Zeroing in on aberrant membrane trafficking in molecular pathogenesis of Parkinson's disease

• Project/Area Number: 26461263
• 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, 大学病院, 講師 (70361079)
• Co-Investigator(Renkei-kenkyūsha): Nagai Yoshitaka 大阪大学, 大学院医学系研究科, 教授 (60335354)
• Research Collaborator: Sugeno Naoto 東北大学, 大学病院, 助教 (30509550)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: パーキンソン病 / PARK17 / VPS35 / レトロマー / エンドソーム / カテプシンD / アルファシヌクレイン / ショウジョウバエモデル / メンブレントラフィック / DNAJC13 / αシヌクレイン / アクチン / 神経変性 / 神経変性疾患 / プリオン仮説 / 小胞輸送 / ESCRT / 異常タンパク凝集 / コンディショナルノックアウトマウス / 異常蛋白伝播 / 多系統萎縮症 / シヌクレイノパチー

Outline of Final Research Achievements

In this study, we first showed that the silencing of VPS35 in cultured cells caused a reduction in the distribution of CI-MPR and impaired the maturation of CTSD. Second, we found that the amount of pro-CTSD was substantially increased not only in the culture medium of the VPS35-deficient cells but also in the CSF from sporadic PD patients. Third, we demonstrated that silencing VPS35 impairs the maturation of CTSD, which occurs concomitant with a striking accumulation of αSYN in lysosomes. Finally, we showed that the RNAi-mediated silencing of dVPS35 not only induced the accumulation of the insoluble αSYN species in the brain but also exacerbated mild eye disorganization, as well as locomotor impairment in the flies expressing the human wt-αSYN. Cumulatively, these data suggest that the retromer-dependent sorting machinery plays a role in αSYN catabolism by modulating the intracellular processing and activation of CTSD and might thereby contribute to the pathogenesis of PD.

