Biological significance and molecular basis of lectin receptor-mediated self-recognition

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H00505
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Osaka University
• Principal Investigator: Yamasaki Sho 大阪大学, 微生物病研究所, 教授 (40312946)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: レクチン受容体 / Mincle / ミクログリア

Outline of Final Research Achievements

Gaucher disease (GD) is the most common lysosomal storage disease caused by recessive mutations in the degrading enzyme of β-GlcCer. However, it remains unclear how β-GlcCer causes severe neuronopathic symptoms, which are not fully treated by current therapies. We herein found that β-GlcCer accumulating in GD activated microglia through Mincle to induce phagocytosis of living neurons, which exacerbated Gaucher symptoms. This process was augmented by TNF secreted from activated microglia that sensitized neurons for phagocytosis. This characteristic pathology was also observed in human neuronopathic GD. Blockade of these pathways in mice with a combination of FDA-approved drugs, minocycline and etanercept, effectively protected neurons and ameliorated neuronopathic symptoms. In this study, we propose that limiting unrestrained microglia activation using drug repurposing provides a quickly applicable therapeutic option for fatal neuronopathic GD.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

ゴーシェ病はグルコシルセラミドと呼ばれる糖脂質が蓄積することで発症する遺伝性難病である。致死性の神経症状を合併するが、詳細な分子メカニズムは不明で有効な治療法が存在しない。本研究では、グルコシルセラミドによって脳の免疫細胞であるミクログリアが直接活性化され、神経細胞を食べてしまうことで神経細胞が減少し、致死性の障害に繋がることを明らかにした。本研究成果により、ゴーシェ病の新たな治療法が見出され、これまで治療法がなかった致死性の神経型ゴーシェ病を先天的に患う小児患者やその家族に希望を与えるものと期待される。