Elucidation for the regulation of motility and lifespan by proteostasis(Fostering Joint International Research)

2019 Fiscal Year Final Research Report

• Project/Area Number: 16KK0156
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Cell biology
• Research Institution: Hokkaido University
• Principal Investigator: Kitamura Akira 北海道大学, 先端生命科学研究院, 講師 (10580152)
• Project Period (FY): 2017 – 2019
• Keywords: タンパク質恒常性 / タンパク質凝集体 / 神経変性疾患 / 筋萎縮性側索硬化症 / 線虫 / TRAST分光法 / 蛍光寿命イメージング顕微鏡

Outline of Final Research Achievements

The accumulation of misfolded proteins formed upon disruption of intracellular proteinstasis often results in the formation of aggregates in the cell. Such protein aggregates are thought to be toxic and cause death of neurons. However, the mechanism of reducing the toxicity of the aggregates formed in the cells at the individual level has not been elucidated, and its application to the treatment of specific neurodegenerative diseases has not been possible. In this study, we established a nematode strain expressing TDP25, a causative protein of amyotrophic lateral sclerosis (ALS), and analyzed its motility and lifespan. We further established a novel fluorescence spectroscopy method and a system to read out the structure of RNAs that bind to aggregate proteins in living cells. We also established a method to read out the status of intracellular macromolecular crowding, which is thought to be involved in aggregation formation, using the fluorescence lifetime of GFP.

Free Research Field

細胞生物学・生物物理学

Academic Significance and Societal Importance of the Research Achievements

線虫は成虫で全長1ミリメートルほどの大きさの虫であるが，神経系・筋肉組織を有し，神経変性疾患のようなヒト疾患のモデル生物として広く用いられている．本研究では，筋萎縮性側索硬化症 (ALS)の原因と考えられる凝集性タンパク質を線虫で発現する系を確立し，その運動能と寿命が低下することを実証した．本成果は，ALSをはじめとする神経変性疾患の原因究明のために重要な基盤手法となり得る．また他に二件の国際共同研究体制を組織することができ，どちらも生細胞内の分子構造を読み出すだめの重要な手法を確立することができた．