Zeroing in on membrane trafficking: its implication for molecular pathogenesis and curative therapy of Parkinson's disease
| Project/Area Number |
17K09744
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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 | Tohoku University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 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 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | パーキンソン病 / メンブレントラフィック / エンドソーム / αシヌクレイン / DNAJC13 / ドパミントランスポータ－ / flotillin-1 / プリオン様伝播 / PARK21 / 異常タンパク伝播 / DAT / アルファシヌクレイン / ドパミントランスポーター / フロチリン-1 / エンドサイトーシス / 網羅的解析 / アクチン / ショウジョウバエ / ドパミン神経変性 |
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| Outline of Final Research Achievements |
We have started this year of research focusing on the following projects: (i) intracellular vesicular trafficking and alpha-synuclein (αS) accumulation and neurodegeneration, and (ii) cell-to-cell spreading of aS. In the first project, we have now investigated how mutat DNAJC13 could drive neurrodegeneration leading to PD. Through this study, the co-expression of mutant DNAJC13 and αS in cells resulted in accumulation of αS due to defective endosomal trafficking. Furthermore, we found that expressing mutant DNAJC3 with αS in fly brains enhanced the accumulation of insoluble αS, and resulted in a loss of dopaminergic neurons. These defects had a significant impact on the motor performance of flies. In another project, we are elucidating the mechanisms of αS propagation using cellular and animal models. Through these observations, we found that flotillin-1 co-assembled with extracellular αS on cell surface, and αS enters into cells by hijacking the endocytic trafficking of DAT.
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| Academic Significance and Societal Importance of the Research Achievements |
パーキンソン病をはじめとする神経変性疾患の原因究明と治療は、高齢化が進む21世紀において全世界的な課題である。一方、これらの疾患の発症機序は完全には解明されておらず、治療は対症療法に限定されており、進行抑制・根本的治療法は存在しない。本研究により明らかにされた病態メカニズムや創薬シーズは、症状進行による社会的資産の毀損の回避を介して医療・福祉への貢献に繋がることが期待され、創薬産業へのインパクトも大きいと予想される。
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Report
(4 results)
Research Products
(47 results)
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[Journal Article] Clinical and metabolic changes in Parkinson's disease with atrophy in the nucleus basalis of Meynert2020
Author(s)
Gang M, Baba T, Hosokai Y, Nishio Y, Kikuchi A, Hirayama K, Hasegawa T, Aoki M, Takeda A, Mori E, Suzuki K
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Journal Title
Mov Disord
Volume: in press
Issue: 5
Pages: 825-832
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Longitudinal changes in 18F-THK5351 PET in corticobasal syndrome2019
Author(s)
Ezura M, Kikuchi A, Ishiki A, Okamura N, Hasegawa T, Harada R, Watanuki S, Funaki Y, Hiraoka K, Baba T, Sugeno N, Oshima R, Yoshida S, Kobayashi J, Kobayashi M, Tano O, Nakashima I, Mugikura S, Iwata R, Taki Y, Furukawa K, Arai H, Furumoto S, Tashiro M, Yanai K, Kudo Y, Takeda A, Aoki M
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Journal Title
Eur J Neurol
Volume: 26
Issue: 9
Pages: 1205-1211
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Unveiling the coupling of flotillin-1 and extracellular α-synuclein: relevance to dopamine transporter trafficking and Lewy body formation2019
Author(s)
Kobayashi J, Hasegawa T, Sugeno N, Yoshida S, Miki Y, Fukuda M, Kawahata I, Yamakuni T, Tomiyama A, Kawata Y, Ezura M, Kikuchi A, Baba T, Wakabayashi K, Takeda A, Aoki M
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Journal Title
FASEB Journal
Volume: 33
Issue: 9
Pages: 10240-10256
DOI
Related Report
Peer Reviewed
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[Journal Article] Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis.2019
Author(s)
Carballo-Carbajal I, Laguna A, Romero-Gimenez J, Cuadros T, Bove J, Martinez-Vicente M, Parent A, Gonzalez-Sepulveda M, Penuelas N, Torra A, Rodrguez-Galvan B, Ballabio A, Hasegawa T, Bortolozzi A, Gelpi E and Vila M.
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Journal Title
Nat Commun
Volume: 10
Issue: 1
Pages: 973-973
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Parkinson’s disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through perturbation of endosomal trafficking.2018
Author(s)
Yoshida S, Hasegawa T, Suzuki M, Sugeno N, Kobayashi J, Ueyama M, Fukuda M, Ido-Fujibayashi A, Sekiguchi K, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y and Aoki M.
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Journal Title
Hum Mol Genet.
Volume: 27
Issue: 5
Pages: 823-836
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.2019
Author(s)
Hasegawa T, Kobayashi J, Sugeno N, Yoshida S, Akiyama T, Fujimori K, Hatakeyama H, Miki Y, Kanzaki M, Wakabayashi K, Okano H, Aoki M.
Organizer
5th World Parkinson Congress
Related Report
Int'l Joint Research
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[Presentation] Mutant DNAJC13 modulates accumulation and toxicity of α-synuclein through altered endosomal trafficking in cell and fly models of Parkinson’s disease.2017
Author(s)
Hasegawa T, Yoshida S, Suzuki M, Sugeno N, Kobayashi J, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y, Aoki M.
Organizer
The 21th International Congress of Parkinson's Disease and Movement Disorders, Vancouver, Canada
Related Report
Int'l Joint Research
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[Presentation] Parkinson's disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through alteration of endosomal trafficking.2017
Author(s)
Hasegawa T, Yoshida S, Suzuki M, Sugeno N, Kobayashi J, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y, Aoki M.
Organizer
XXIII World Congress of Neurology, Kyoto, Japan
Related Report
Int'l Joint Research
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[Presentation] Parkinson’s disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through alteration of endosomal trafficking.2017
Author(s)
Hasegawa T, Yoshida S, Suzuki M, Sugeno N, Kobayashi J, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y, Aoki M.
Organizer
Neuroscience 2017, Washington DC, USA
Related Report
Int'l Joint Research
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