Hopes for the treatment of ASL as Osaka University clarifies the function of RGMa in the brain

Amyotrophic lateral sclerosis (ALS) is a fatal, intractable disease of unknown cause, in which degeneration of motor neurons causes progressive muscle atrophy. A research group led by Assistant Professor Tatsusada Okuno, Visiting Academic Staff Mikito Shimizu, Visiting Academic Staff Naoyuki Shiraishi, Visiting Academic Staff Satoru Tada, Professor Hideki Mochizuki, and Professor Toshihide Yamashita of Osaka University Graduate School of Medicine has discovered that increased levels of RGMa (repulsive guidance molecule-a), an axon guidance factor, are found in the cerebrospinal fluid (CSF) of ALS patients. Their work was published in Science Advances.

The group found that ALS patients with higher RGMa concentrations in their cerebrospinal fluid tended to have more severe symptoms. In cultured neurons, RGMa reduced barrier function of neurons and promoted the entry of abnormal proteins into the cells. Administration of an anti-RGMa antibody to ALS model mice reduced abnormal protein aggregation and significantly prolonged survival. RGMa may be a prognostic biomarker in ALS, and neutralizing antibodies to RGMa may be considered as novel therapies.

Shimizu said, "After finding increased RGMa in cerebrospinal fluid of ALS patients and noticing the effectiveness of an RGMa antibody in an ALS model, we had difficulty considering and proving the pathophysiology linking RGMa and ALS, but we were able to discover a new aspect of pathophysiology of ALS after trial and error. We are indebted to our co-authors who specialize in ALS, RGMa, neuropathology, neuronal cell culture, and animal experiments, respectively, for their generous assistance. We will be very happy if these results help in the development of new diagnostic and therapeutic methods."

Journal Information
Publication: Science Advances
Title: RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS
DOI: 10.1126/sciadv.adg3193