Detection of misfolded Cu/Zn-superoxide dismutase proteins with Caenorhabditis elegans

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21290
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 38:Agricultural chemistry and related fields
• Research Institution: Keio University
• Principal Investigator: Furukawa Yoshiaki 慶應義塾大学, 理工学部(矢上), 教授 (40415287)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: ミスフォールディング

Outline of Final Research Achievements

Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) proteins is a pathological hallmark of a neurodegenerative disease, familial amyotrophic lateral sclerosis (fALS). Here, we describe a unique method to detect misfolded SOD1 by using a nematode, Caenorhabditis elegans. A mutant SOD1 protein is known to misfold into either amyloid-like, insoluble aggregates or disulfide-crosslinked, soluble oligomers in vitro. When those misfolded SOD1 proteins in vitro were administered to the worms, we observed adverse effects of the oligomers but not the aggregates on C. elegans such as shortened lifespan, decreased motility, and deteriorated defecation. While a mechanism behind the trapping of worms with the oligomers remains obscure, this study reveals that C. elegans has potential to detect misfolded proteins even in a sub-micromolar concentration.

Free Research Field

タンパク質科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、食材に含まれるタンパク質が、その構造に依存して毒性を発揮する可能性を検証した。天然構造から異常化した「ミスフォールド型」タンパク質の経口摂取はほとんど検討されていないが、線虫をモデルにして得られる本研究の成果を基盤として、ミスフォールド型タンパク質の摂取が生体に及ぼす影響を明らかにできれば、より良い食生活に向けた指針をタンパク質分子レベルで提案でき、社会的な意義も大きく挑戦的な課題である。