IGF-1R Reduction Triggers Neuroprotective Signaling Pathways in Spinal Muscular Atrophy Mice.
Journal of Neuroscience. 2015-08-26; 35(34): 12063-12079
DOI: 10.1523/JNEUROSCI.0608-15.2015
Read on PubMed
1. 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.
Biondi O(1), Branchu J(1), Ben Salah A(1), Houdebine L(1), Bertin L(1), Chali
F(1), Desseille C(1), Weill L(1), Sanchez G(2), Lancelin C(1), Aïd S(3), Lopes
P(4), Pariset C(1), Lécolle S(1), Côté J(2), Holzenberger M(3), Chanoine C(1),
Massaad C(1), Charbonnier F(5).
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, .
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.
Copyright © 2015 the authors 0270-6474/15/3512063-17$15.00/0.
DOI: 10.1523/JNEUROSCI.0608-15.2015
PMCID: PMC6705454
PMID: 26311784 [Indexed for MEDLINE]