| Project/Area Number |
18K19430
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 48:Biomedical structure and function and related fields
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
伊集院 壮 神戸大学, 医学研究科, 助教 (00361626)
梶本 武利 神戸大学, 医学研究科, 助教 (00509953)
岡田 太郎 神戸大学, 医学研究科, 准教授 (80304088)
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| Project Period (FY) |
2018-06-29 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
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| Keywords | スフィンゴシン１燐酸 / S1P受容体 / αシヌクレイン / パーキンソン病 / レビー小体 |
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| Outline of Final Research Achievements |
α-Synuclein (α-Syn), a key protein associated with the pathogenesis of Parkinson’s disease, exists in higher concentrations in the plasma and cerebrospinal fluids than in healthy counterparts. We studied the effect of extracellular α-Syn on cellular functions and found that it drove S1P1 receptor out of lipid rafts of the plasma membranes, which resulted in uncoupling of the receptor from Gi protein. This result suggests that extracellular α-Syn causes the inhibition of cargo (cellularα-Syn) sorting into exosomal vesicles, leading to the increase in cytoplasmic concentrations of cellular α-Syn. Furthermore, we found that S1P directly bound to and activate PKCζ, which suggests that S1P/ PKCζsignaling may regulate the cytoplasmic concentrations ofα-Syn through the modulation of lysosomal function.
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| Academic Significance and Societal Importance of the Research Achievements |
パーキンソン病の９割以上を占める特発性パーキンソン病の病態解析は進んでいない。本研究の特徴はパーキンソン病の原因タンパク質αシヌクレイン（α-Syn）が患者の血清に高濃度に存在し、病気の進展に関与する可能性に着目し、細胞外α-Synの有するシグナル伝達系への変容能力を見出した点にある。特に細胞外α-Synが細胞内小胞膜上のS1P1受容体に作用し、Giタンパク質の活性化を阻害することで、エキソソームとしてα-Synの放出が減少し、細胞内濃度上昇を来たすことを示した。本研究はパーキンソン病の病態の理解に寄与し、分子標的治療薬開発に向けた緒となる結果を提供できた。
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