| Project/Area Number |
20K16596
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Nagoya University |
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Principal Investigator |
LI JIAYI 名古屋大学, 医学系研究科, 研究員 (40867420)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | ALS / TDP-43 / neuron / oligodendrocyte / myelin / ニューロン / オリゴデンドロサイト / 髄鞘 / TPD-43 |
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| Outline of Research at the Start |
Progressive gray-matter demyelination and reactive changes in OPCs were observed in ALS patients (Kang SH et al., 2013) and TDP-43 aggregates were detected only in neuron and oligodendrocyte (OLG) in ALS patients, whereas oligodendrocyte (OLG)-neuron interaction mechanisms in ALS are still poorly understood. Exosomal miRNAs play great roles in glia-neuron interaction. Studying the exosomal miRNAs mediated OLG-neuron communication is of significance to understand the pathological mechanisms for ALS and to find new therapeutic targets for ALS.
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| 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.
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| 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。
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