Repulsive Guidance Molecule-a and Demyelination: Implications for Multiple Sclerosis

Abstract

Drug development for neurodegenerative and neuroinflammatory diseases such as multiple sclerosis and traumatic brain injury is challenging. One promising strategy is to target a molecule with multiple biological actions affecting divergent pathophysiological disease phases simultaneously since these diseases arise from multiple pathological phases. In recent years, we pursued this strategy with a focus on multiple sclerosis and spinal cord injury and found that repulsive guidance molecule-a (RGMa) inhibits regeneration of injured CNS axons following spinal cord injury. We also found that RGMa enhances CD4(+) T cell activation facilitating CNS demyelination in an animal model of MS, mouse experimental autoimmune encephalomyelitis (EAE), which supports the idea that RGMa has distinct pathological actions. The multiple functions of RGMa in the CNS and the immune system would provide a therapeutic opportunity to concurrently block the autoimmune reactions and axon injury in neurodegenerative and neuroinflammatory diseases. In this article, we introduce the therapeutic potential of targeting RGMa as a novel intervention for MS and spinal cord injury.