Zeroing in on membrane trafficking: its implication for molecular pathogenesis and curative therapy of Parkinson's disease

• Project/Area Number: 17K09744
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: Hasegawa Takafumi 東北大学, 医学系研究科, 准教授 (70361079)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥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)
• 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

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.

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。

Research Products

• [Int'l Joint Research] University of British Columbia(Canada)
• [Int'l Joint Research] Lund University(Sweden)
• [Journal Article] Clinical and metabolic changes in Parkinson's disease with atrophy in the nucleus basalis of Meynert (2020)
  • Author(s): Gang M, Baba T, Hosokai Y, Nishio Y, Kikuchi A, Hirayama K, Hasegawa T, Aoki M, Takeda A, Mori E, Suzuki K
  • Journal Title: Mov Disord Volume: in press Issue: 5 Pages: 825-832
  • DOI: 10.1002/mds.27988
  • Peer Reviewed / Open Access
• [Journal Article] 「シヌクレイノパチーの新たな展開」－αシヌクレインを標的としたパーキンソン病の疾患修飾薬開発戦略 (2020)
  • Author(s): 長谷川隆文
  • Journal Title: BRAIN and NERVE Volume: 72 Pages: 143-150
• [Journal Article] 鼎談 治療標的としてのαシヌクレイン (2020)
  • Author(s): 長谷川隆文、下畑享良、桑原聡
  • Journal Title: BRAIN and NERVE Volume: 72 Pages: 97-105
• [Journal Article] Mutation analysis of LRP10 in Japanese patients with familial Parkinson’s disease, progressive supranuclear palsy, and fronto-temporal dementia (2019)
  • Author(s): Daida K, Nishioka K, Li Y, Yoshino H, Kikuchi A, Hasegawa T, Funayama M, Hattori N
  • Journal Title: Neurobiol Aging Volume: 84 Pages: 235.e11-235.e16
  • DOI: 10.1016/j.neurobiolaging.2019.08.030
  • Peer Reviewed
• [Journal Article] Longitudinal changes in 18F-THK5351 PET in corticobasal syndrome (2019)
  • 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
  • Journal Title: Eur J Neurol Volume: 26 Issue: 9 Pages: 1205-1211
  • DOI: 10.1111/ene.13966
  • Peer Reviewed / Open Access
• [Journal Article] Unveiling the coupling of flotillin-1 and extracellular α-synuclein: relevance to dopamine transporter trafficking and Lewy body formation (2019)
  • 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
  • Journal Title: FASEB Journal Volume: 33 Issue: 9 Pages: 10240-10256
  • DOI: 10.1096/fj.201802051r
  • Peer Reviewed
• [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.
  • Journal Title: Nat Commun Volume: 10 Issue: 1 Pages: 973-973
  • DOI: 10.1038/s41467-019-08858-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glymphatic systemー脳のゴミとその処理 (2019)
  • Author(s): 長谷川隆文
  • Journal Title: Clinical Neuroscience Volume: 37 Pages: 87-89
• [Journal Article] パーキンソン病診療最前線：パーキンソン病の成因研究 (2019)
  • Author(s): 長谷川隆文
  • Journal Title: Pharma Medica Volume: 37 Pages: 9-13
• [Journal Article] PEG-J tube breakage in a patient with Parkinson's disease receiving levodopa-carbidopa intestinal gel therapy. (2018)
  • Author(s): Soga T, Sugeno N, Baba T, Jin X, Koike T, Hasegawa T, Aoki M.
  • Journal Title: Neurol Clin Neurosci Volume: 6 Issue: 6 Pages: 197-198
