Neuroprotective Effect of Sonic Hedgehog Mediated PI3K/AKT Pathway in Amyotrophic Lateral Sclerosis Model Mice

The Sonic Hedgehog (SHH) signaling pathway is related to the progression of various tumors and nervous system diseases. Still, its specific role in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remains studied. This research investigates the role of SHH and PI3K/AKT signaling pathway proteins on ALS development in a SOD1-G93A transgenic mouse model. After injection of SHH and PI3K/AKT signaling pathway inhibitors or agonists in hSOD1-G93A (9 weeks of age) transgenic mice, we studied skeletal muscle pathology using immunohistochemical staining and Western blot methods. In addition, recorded data on rotation time, weight, and survival were analyzed for these mice. Our study showed that the expression of SHH, Gli-1 and p-AKT in ALS mice decreased with the progression of the disease. The expression of p-AKT changed together with Gli-1 while injecting PI3K/AKT signaling pathway inhibitor or agonist; SHH and Gli-1 protein expression remained unchanged; p-AKT protein expression significantly decreased while injecting PI3K/AKT signaling pathway inhibitor. These results indicate that SHH has a regulatory effect on PI3K/AKT signaling pathway. In behavioral experiments, we found that the survival time of hSOD1-G93A mice was prolonged by injection of SHH agonist while shortened by injection of SHH inhibitor. In conclusion, we confirmed that the SHH pathway played a neuroprotective role in ALS by mediating PI3K/AKT signaling pathway.