Elucidation of molecular mechanisms of Parkinsons disease causative genes of a-synuclein aggregation and propagation

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07830
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Juntendo University
• Principal Investigator: Inoshita Tsuyoshi 順天堂大学, 大学院医学研究科, 特任助教 (20601206)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: パーキンソン病 / 神経科学 / 小胞輸送 / LRRK2

Outline of Final Research Achievements

In order to elucidate the pathogenesis of the neurodegenerative disease Parkinson's disease, we attempted to clarify the correlation between the causative genes, and identified that the LRRK2 gene correlates with other causative genes. In addition, functional deletion of multiple causative genes including LRRK2 causes accumulation of small GTPase, Arl8, which is localized in acidic organelles and also in dense-core vesicles containing neurotransmitters. This study found that the accumulation of Arl8 at synaptic terminals was due to excessive enhancement of anterograde transport of cored vesicles, and the involvement of Rab3 and unc-104.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

本研究結果は、細胞内のオルガネラ動態制御に関わるPD関連遺伝子の相関関係を明らかにし、より中心的な役割を持つ遺伝子としてLRRK2を特定した。さらに、他のPD関連遺伝子の機能欠失単独でも起きるArl8の動態異常に関わる分子機構として、unc-104を介した有芯小胞の順行輸送を特定したことで、この分子機構の正常化がPD患者へのより広範な治療法に繋がること期待できる。適切な治療標的の最適な治療法の特定が難しいPDの研究や新規治療法開発において。順行輸送のさらなる研究やその正常化を可能にする新規薬剤の開発は、PDの新規治療法の発見に繋がることが期待できる。