Understanding the Molecular Mechanisms of Lipid Metabolism Disruption-induced Age-Related Neurodegeneration

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K14835
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Niigata University
• Principal Investigator: Nitta Yohei 新潟大学, 脳研究所, 特任助教 (30800429)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: ショウジョウバエ / 脂質代謝 / 神経変性

Outline of Final Research Achievements

In this study, I have attempted to elucidate the molecular mechanism by which neurons degenerate from axon terminals in an age-dependent manner caused by disorder of lipid metabolism. I found that the neurodegeneration is triggered by the induction of disturbances in phospholipid metabolism immediately following the differentiation of neurons. Interestingly, the onset of neurodegeneration is not immediate; elongation and projection are normal. It is possible that the disturbance of the phospholipid metabolism affects the morphological maintenance mechanism of the neuron. By genetic analysis, we identified that this degeneration was caused by a decrease in phosphatidylinositol 4,5-bisphosphate (PI (4,5) P2). PI3K and PLC, the major metabolic enzymes of PI (4,5) P2, are not involved, suggesting that an unknown molecular mechanism may control this degeneration.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

本研究によって、分化直後の神経細胞が頑健性を獲得するのにリン脂質の代謝が必須なことが明らかとなった。この現象は細胞膜に局在するリン脂質の1つであるPI(4,5)P2が関与している。興味深いことに神経細胞の発生が完了した後にPI(4,5)P2を減少させても変性が観察されなかったことから、PI(4,5)P2依存的かつ時期特異的な神経細胞の頑健性獲得メカニズムの存在を強く示唆している。神経変性疾患においても、神経細胞のリン脂質の組成が異常になることが知られており、本研究によって提供される知見によって神経細胞変性の抑制が期待できる。