Functional roles of paranoidal axoglial junctions in IP3R1 distribution in myelinated axons.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K01949
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Basic / Social brain science
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: ISHIBASHI TOMOKO 東京薬科大学, 薬学部, 助教 (50453808)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: パラノーダルジャンクション / 小胞体ミトコンドリア近接領域 / プルキンエ細胞軸索 / 髄鞘（ミエリン） / IP3R1

Outline of Final Research Achievements

Myelin loops attach to the axonal membrane and form paranodal axoglial junctions (AGJ) at paranodes adjacent to nodes of Ranvier. AGJ play important roles in the organization and maintenance of molecular domains in myelinated axons. To better understand how AGJ regulate axonal functioning, we studied cerebroside sulfotransferase knockout (CSTko) mice that partially lack of AGJ. In CSTko cerebellar Purkinje axons, IP3R1-positive focal accumulations were the earliest finding in the axonal swellings, and subsequent the accumulation of MAM-related proteins were observed. CSTko/IP3R1heterozygote mice have less than half the normal level of IP3R1, and we found a marked decrease of the number of swellings, which suggesting that the focal accumulation of IP3R1 triggers cerebellar Purkinje axonal swellings and subsequent Purkinje cell death in CSTko mice. Our results imply that AGJ may have an important role in Ca2+ homeostasis in myelinated Purkinje axons.

Free Research Field

神経生物学

Academic Significance and Societal Importance of the Research Achievements

脊椎動物神経軸索の多くは、生後軸索周囲に髄鞘を形成することにより跳躍伝導を可能にする。しかしながら一旦形成された髄鞘が障害を受けると、無髄軸索に戻るのではなく軸索変性が生じる。軸索に髄鞘を繋ぎ止める部位であるAGJは、損傷を受けやすい構造であり、わずかなAGJの崩壊が限局した軸索腫脹を引き起こすことが本研究から示唆された。また、軸索腫脹の引き金が、カルシウム恒常性維持に関与する分子IP3R1の軸索局所での過剰発現であることを示し、IP3R1の発現を抑制すると軸索腫脹およびその後の神経細胞死を改善することができた。この結果は多発性硬化症など脱髄性疾患の初期病態を理解する一助となると考えられる。