y) are differentiated. Juvenile fALS is most frequently caused by mutations in ALS2, SETX, spatacsin, or Sigmar1 and adult fALS by mutations in C9orf72, SOD1, TARDBP, and FUS. Onset, phenotype, progression, and outcome of ALS are variable between different mutations, different genes, and different countries. Differentiation between sALS and fALS cases becomes artificial. Conclusions further progress has been made over the last year in the clarification and understanding of the etiology and pathogenesis of MNDs. However, further effort is needed to answer the many remaining questions.
    European journal of medical genetics 02/2014; 57(2-3). DOI:10.1016/j.ejmg.2014.01.002 · 1.49 Impact Factor
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    ABSTRACT: Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1), which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA.
    PLoS ONE 12/2014; 9(12):e115473. DOI:10.1371/journal.pone.0115473 · 3.53 Impact Factor
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    ABSTRACT: Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct SMN2 exon 7 splicing, stabilize SMN/SMNΔ7 protein, manipulate SMN-regulated pathways and SMN1 gene delivery by viral vectors. This review focuses on the aspects of target discovery, validations and outcome measures for a promising therapy of SMA.
    Future medicinal chemistry 06/2014; 6(9):1081-99. DOI:10.4155/fmc.14.63 · 4.00 Impact Factor