Targeting Repulsive Guidance Molecule A to Promote Regeneration and Neuroprotection in Multiple Sclerosis

Abstract

Repulsive guidance molecule A (RGMa) is a potent inhibitor of neuronal regeneration and a regulator of cell death, and it plays a role in multiple sclerosis (MS). In autopsy material from progressive MS patients, RGMa was found in active and chronic lesions, as well as in normal-appearing gray and white matter, and was expressed by cellular meningeal infiltrates. Levels of soluble RGMa in the cerebrospinal fluid were decreased in progressive MS patients successfully treated with intrathecal corticosteroid triamcinolone acetonide (TCA), showing functional improvements. In vitro, RGMa monoclonal antibodies (mAbs) reversed RGMa-mediated neurite outgrowth inhibition and chemorepulsion. In animal models of CNS damage and MS, RGMa antibody stimulated regeneration and remyelination of damaged nerve fibers, accelerated functional recovery, and protected the retinal nerve fiber layer as measured by clinically relevant optic coherence tomography. These data suggest that targeting RGMa is a promising strategy to improve functional recovery in MS patients.

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

“…The role of RGMs in axon guidance and neurite growth inhibition during development has been shown in frog and chick embryos, while in vivo evidence for the neurite growth inhibitory effects of RGMs in mammals is provided by the ability of RGM blockage to promote central nervous system (CNS) axon regeneration. Other important effects of RGM on cell death, migration, and differentiation have also been confirmed (Boxes 1 and 2) [11,13,[47][48][49]. The neurite growth inhibitory effects of RGMs have been studied extensively and rely on signaling by Rho-GTPases downstream of RGMa.…”

“…RGMs bind the type 1 transmembrane protein Neogenin ( Figure 1A) and many of the reported biological effects of RGMs rely on Neogenin receptor functions, such as axon guidance or neuronal survival [3,4]. RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].…”

“…Over the past few years, many groups have confirmed the ability of RGMs to induce axon repulsion, neurite growth inhibition, and growth cone collapse using different types of neuron [11,13,29,[43][44][45][46]. The role of RGMs in axon guidance and neurite growth inhibition during development has been shown in frog and chick embryos, while in vivo evidence for the neurite growth inhibitory effects of RGMs in mammals is provided by the ability of RGM blockage to promote central nervous system (CNS) axon regeneration.…”

“…The C-terminal domain (C-RGM) forms a tight β-sandwich structure and harbors a 'GDPH' cleavage site, which mediates autoproteolysis ( Figure 1A). C-RGM is the major high-affinity interaction site for Neogenin [16], with an additional Neogenin-binding site positioned in N-RGM, as suggested by antibody-blocking experiments [11]. In the C-RGM-Neogenin (NEO1) complex structure, two RGM molecules act as a molecular staple bringing together the juxtamembrane fibronectin type III (FNIII) domains of two Neogenin receptors ( Figure 1B) [16].…”

“…RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].Although the molecular mechanisms underlying the biological effects and signaling modes of RGMs have long remained unknown, recent work has unveiled several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. These insights include high-resolution structural data of binary or tertiary protein complexes, the unique processing of RGMs into protein fragments with distinct functions, and the identification of a novel molecular mechanism to control ligand-induced ectodomain shedding of Neogenin.…”