The study of Sulfonylurea receptor(SUR) in TDP-43 pathology

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17022
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: National Center for Geriatrics and Gerontology
• Principal Investigator: Quan Xiuming 国立研究開発法人国立長寿医療研究センター, 認知症先進医療開発センター, 研究員 (70812395)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: Sulfonylurea receptor / TDP-43 / 加齢性海馬硬化症 / 代謝 / 神経変性

Outline of Final Research Achievements

In this study, we found that Sur deficiency did not cause age-related neurodegeneration or neuronal dysfunction in flies. However, mutation in Sur shortened lifespan of flies. To understand the association of SUR and TDP-43 pathology, we asked whether Sur deficiency affects the TDP-43 expression and phosphorylated levels in flies. Contrast to our expectation, Sur deficiency did not alter total or phosphorylated TDP-43 levels. Next, we examined the effect of Sur deficiency on TDP-43 flies, and observed enhanced reduction of survivals in Sur/TDP-43 flies when compared to TDP-43 flies. To elucidate the mechanism by which Sur deficiency enhanced TDP-43 toxicity, we analyzed the metabolic changes. Interestingly, accompanied with a reduction in ATP levels, metabolites in several pathways showed significant alterations in Sur mutant fly heads. The results above suggest that SUR dysfunction disrupts the metabolomic homeostasis in fly brains which may enhanced TDP-43 toxicity.

Free Research Field

神経変性疾患

Academic Significance and Societal Importance of the Research Achievements

SUR は糖尿病と心筋症、加齢性海馬硬化症のリスク因子であることが報告された。しかし、Surの欠損が神経変性疾患の発症・進展における意義は未だ不明である。本研究では、ショウジョウバエモデルにおけるSur機能欠損が寿命、代謝へもたらす影響を明らかにし、TDP-43の神経毒性を強めることを証明した。これらの結果は加齢性海馬硬化症のみならず、TDP-43病理を呈する神経変性疾患の普遍的なメカニズムの理解と新たな予防・治療戦略の確立につなげることが期待できる。