Investigating roles of exosome microRNAs related to interactions between oligodendrocyte and neuron for ALS pathogenesis

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16596
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nagoya University
• Principal Investigator: LI JIAYI 名古屋大学, 医学系研究科, 研究員 (40867420)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: ALS / TDP-43 / neuron / oligodendrocyte / myelin

Outline of Final Research Achievements

In ALS, nuclear TDP-43 is mislocalized to cytoplasm and forms aggregates in neurons and oligodendrocytes. Previous studies suggest that loss of TDP-43 function in motor neurons induces and facilitates neurodegeneration in ALS pathogenesis. However, mechanisms of neuron-oligodendrocyte interaction in ALS are still poorly understood. In this study, we generated neuron-specific TDP-43 knockout mice and analyzed the neuron-OLG relationship in the TDP-43 loss-of-function conditions. In the pathological analysis, there was no obvious neuronal loss, but a decrease in myelin formations was observed, especially in the hippocampal region of TDPcKO mice. RNAseq analysis using neuron-specific mRNA identified several molecules expressed in neurons that promote OLG differentiation and myelin formation. Factor A among the identified factors was introduced into the hippocampus of TDPcKO mice in a neuron-specific manner, and restoration of myelin was confirmed.

Free Research Field

内科学

Academic Significance and Societal Importance of the Research Achievements

ALS病態解析研究はニューロンやミクログリア、アストロサイトを用いた解析で進められてきたが、OLGとニューロンの関連は未解明な点が多い。本研究ではニューロンにおけるTDP-43がミエリンの誘導を制御していること、ALS病態ではその制御が破綻している可能性が示唆された。ALS病態におけるミエリン-OLGの障害は更なるニューロン-軸索障害を引き起こす”負の連鎖”に陥っている可能性がある。本研究によりALS病態の理解を深めることは学術的に意義があり、本研究成果はALSの治療薬開発にも寄与しうるため社会的意義も高いと考えられる。