Exploration of nucleic acid drugs inhibiting tau dendritic spine accumulation caused by the novel splice variant of KANSL1 mRNA

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K15999
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Nihon University
• Principal Investigator: TANAKA Toru 日本大学, 薬学部, 専任講師 (30823702)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: tau / KANSL1 / アルツハイマー病 / 翻訳調節 / 核酸医薬 / アンチセンスオリゴヌクレオチド

Outline of Final Research Achievements

In this study, we aimed to discover nucleic acid drugs that inhibit the process of accumulation and aggregation of tau, a causative molecule of Alzheimer’s disease, in the dendritic spines of neurons. It was revealed that the novel splice variant of KANSL1 mRNA, which is complementary to tau mRNA, interacts with it, leading to the activation of tau mRNA translation. Furthermore, we were able to identify nucleic acid pharmaceuticals that inhibit this interaction. These findings were reported at the 43rd, 44th, 45th, and 46th Annual Meetings of the Molecular Biology Society of Japan and the 143rd and 144th Annual Meetings of the Pharmaceutical Society of Japan.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果から、tau mRNAにKANSL1 mRNAの新奇スプライスバリアントが相互作用することによって、tau mRNAの翻訳が活性化されることが明らかとなった。このことからこれらmRNAの相互作用を阻害できれば、tauの樹状突起での蓄積・凝集を防ぐことにつながり、アルツハイマー病の治療が期待できる。また、tau遺伝子とKANSL1遺伝子の関係のように、互いに逆向きに転写され相補的な転写産物が生じる遺伝子のペアは数多く存在し、mRNA-mRNA相互作用が新たな遺伝子発現調節機構であることが示唆される。