RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.Shimizu Mikito, Shiraishi Naoyuki, Tada Satoru, et al. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science Advances 9, 686 (2023); https://doi.org/10.1126/sciadv.adg3193

Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19

Abstract The coronavirus disease 2019 (COVID-19) remains an epidemic worldwide. Most patients suffer residual symptoms, the so-called “Long COVID,” which includes respiratory and neuropsychiatric symptoms. Brain Fog, one of the symptoms of Long COVID, is a major public health issue because it can impair patients’ quality of life even after recovery from the disease. However, neither the pathogenesis nor the treatment of this condition remains unknown. We focused on serum ferritin levels in this study and collected information on the onset of Brain Fog through questionnaires and found that high ferritin levels during hospitalization were associated with the occurrence of Brain Fog. In addition, we excluded confounders as far as possible using propensity score analyses and found that ferritin was independently associated with Brain Fog in most of the models. We conducted phase analysis and evaluated the interaction of each phase with ferritin levels and Brain Fog. We found a positive correlation between serum ferritin levels during hospitalization and Brain Fog after COVID-19. High ferritin levels in patients with Brain Fog may reflect the contribution of chronic inflammation in the development of Brain Fog. This study provides a novel insight into the pathogenic mechanism of Brain Fog after COVID-19