Molecular mechanisms of the onset of major depression induced by oligodendrocyte dysfunctions

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07073
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kindai University
• Principal Investigator: MIYATA Shingo 近畿大学, 東洋医学研究所, 教授 (70403194)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: オリゴデンドロサイト / タンパクメチル化 / 慢性ストレス / PI3Kシグナル

Outline of Final Research Achievements

Repeated stressful events are associated with the onset of major depressive disorder. We previously showed oligodendrocyte-specific activation of the serum/glucocorticoid-regulated kinase 1 cascade, increased expression of axon-myelin adhesion molecules, and elaboration of the oligodendrocytic arbor in the corpus callosum of chronically stressed mice. In the current study, we demonstrate that the Na-K ATPase level and membrane potential of oligodendrocytes were reduced by chronic stress exposure. Furthermore, we found that oligodendrocyte primary cultures subjected to chronic stress resulted in changes of protein arginine methylation levels in several RNA-binding proteins. Our these findings suggest that chronic stress disrupts the organization of the nodes of Ranvier by suppressing the Na-K ATPase levels in oligodendrocytes, and that specific white matter abnormalities are closely associated with major depressive disorder onset.

Free Research Field

神経化学

Academic Significance and Societal Importance of the Research Achievements

本研究成果から、慢性ストレス暴露によるうつ病発症には脳白質オリゴデンドロサイトにおけるアルギニンメチル化レベルの変化と関連するリン酸化シグナルカスケードの活性化が重要な役割を果たす可能性を明らかに出来た事に加えて、オリゴデンドロサイトから軸索への情報伝達機構の重要性についても明らかに出来た。すなわち、脳白質オリゴデンドロサイトでのリン酸化シグナル機能異常をキーとしたうつ病治療のための創薬という臨床応用への基盤を確立できたものと考えられた。