  • DOI: 10.1111/ncn3.12220
  • Peer Reviewed
• [Journal Article] αシヌクレイン細胞間伝播を標的としたシヌクレイノパチー疾患修飾療法の開発 (2018)
  • Author(s): 長谷川隆文
  • Journal Title: Brain and Nerve Volume: 70 Pages: 551-556
  • NAID: 40021572953
• [Journal Article] Zeroing in on membrane trafficking in pathogenesis of PD. (2018)
  • Author(s): 長谷川隆文
  • Journal Title: Medical Science Digest Volume: 7 Pages: 115-117
• [Journal Article] Cutting Edge－メンブレントラフィックに着目したパーキンソン病の病態解明 (2018)
  • Author(s): 長谷川隆文
  • Journal Title: Medical Science Digest Volume: 44 Pages: 5-7
• [Journal Article] DnaJ/Hsp40 family and Parkinson’s disease. (2018)
  • Author(s): Hasegawa T, Yoshida S, Sugeno N, Kobayashi J, Aoki M.
  • Journal Title: Front Neurosci Volume: 11 Pages: 743-743
  • DOI: 10.3389/fnins.2017.00743
  • Peer Reviewed / Open Access
• [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.
  • Journal Title: Hum Mol Genet. Volume: 27 Issue: 5 Pages: 823-836
  • DOI: 10.1093/hmg/ddy003
  • Peer Reviewed / Open Access
• [Journal Article] Membrane Trafficking Illuminates a Path to Parkinson’s Disease (2017)
  • Author(s): Hasegawa T, Sugeno N, Kikuchi A, Baba T, Aoki M.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 242 Issue: 1 Pages: 63-76
  • DOI: 10.1620/tjem.242.63
  • NAID: 130005679072
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A. (2017)
  • Author(s): Willen K, Edgar JR, Hasegawa T, Tanaka N, Futter CE, Gouras GK.
  • Journal Title: Mol Neurodeg Volume: 12 Issue: 1 Pages: 61-61
  • DOI: 10.1186/s13024-017-0203-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 生命の恒常性を支えるメンブレントラフィック研究の最前線：メンブレントラフィックから探るパーキンソン病の分子病態 (2020)
  • Author(s): 長谷川隆文
  • Organizer: 第125回日本解剖学会総会・全国学術集会
  • Invited
• [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, Ezura M, Kikuchi A, Takeda A, Aoki M.
  • Organizer: International Congress of Parkinosn’s Disease and Movement Disorders 2020
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [Presentation] パーキンソン病の新規治療戦略－α-synuclein凝集・伝播を標的としたPD疾患修飾療法開発の現況 (2019)
  • Author(s): 長谷川隆文
  • Organizer: 第37回日本神経治療学会学術集会
  • Invited
• [Presentation] 神経免疫と神経変性－シヌクレイノパチーを対象とした免疫療法の現況 (2019)
  • Author(s): 長谷川隆文
  • Organizer: 第31回日本神経免疫学会学術集会
  • Invited
• [Presentation] メンブレントラフィッキングの破綻とパーキンソン病－VPS35とDNAJC13を中心に (2019)
  • Author(s): 長谷川隆文
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] オルガネラ間の連携破綻からみた神経疾患の発症メカニズム－メンブレントラフィック障害に着目したパーキンソン病の分子病態解析 (2019)
  • Author(s): 長谷川隆文
  • Organizer: NEURO2019 第62回日本神経化学会大会・第42回日本神経科学大会
  • Invited
• [Presentation] Controversy：α-シヌクレイン凝集抑制治療は、疾患修飾治療になりうるか？－Yesの立場から (2019)
  • Author(s): 長谷川隆文
  • Organizer: 第13回パーキンソン病・運動障害疾患コングレス
  • Invited
• [Presentation] Genotype-phenotype correlation of LRP10 mutations among familial Parkinson’s disease. (2019)
  • Author(s): Daida K, Li Y, Funayama M, Ogaki K, Yoshino H, Kikuchi A, Hasegawa T, Nishioka K, Hattori N.
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] 神経変性疾患の病態：レビー小体病の多様性は何処から生じるか？－蛋白伝播メカニズムから判ってきたこと (2019)
  • Author(s): 長谷川隆文
  • Organizer: 第60回日本神経学会学術大会
  • Invited
