Elucidation of the mechanism of gain-of-toxic function by abnormal subcellular localization of cerebral small vessel disease-related mutant TREX1

Research Project

Project/Area Number	18K07522
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 52020:Neurology-related
Research Institution	Niigata University
Principal Investigator	Kato Taisuke 新潟大学, 脳研究所, 特任准教授 (30598496)
Project Period (FY)	2018-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000) Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords	TREX1 / RVCL / DNA損傷毒性 / 二本鎖DNA切断 / 細胞老化 / SASP / DNA damage / 脳小血管病 / 老化
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.
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。