Analysis of molecular mechanism of synaptic vesicle dynamics which regulated by Parkinson's disease causative genes and identification of therapeutic target of Parkinson's disease related genes.
| Project/Area Number |
16K09679
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Juntendo University |
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Principal Investigator |
Inoshita Tsuyoshi 順天堂大学, 医学(系)研究科(研究院), 助教 (20601206)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | パーキンソン病 / 神経変性 / 小胞動態 / ショウジョウバエ / 軸索輸送 / αシヌクレイン / 神経科学 / 小胞輸送 / LRRK2 / 神経機能 / シナプス機能制御 |
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| Outline of Final Research Achievements |
To understand the pathogenic mechanism of Parkinson's disease (PD), a neurodegenerative disease, and search for new therapeutic targets, we analyzed the genetic correlation between eight PD-related genes. Our results revealed that the PD causative gene LRRK2 has a central role. We also demonstrated that loss of LRRK2 function and expression of pathogenic mutants cause Arl8 accumulation in synapses associated with axonal transport abnormalities. In addition, accumulation of α-synuclein in Arl8-accumulating synapses and co-localization of Arl8 and α-synuclein in autopsy brain of PD patients were revealed. These findings suggested that LRRK2 regulates axonal transport of Arl8 and α-synuclein and disorder of their axon transport might be involved in PD onset.
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| Academic Significance and Societal Importance of the Research Achievements |
神経変性疾患の一つパーキンソン病は、加齢が発症リスクであるが、根本的な治療法は確立されておらず、超高齢化が進む本邦では新規治療法の開発が強く求められている。既に20個以上の原因遺伝子やリスク遺伝子が同定されているが、最適な治療標的特定のためには、より中心的な遺伝子の特定が必要である。本研究は、PD原因遺伝子LRRK2と他の4個のPD関連遺伝子との遺伝的相関を明らかにすることで、LRRK2が制御する分子機構が広範なPD患者への治療標的となることを明らかにした。さらに、LRRK2によるArl8やαシヌクレインの軸索輸送制御機構を明らかにし、軸索輸送の正常化がPD治療に貢献する可能性を示した。
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Report
(5 results)
Research Products
(11 results)
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[Journal Article] Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila2017
Author(s)
Tsuyoshi Inoshita , Taku Arano, Yuka Hosaka, Hongrui Meng, Yujiro Umezaki, Sakiko Kosugi, Takako Morimoto, Masato Koike, Hui-Yun Chang, Yuzuru Imai, Nobutaka Hattori
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Journal Title
Human Molecular Genetics
Volume: 印刷中
Related Report
Peer Reviewed
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