Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update

Abstract

Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.

Keywords: amyotrophic lateral sclerosis; auditory neuropathy; epilepsy; multiple sclerosis; neuromyelitis optica spectrum disorder; repulsive guidance molecule-a; spinal cord injury; stroke.

Figure 1

Overview of the mechanism of RGMa in the central nervous system. RGMa expressed in Th17 cells, via its interaction with neogenin, activates signaling pathways that inhibit axon growth and neuronal survival. Activation of RhoA, inactivation of Ras, and induction of Akt dephosphorylation contribute to the collapse of the growth cone and play an important role in axon guidance and regulation of neuronal death and survival. These signaling cascades play a crucial role in inflammation and angiogenesis, which are central to the pathophysiology of EAE. RGMa: repulsive guidance molecule-a, Th17: T-helper 17 cells, Akt: protein kinase B, RhoA: ras homolog gene family member A, EAE: experimental autoimmune encephalomyelitis, pT and pS: dephosporylation at sites Threonin-308 and Serine-473.