Regulatory mechanisms of spine formation and synaptic plasticity by ubiquitination; toward the treatment of dementia

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07334
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Gunma University (2021-2022); Foundation for Biomedical Research and Innovation at Kobe (2020)
• Principal Investigator: Kawabe Hiroshi 群馬大学, 大学院医学系研究科, 教授 (00582454)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ユビキチン化 / 超解像顕微鏡

Outline of Final Research Achievements

We started this study to examine whether Nedd4-2 is important for spine morphology and synaptic plasticity using neuron-specific Nedd4-2 conditional KO mice (Nedd4-2 cKO). We discovered that Nedd4-2 cKO showed an interesting phenotype in synaptic plasticity. We have confirmed that the expression levels of identified substrate proteins are increased in Nedd4-2 cKO. We have shown that this elevated expression of substrate proteins is responsible for the synaptic plasticity phenotype. We have also developed a super-resolution microscopy technique to examine how the micro-localization of synaptic component proteins and synaptic micro-morphology are altered in Nedd4-2 cKO.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

神経科学研究の領域で、特異的ユビキチン化の意義は神経変性疾患を中心に研究されてきた。この研究分野において日本は世界をリードしている。一方で、神経細胞の正常な機能、特にシナプスにおける機能における特異的ユビキチン化の意義はほとんど研究されてこなかった。本研究では未知な部分が多いシナプス可塑性の制御における特異的ユビキチン化の役割を世界に先駆けて明らかにした。この成果は記憶のメカニズムが明らかになるだけでなく、Nedd4-2による基質タンパク質のユビキチン化を制御することで認知症の治療法の開発へと発展する可能性が期待できる。