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2022 Fiscal Year Final Research Report

Unraveling mechanisms of In vivo transmission of aggregated TDP-43 in sporadic ALS

Research Project

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Project/Area Number 20H03589
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionNagoya University

Principal Investigator

Yohei Iguchi  名古屋大学, 医学部附属病院, 助教 (80790659)

Co-Investigator(Kenkyū-buntansha) 佐橋 健太郎  名古屋大学, 医学部附属病院, 講師 (90710103)
勝野 雅央  名古屋大学, 医学系研究科, 教授 (50402566)
Project Period (FY) 2020-04-01 – 2023-03-31
KeywordsTDP-43 / protein aggregation / prion-like propagation
Outline of Final Research Achievements

In this study, we used neuron-specific Cre mice and TDP-43-GFP-loaded AAV-Flex vector to express TDP-43 in the mouse brain and spinal cord in a neuron-specific manner and to examine its process of propagation. Overexpression of TDP-43 in the cytoplasm of neurons resulted in extensive TDP-43 expansion in remote areas of fiber communication. Expression of aggregation-prone TDP-43 was found to propagate to oligodendrocytes (OLGs) on the injection side instead of propagating to remote regions. We also confirmed that activation of neural activity promotes this neuron-OLG propagation, suggesting that neural hyperexcitability contributes to the expansion of TDP-43 pathology in ALS.

Free Research Field

Neurology

Academic Significance and Societal Importance of the Research Achievements

多くの孤発性ALS患者は一側肢の筋力低下や筋萎縮、球麻痺といった局所症状で発症し、近接部位に病変が進展していく。本研究でTDP-43がニューロン間やニューロンーオリゴデンドロサイト間を伝播することが動物実験で示された。明確な遺伝的背景を持たない孤発性ALS患者を発症前に診断することは現状では困難であり、診断された時点ではTDP-43凝集は一定の部位で始まっていることが想定されるため、病変の進展を阻止する治療介入はより現実的と考えられ、進行抑止療法の有力な標的となる可能性がある。

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Published: 2024-01-30  

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