Repulsive guidance molecule A (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein. It was originally identified as a neuronal growth cone-collapsing factor and is involved in axon guidance, neuronal differentiation, and survival via binding to its receptor neogenin [4]. It also plays a role in immune regulation, inflammation, and angiogenesis. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In ALS, the concentration of RGMa was elevated in the cerebrospinal fluid of both patients and transgenic mSOD1 mice. Treatment with anti-RGMa monoclonal antibody ameliorated clinical symptoms in mSOD1 mice by decreasing mutant SOD1 protein accumulation in motor neurons, likely by reinforcing the neuronal actin barrier [1]. In ischemic stroke, knockdown of RGMa shifted neuronal energy metabolism towards oxidative phosphorylation and the pentose phosphate pathway, protecting mice from ischemic reperfusion injury, potentially by regulating the USP10-mediated deubiquitination of PGK1 [2]. In NMO, RGMa-mAb treatment ameliorated AQP4-IgG-induced astrocytopathy and clinical exacerbation, suppressed neutrophil infiltration, and alleviated neuropathic pain, as RGMa signaling in macrophages drives neutrophil-related astrocytopathy [3].

In summary, RGMa is multifunctional, playing roles in neuronal development, metabolism, and immune-related pathologies. KO/CKO mouse models have revealed its significance in diseases like ALS, ischemic stroke, and NMO, providing potential therapeutic targets for these conditions.

References:

1. Shimizu, Mikito, Shiraishi, Naoyuki, Tada, Satoru, Okuno, Tatsusada, Mochizuki, Hideki. 2023. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. In Science advances, 9, eadg3193. doi:10.1126/sciadv.adg3193. https://pubmed.ncbi.nlm.nih.gov/37992159/

2. Wang, Zijie, Zhang, Shaoru, Cheng, Ruiqi, Jiang, Anan, Qin, Xinyue. 2024. Knockdown of RGMA improves ischemic stroke via Reprogramming of Neuronal Metabolism. In Free radical biology & medicine, 218, 41-56. doi:10.1016/j.freeradbiomed.2024.03.020. https://pubmed.ncbi.nlm.nih.gov/38556067/

3. Iwamoto, Shosuke, Itokazu, Takahide, Sasaki, Atsushi, Fujihara, Kazuo, Yamashita, Toshihide. 2022. RGMa Signal in Macrophages Induces Neutrophil-Related Astrocytopathy in NMO. In Annals of neurology, 91, 532-547. doi:10.1002/ana.26327. https://pubmed.ncbi.nlm.nih.gov/35167145/

4. Fujita, Yuki, Yamashita, Toshihide. 2017. The roles of RGMa-neogenin signaling in inflammation and angiogenesis. In Inflammation and regeneration, 37, 6. doi:10.1186/s41232-017-0037-6. https://pubmed.ncbi.nlm.nih.gov/29259705/