• [Presentation] More than just taking out the garbage-Expanding landscape of autophagy and lysosome function in neurological diseases. “Traffic jam in a cell”－Endo-lysosomal dysfunction as a convergent mechanism of neurodegenerative diseases. (2019)
  • Author(s): Hasegawa T
  • Organizer: 第60回日本神経学会学術大会
  • Invited
• [Presentation] Extracellular α-synuclein enters dopaminergic neurons by modulating flotillin-1-assisted dopamine transporter endocytosis. (2019)
  • Author(s): Hasegawa T, Kobayashi J, Sugeno N, Yoshida S, Ezura M, Kikuchi A, Takeda A, Aoki M.
  • Organizer: Japan-UK Neuroscience Symposium 2019
  • Int'l Joint Research / Invited
• [Presentation] Extracellular α-synuclein internalizes into dopaminergic neurons by hijacking flotillin-1-assisted dopamine transporter endocytosis (2019)
  • Author(s): Hasegawa T, Kobayashi J, Sugeno N, Yoshida S, Ezura M, Kikuchi A, Takeda A, Aoki M.
  • Organizer: AD/PD2019
  • Int'l Joint Research
• [Presentation] Extracellular α-synuclein internalizes into cells by modulating flotillin-1-assisted endocytosis of DAT. (2018)
  • Author(s): Hasegawa T, Kobayashi J, Sugeno N, Yoshida S, Ezura M, Kikuchi A, Takeda A, Aoki M.
  • Organizer: Neuroscience 2018
  • Int'l Joint Research
• [Presentation] Prion-like phenomenon：from myth to reality：Endosomal pathway: a molecular basis for prion-like phenomenon in synucleinopathy. (2018)
  • Author(s): 長谷川隆文
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] パーキンソン病の最新知見－蛋白伝播メカニズムから考えるレビー小体病の多様性 (2018)
  • Author(s): 長谷川隆文
  • Organizer: 第41回日本神経科学大会
  • Invited
• [Presentation] 神経化学からみた神経疾患 -ベンチとベットサイドの間：パーキンソン病の共通病態としてのエンドソーム輸送障害 (2018)
  • Author(s): 長谷川隆文
  • Organizer: 第61回日本神経化学会大会・第40回日本生物学的精神医学会 合同大会
• [Presentation] 難病病態解明と新治療法：異常タンパク伝播－分子病態から考えるパーキンソン病の新規治療戦略 (2018)
  • Author(s): 長谷川隆文
  • Organizer: 第6回日本難病医療ネットワーク学会
• [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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [Presentation] Deciphering the molecular mechanism behind the prion-like spread of α-synuclein. (2017)
  • Author(s): Hasegawa T.
  • Organizer: The 11th International Conference on Complex Medical Engineering, Schenzhen, China
  • Int'l Joint Research / Invited
• [Presentation] Endosomal pathway: a key regulator for prion-like phenomenon in synucleinopathy (2017)
  • Author(s): 長谷川隆文
  • Organizer: 第60回日本神経化学会大会、仙台
  • Invited
• [Book] 非定型パーキンソニズム －基礎と臨床 III. 病態解明と治療法の確立に向けて αシヌクレイン (2019)
  • Author(s): 長谷川隆文（下畑享良 編）
  • Total Pages: 242
  • Publisher: 文光堂
  • ISBN: 9784830615474
• [Remarks] 脳内の交通渋滞がパーキンソン病を誘発する
  • URL: https://www.tohoku.ac.jp/japanese/2018/01/press20180117-01.html
• [Remarks] 脳内の交通渋滞がパーキンソン病を誘発する
  • URL: http://resou.osaka-u.ac.jp/ja/research/2018/20180117_1
• [Patent(Industrial Property Rights)] パーキンソン病又はレビー小体病の治療剤及びそのスクリーニング方法 (2019)
  • Inventor(s): 国立大学法人東北大学、プロトセラ株式会社
  • Industrial Property Rights Holder: 国立大学法人東北大学、プロトセラ株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 特許願 (2019)
  • Inventor(s): 東北大学、プロトセラ（株）
  • Industrial Property Rights Holder: 東北大学、プロトセラ（株）
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas