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
Language: 
English
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.

Author(s): 
Branchu, Julien
Biondi, Olivier
Chali, Farah
Collin, Thibault
Leroy, Felix
Mamchaoui, Kamel
Makoukji, Joelle
Pariset, Claude
Lopes, Philippe
Massaad, Charbel
Chanoine, Christophe
Charbonnier, FrÈdÈric
Item Type: 
Journal Article
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience
Journal Abbreviation: 
J. Neurosci.
Publication Date: 
3/6/2013
Publication Year: 
2013
Pages: 
4280-4294
Volume: 
33
Issue: 
10
ISSN: 
1529-2401
DOI: 
10.1523/JNEUROSCI.2728-12.2013
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 23467345

Turabian/Chicago Citation

Julien Branchu, Olivier Biondi, Farah Chali, Thibault Collin, Felix Leroy, Kamel Mamchaoui, Joelle Makoukji, Claude Pariset, Philippe Lopes, Charbel Massaad, Christophe Chanoine and FrÈdÈric Charbonnier. 3/6/2013. "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." The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 33: 10: 4280-4294. 10.1523/JNEUROSCI.2728-12.2013.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1523/JNEUROSCI.2728-12.2013 | issn = 1529-2401 | volume = 33 | pages = 4280-4294 | last = Branchu | first = Julien | coauthors = Biondi, Olivier, Chali, Farah, Collin, Thibault, Leroy, Felix, Mamchaoui, Kamel, Makoukji, Joelle, Pariset, Claude, Lopes, Philippe, Massaad, Charbel, Chanoine, Christophe, Charbonnier, FrÈdÈric | 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 | journal = The Journal of Neuroscience: The Official Journal of the Society for Neuroscience | date = 3/6/2013 | pmid = | pmc = }} </ref>