2019 Fiscal Year Final Research Report
Identification of PDI S-nitrosylated site and the relation S-nitrosylated PDI with neurodegeneration
| Project/Area Number |
19K21219
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| Project/Area Number (Other) |
18H06099 (2018)
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund (2019)
Single-year Grants (2018) |
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| Review Section |
0801:Pharmaceutical sciences and related fields
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| Research Institution | Tohoku University |
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Principal Investigator |
Ogura Jiro 東北大学, 大学病院, 助教 (20580640)
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| Project Period (FY) |
2018-08-24 – 2020-03-31
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| Keywords | 神経変性疾患 / PDI / S-ニトロシル化 / 基質結合ドメイン / 小胞体ストレス |
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| Outline of Final Research Achievements |
S-nitrosylated PDI was detected in the postmortem brain in various neurodegenerative disease patients. The cysteines at active motif of PDI are speculated to be S-nitrosylation sites but some studies recently reported the results contradicted the hypothesis. In this study, we confirm that PDI C343 at the substrate binding domain of PDI is S-nitrosylation site using SH-SY5Y cells. Although active site S-nitrosylation is reversible by reduced glutathione, S-nitrosylation of C343 is comparative stable. Moreover, S-nitrosylation at C343 of PDI induces the IRE1α phosphorylation. The results of our study provide a new insight into the proceeding neurodegeneration, and may be useful for the drug development for neurodegenerative diseases.
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| Free Research Field |
医療薬学
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| Academic Significance and Societal Importance of the Research Achievements |
PDIはa、a' domainの両活性中心に酸化力の強いSH基を有し、抗酸化物質を容易に捕捉する。実際、生体内抗酸化物質であるグルタチオンはa domainに存在するSH基に捕捉される。一方、神経変性疾患の予防効果を持つとして注目されるフラボノイド類はSNO化部位であるC343を含むb' domainに結合する。この特性はフラボノイド類の構造的特徴に由来し、構造が類似する化合物は同様の特性を示す可能性が高い。このため、本研究によりPDIのSNO化部位が同定されたことにより、今後様々なフラボノイド類のPDI脱SNO化作用を検証することで、将来的な認知症予防の実現に繋がると期待される。
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