Elucidation of intracellular environmental factors that produce a risk for alpha-Synuclein seeding

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03453
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Juntendo University
• Principal Investigator: Imai Yuzuru 順天堂大学, 大学院医学研究科, 先任准教授 (30321730)
• Co-Investigator(Kenkyū-buntansha): 井下 強 順天堂大学, 大学院医学研究科, 特任助教 (20601206) ; 柴 佳保里 順天堂大学, 大学院医学研究科, 准教授 (30468582)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: α-Synuclein / パーキンソン病 / 脂質 / ミトコンドリア / ショウジョウバエ / iPS細胞

Outline of Final Research Achievements

The purpose of this project was to clarify the mechanisms by which mitochondrial and lipid alteration are factors in α-Synuclein aggregation using iPS cells and Drosophila models. In models of mitochondria-associated Parkinson's disease (PD) causative gene CHCHD2, lysosomal dysfunction is suggested to lead to α-Synuclein aggregation and degradation. On the other hand, omics analysis was conducted using mutant flies for PD causative genes PLA2G6 and VPS13C, which are involved in lipid metabolism, and C19orf12, a causative gene for neurodegeneration with brain iron accumulation, to screen for α-Synuclein aggregation risk lipids and their responsible enzymes. A candidate gene was successfully identified.

Free Research Field

病態医化学

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病の発症の主要な原因はα-Synucleinの凝集が神経回路を伝播・拡大することであると考えられている。従って、凝集の原因を明らかにし、疾患の予防に努めることがパーキンソン病克服の最良の方法である。本課題で進めたα-Synuclein凝集の原因となるミトコンドリア遺伝子変異によるリソソーム機能の低下、リスク脂質代謝遺伝子の同定、リスクとなる脂質膜の状態の理解は、疾患の予防手段を開発するために寄与すると考える。