Studies on the regulatory mechanism of aggresome formatiion and clearance

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02072
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Juntendo University
• Principal Investigator: Imoto Masaya 順天堂大学, 大学院医学研究科, 特任教授 (60213253)
• Co-Investigator(Kenkyū-buntansha): 斉木 臣二 筑波大学, 医学部, 教授 (00339996) ; 野田 展生 北海道大学, 遺伝子病制御研究所, 教授 (40396297)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アグリソーム / アルファシヌクレイン / パーキンソン疾患 / 液-液相分離

Outline of Final Research Achievements

We have analyzed the formation mechanism of aggresomes, whose accumulation is thought to be a cause of the onset of Parkinson's disease (PD) by using a compound that controls the accumulation of aggresomes. We have obtained JU23, a potent derivative of miclxin, a compound that promotes aggresome formation, and obtained candidate proteins whose interaction with α-synuclein (α-Syn), a component of aggresome, is reduced by the action of JU23. On the other hand, ubiquilin 2 induces aggregation of α-Syn through liquid-liquid phase separation (LLPS), and we found that the small molecule compound SO286 inhibits α-Syn aggregation by modulating ubiquilin 2 LLPS.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

ケミカルバイオロジーの手法で，アグリソーム形成，特にα-シヌクレイン(α-Syn)凝集の制御機構の解析を行うなかから，それに関わるタンパク質候補を同定したことは，パーキンソン疾患の新しい治療薬開発に向けて新たな治療標的を提案したことになる．また，アグリソーム形成は他の神経変性疾患でも見られる減少であることから，他の神経変性疾患の創薬研究にも応用できる可能性を持つ重要性を有している．