title: IGF-1R Reduction Triggers Neuroprotective Signaling Pathways in Spinal Muscular Atrophy Mice.
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.
  
  
  CONCLUSIONS
  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.
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Olivier
authors: O
authors: Biondi
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Julien
authors: J
authors: Branchu
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Amina
authors: A
authors: Ben Salah
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Léo
authors: L
authors: Houdebine
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Lise
authors: L
authors: Bertin
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Farah
authors: F
authors: Chali
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Céline
authors: C
authors: Desseille
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Laure
authors: L
authors: Weill
authors: Centre for Neuromuscular Disease and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, and.
authors: Gabriel
authors: http://orcid.org/0000-0001-9338-0484
authors: G
authors: Sanchez
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Camille
authors: C
authors: Lancelin
authors: INSERM and Sorbonne Universities, Université Pierre et Marie Curie, Paris, France, and.
authors: Saba
authors: S
authors: Aïd
authors: 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.
authors: Philippe
authors: P
authors: Lopes
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Claude
authors: C
authors: Pariset
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Sylvie
authors: S
authors: Lécolle
authors: Centre for Neuromuscular Disease and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, and.
authors: Jocelyn
authors: J
authors: Côté
authors: INSERM and Sorbonne Universities, Université Pierre et Marie Curie, Paris, France, and.
authors: Martin
authors: http://orcid.org/0000-0003-4869-725X
authors: M
authors: Holzenberger
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Christophe
authors: C
authors: Chanoine
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
authors: Charbel
authors: C
authors: Massaad
authors: Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France, frederic.charbonnier@parisdescartes.fr.
authors: Frédéric
authors: F
authors: Charbonnier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017526:Receptor, IGF Type 1
keywords: IGF-1R; SMN; gene expression; model mice; signaling pathways; spinal muscular atrophy