Activation of the Notch Signaling Pathway and Cellular Localization of Notch Signaling Molecules in the Spinal Cord of SOD1-G93A ALS Model Mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron loss and gliosis in the spinal cord, brain stem and cortex. The Notch signaling pathway has been reported to be dysfunctional in neurodegenerative diseases, including ALS. However, the exact mechanism is still unclear. Here, we detected Notch signaling activation in proliferating glial cells, Notch inactivation in motor neurons in the spinal cord of the SOD1-G93A model, and dramatic changes of cellular relocalization of Notch pathway signaling molecules, including activated Notch intracellular domain (NICD), Notch ligands (Jagged1 and DLL4) and the target gene Hes1. We found that Notch activation was universal in proliferating astrocytes and that the Notch ligand Jagged1 was uniquely upregulated in proliferating microglia, while DLL4 expression was increased in both activated astrocytes and degenerating oligodendrocytes. Our results indicate that microglia may play an important role in the intercellular receptor-ligand interaction of the Notch signaling pathway and contribute to the pathogenesis of motor neuron loss in ALS mice. Further experiments are required to clarify the exact mechanism responsible for Notch dysfunction in ALS.