Analyses for molecular chaperones regulating liquid-liquid phase separation in amyotrophic lateral sclerosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16583
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nara Medical University
• Principal Investigator: Nanaura Hitoki 奈良県立医科大学, 医学部, 助教 (00827909)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 筋萎縮性側索硬化症 / 前頭側頭型認知症 / 液-液相分離 / シャペロン / アミロイド / 神経変性疾患

Outline of Final Research Achievements

Aggregation and mislocalization of RNA binding proteins (RBPs) are observed in amyotrophic lateral sclerosis and other neurodegenerative diseases. Regulating self-association of RBPs to suppress the formation of pathogenic fibrils is crucial in the prevention of neurodegenerative diseases. Nuclear import receptors (NIRs) karyopherin-β2 (Kapβ2) not only controls the nucleocytoplasmic distribution of RBPs but also acts as a phase modifier to regulate self-association of FUS by recognizing proline–tyrosine nuclear localization signal. Exploiting multiple biochemical and biophysical techniques, we revealed in this study that arginine-rich poly-dipeptides from repeat expansion in C9orf72 impede the ability of NIRs to modify phase transitions of RBPs.

Free Research Field

脳神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究により、毒性ペプチドが、相分離制御シャペロンの機能を阻害する詳細な分子メカニズムが明らかとなった。相分離の制御とその破綻に着目した本研究成果から、ALSをはじめとする神経変性疾患の病態解明、新たな治療法開発につながることが期待される。