2020 Fiscal Year Final Research Report
Elucidation of the mechanism of gain-of-toxic function by abnormal subcellular localization of cerebral small vessel disease-related mutant TREX1
Project/Area Number |
18K07522
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52020:Neurology-related
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Research Institution | Niigata University |
Principal Investigator |
Kato Taisuke 新潟大学, 脳研究所, 特任准教授 (30598496)
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Keywords | TREX1 / RVCL / DNA損傷毒性 / 二本鎖DNA切断 / 細胞老化 / SASP |
Outline of Final Research Achievements |
From quantitative analysis of double-stranded DNA break (DSB) foci, we found that the RVCL-associated TREX1 mutant protein induces DSB, and that this toxicity depends on the exonuclease activity and nuclear localization of TREX1. Furthermore, we found that this DNA toxicity is unique to RVCL mutations, as it is not induced in other autoimmune disease-associated TREX1 mutants. We found that persistent expression of this RVCL mutant TREX1 in normal human fibroblasts induced cellular senescence. Furthermore, we found that cellular senescence-associated secretory phenotype (SASP) was simultaneously induced in the senescent cells induced by expression of RVCL-mutant TREX1.
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Free Research Field |
分子神経生物学
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Academic Significance and Societal Importance of the Research Achievements |
TREX1遺伝子変異で発症する疾患のうち、RVCLに関わる変異のTREX1へ与える作用が不明であった。本研究結果は、これまで不明とされてきたRVCL関連変異TREX1の、RVCL発症に関わる分子機構に対し、RVCL変異特異的なDNA損傷毒性という機能獲得を発見し、初めて本症の分子メカニズム解明の突破口を開いた。 RVCLは、中年期に発症し、死に至る非常に重篤な疾患である。本研究結果は、この重篤な遺伝性疾患の治療法の開発に向けた、画期的な一歩となる可能性が高い。
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