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J Neurosci. 2015 Aug 26;35(34):12063-79. doi: 10.1523/JNEUROSCI.0608-15.2015.

IGF-1R Reduction Triggers Neuroprotective Signaling Pathways in Spinal Muscular Atrophy Mice.

Author information

1
Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
2
Centre for Neuromuscular Disease and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, and.
3
INSERM and Sorbonne Universities, Université Pierre et Marie Curie, Paris, France, and.
4
Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France, Université d'Evry-val-d'Essonne, Evry 91025, France.
5
Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France, frederic.charbonnier@parisdescartes.fr.

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the selective loss of spinal motor neurons due to the depletion of the survival of motor neuron (SMN) protein. No therapy is currently available for SMA, which represents the leading genetic cause of death in childhood. In the present study, we report that insulin-like growth factor-1 receptor (Igf-1r) gene expression is enhanced in the spinal cords of SMA-like mice. The reduction of expression, either at the physiological (through physical exercise) or genetic level, resulted in the following: (1) a significant improvement in lifespan and motor behavior, (2) a significant motor neuron protection, and (3) an increase in SMN expression in spinal cord and skeletal muscles through both transcriptional and posttranscriptional mechanisms. Furthermore, we have found that reducing IGF-1R expression is sufficient to restore intracellular signaling pathway activation profile lying downstream of IGF-1R, resulting in both the powerful activation of the neuroprotective AKT/CREB pathway and the inhibition of the ERK and JAK pathways. Therefore, reducing rather than enhancing the IGF-1 pathway could constitute a useful strategy to limit neurodegeneration in SMA.

SIGNIFICANCE STATEMENT:

Recent evidence of IGF-1 axis alteration in spinal muscular atrophy (SMA), a very severe neurodegenerative disease affecting specifically the motor neurons, have triggered a renewed interest in insulin-like growth factor-1 (IGF-1) pathway activation as a potential therapeutic approach for motor neuron diseases. The present study challenges this point of view and brings the alternative hypothesis that reducing rather than enhancing the IGF-1 signaling pathway exerts a neuroprotective effect in SMA. Furthermore, the present data substantiate a newly emerging concept that the modulation of IGF-1 receptor expression is a key event selectively determining the activation level of intracellular pathways that lie downstream of the receptor. This aspect should be considered when designing IGF-1-based treatments for neurodegenerative diseases.

KEYWORDS:

IGF-1R; SMN; gene expression; model mice; signaling pathways; spinal muscular atrophy

PMID:
26311784
DOI:
10.1523/JNEUROSCI.0608-15.2015
[Indexed for MEDLINE]
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