Wnt5a Protects Motor Neuron in Amyotrophic Lateral Sclerosis by Regulating Wnt/Ca2+ Signaling Pathway

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that lead to the degeneration and death of motor neurons (MNs). Wnt signaling participates in multiple neurodegenerative processes. Wnt5a is a critical signaling molecule in Wnt signaling pathway. Intracellular Ca2+ homeostasis is disrupted in a number of neurodegenerative diseases, and Ca2+/Calmodulin dependent protein kinase II (CaMKII) involved in various diseases associated with Ca2+ signaling abnormalities. Here, we found that Wnt5a modulated MNs degeneration during ALS. CaMKII is a key effector of signals derived from Wnt/Ca2+ signaling pathway. Its main subtypes CaMKII-α and CaMKII-β were down-regulated in the spinal cord of SOD1G93A transgenic mice (ALS mice) and SOD1 mutant motor neuron like hybrid (NSC-34) cells. In addition, results showed that CaMKII-α and CaMKII-β were positively regulated by Wnt5a in vitro. Using specific CaMKII inhibitor and activator, we found that Wnt5a promoted NSC-34 cells viability and proliferation, inhibited cells apoptosis and promoted cells neurite outgrowth via the Wnt/Ca2+ signaling pathway. These results indicate that Wnt5a confers neuroprotection by promoting neuronal proliferation, inhibiting cell apoptosis and promoting neurite growth through Wnt/Ca2+ signaling pathway. Therefore, targeting Wnt5a can be an effective strategy to treat ALS.