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.

Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy

“…Moreover, overactivation of the ERK/Elk-1 pathway was found in SMA, and inhibition of ERK/Elk-1 contributed to the promotion of SMN expression, lifespan, and symptomatic behavior of SMA mice [21][22][23]. A previous study reported loganin possesses anti-inflammatory effect via inhibiting ERK signaling in SH-SY5Y cells [28]; however, in this study, loganin did not attenuate overactivation of ERK signaling in SMN-deficient NSC34 cells and SMA human fibroblasts.…”

“…In our study, loganin attenuated reduction of neurite length and cell death induced by SMN deficiency. The protective role of Akt pathway on spinal motor neurons of SMA mice and SMN-deficient motor neurons has also been mentioned [21][22][23]43]. Akt is considered as an important pathway for neuronal survival, differentiation and neurite outgrowth [43][44][45][46][47].…”

“…A free recombinant human IGF-1/BP3 complex IPLEX has also been revealed as having potential to prevent muscle wasting and neurodegenerative processes in SMA mice [54]. However, a recent study raises the alternative hypothesis 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 pathway, and this aspect should be considered when designing IGF-1-based treatments for neurodegenerative diseases [22].…”

“…Akt/m-TOR signaling is known to involve the pathogenesis of muscle atrophy in SMA [21][22][23]. Akt/mTOR has been identified for its critical role in mediating muscle growth [22,23].…”

“…Previous studies reveal significant down-regulation of Akt in the neuromuscular system of SMA-like mice [21][22][23]. Moreover, muscle atrophy F-box, MAFbx (also called atrogin-1), and muscle RING Finger 1, MuRF-1 (also called Trim63), are required for muscle atrophy [24].…”