Research Products

• [Int'l Joint Research] The University of British Columbia(カナダ)
• [Journal Article] Longitudinal study of cognitive and cerebral metabolic changes in Parkinson's disease. (2017)
  • Author(s): Baba T, Hosokai Y, Nishio Y, Kikuchi A, Hirayama K, Suzuki K, Hasegawa T, Aoki M, Takeda A, Mori E.
  • Journal Title: J Neurol Sci Volume: 372 Pages: 288-293
  • DOI: 10.1016/j.jns.2016.11.068
  • Peer Reviewed
• [Journal Article] In vivo visualization of tau pathology using 18F-THK5351 PET in corticobasal syndrome. (2016)
  • Author(s): Kikuchi A, Okamura N, Hasegawa T, Harada R, Watanuki S, Funaki Y, Kobayashi M, Tano O, Baba T, Sugeno N, Oshima R, Yoshida S, Kobayashi J, Ezura M, Hiraoka K, Mugikura S, Takase K, Iwata R, Taki Y, Furukawa K, HArai H, Furumoto S, Tashiro M, Yanai K, Kudo Y, Takeda A，Aoki M.
  • Journal Title: Neurology Volume: 87 Issue: 22 Pages: 2309-2316
  • DOI: 10.1212/wnl.0000000000003375
  • Peer Reviewed
• [Journal Article] ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways (2016)
  • Author(s): Oshima R, Hasegawa T, Tamai K, Sugeno N, Yoshida S, Kobayashi J, Kikuchi A, Baba T, Futatsugi A, Sato I, Satoh K, Takeda A, Aoki M and Tanaka N
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 24997-24997
  • DOI: 10.1038/srep24997
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] On the utility of MIBG SPECT/CT in evaluating cardiac sympathetic dysfunction in Lewy body diseases (2016)
  • Author(s): Odagiri H, Baba T, Nishio Y, Iizuka O, Matsuda M, Inoue K, Kikuchi A, Hasegawa T, Aoki M, Takeda A, Taki Y, Mori E
  • Journal Title: PLoS One Volume: 11(4) Issue: 4 Pages: 0152746-0152746
  • DOI: 10.1371/journal.pone.0152746
  • Peer Reviewed / Open Access
• [Journal Article] パーキンソン病と細胞内輸送 (2016)
  • Author(s): 長谷川隆文
  • Journal Title: 脳21 Volume: Vol.19 No.4 Pages: 27-31
• [Journal Article] 検査からみる神経疾患－神経疾患とエクソソーム (2016)
  • Author(s): 長谷川隆文
  • Journal Title: Clinical Neuroscience Volume: 34 Pages: 1388-1390
• [Journal Article] αシヌクレイン細胞間伝播を制御する小胞輸送機構 (2016)
  • Author(s): 長谷川 隆文
  • Journal Title: 最新醫學 Volume: 71 Pages: 46-50
• [Journal Article] A Japanese multicenter survey characterizing pain in Parkinson's disease (2016)
  • Author(s): Kubo SI, Hamada S, Maeda T, Uchiyama T, Hashimoto M, Nomoto N, Kano O, Takahashi T, Terashi H, Takahashi T, Hatano T, Hasegawa T, Baba Y, Sengoku Rl, Watanabe H, Kadowaki T, Inoue M, Kaneko S, Shimura H, Nagayama H
  • Journal Title: Journal of The Neurological Science Volume: 365 Pages: 162-166
  • DOI: 10.1016/j.jns.2016.04.015
  • Peer Reviewed
• [Journal Article] パーキンソン病診療up date 1. プリオン仮説 (2015)
  • Author(s): 長谷川 隆文
  • Journal Title: Pharma Medica Volume: 33 Pages: 9-13
• [Journal Article] 特集：パーキンソン病の治療-パーキンソン病の発症機序 (2015)
  • Author(s): 菅野 直人、長谷川 隆文
  • Journal Title: Current Therapy Volume: 33 Pages: 14-19
• [Journal Article] K63-linked ubiquitination by E3 Ubiquitin Ligase Nedd4-1 facilitates endosomal sequestration of internalized alpha-synuclein. (2014)
  • Author(s): Sugeno N, Hasegawa T, Tanaka N, Fukuda M, Wakabayashi K, Oshima R, Konno M, Miura E, Kikuchi A, Baba T, Anan T, Nakao M, Geisler S, Aoki M, Takeda A.
  • Journal Title: J Biol Chem Volume: 289 Issue: 26 Pages: 18137-18151
  • DOI: 10.1074/jbc.m113.529461
  • Peer Reviewed / Open Access
• [Journal Article] VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease. (2014)
  • Author(s): Miura E, Hasegawa T, Konno M, Suzuki M, Sugeno N, Fujikake N, Geisler S, Tabuchi M, Oshima R, Kikuchi A, Baba T, Wada K, Nagai Y, Takeda A, Aoki M.
  • Journal Title: Neurobio Dis Volume: 71 Pages: 1-13
  • DOI: 10.1016/j.nbd.2014.07.014
  • Peer Reviewed
• [Journal Article] 1.Neural Substrates of Cognitive Subtypes in Parkinson's Disease: A 3-Year Longitudinal Study (2014)
  • Author(s): Shoji Y¸ Nishio Y, Baba T, Uchiyama M, Yokoi K, Ishioka T, Hosokai Y, Hirayama K, Fukuda H, Aoki M, Hasegawa T, Takeda A, Mori E.
  • Journal Title: PLoS ONE Volume: 9(10) Issue: 10 Pages: e110547-e110547
  • DOI: 10.1371/journal.pone.0110547
  • Peer Reviewed / Open Access
• [Journal Article] Olfactory dysfunction and dementia in Parkinson's disease. (2014)
  • Author(s): Takeda A, Baba T, Kikuchi A, Hasegawa T, Sugeno N, Konno M, Miura E, Mori E.
  • Journal Title: J Parkinsons Dis Volume: 4 Issue: 2 Pages: 181-187
  • DOI: 10.3233/jpd-130277
  • Peer Reviewed
• [Journal Article] Rhinorrhea in Parkinson's disease: a consecutive multicenter study in Japan. (2014)
  • Author(s): Kano O, Yoshioka M, Nagayama H, Hamada S, Maeda T, Hasegawa T, Kadowaki T, Sengoku R, Terashi H, Hatano T, Nomoto N, Inoue M, Shimura H, Takahashi T, Uchiyama T, Watanabe H, Kaneko S, Takahashi T, Baba Y, Kubo S; Young Japanese Expert Group for Parkinson's Disease and Movement Disorders: YJ-EXPANDS.
  • Journal Title: Journal of Neurological Science Volume: 343 Issue: 1-2 Pages: 88-90
  • DOI: 10.1016/j.jns.2014.05.039
  • Peer Reviewed
• [Presentation] 動物モデルと治療薬の展望：異常タンパク伝播機構から考えるシヌクレイノパチー疾患修飾療法の展望. (2016)
  • Author(s): 長谷川隆文
  • Organizer: 第10回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都（京都ホテルオークラ）
  • Year and Date: 2016-10-06
  • Invited
• [Presentation] ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways. (2016)
  • Author(s): Hasegawa T, Oshima R, Tamai K, Takeda A, Tanaka N, Aoki M
  • Organizer: The 20th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: ベルリン、ドイツ
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] Movement disorders update: Membrane trafficking and Parkinson’s disease. (2016)
  • Author(s): 長谷川隆文
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸（神戸コンベンションセンター）
  • Year and Date: 2016-05-18
• [Presentation] Forebrain-specific knockout of ESCRT-0/Hrs disrupts protein quality control and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways (2016)
  • Author(s): Oshima R, Hasegawa T, Tamai K, Takeda A, Tanaka N, Aoki M
  • Organizer: The 5th Asian and Oceanian Parkinson’s Disease and Movement Disorders
  • Place of Presentation: マニラ、フィリピン
  • Year and Date: 2016-03-12
  • Int'l Joint Research
• [Presentation] Membrane trafficking in neuronal maintenance and degeneration. (2016)
  • Author(s): Hasegawa T
  • Organizer: Brain Protein Aging and Dementia Control: 1st International Workshop 2016
  • Place of Presentation: 名古屋（名古屋大学鶴友会館）
  • Int'l Joint Research / Invited
• [Presentation] MSAの治療実現のために、何が必要か？: MSAの病態修飾療法－課題と希望. (2016)
  • Author(s): 長谷川隆文
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸（神戸コンベンションセンター）
• [Presentation] パーキンソン病における髄液エキソソーム中microRNA発現プロファイリング (2015)
  • Author(s): 長谷川 隆文
  • Organizer: 第33回日本神経治療学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-11-27
• [Presentation] Knockdown of ESCRT-0 disrupts protein quality control and promotes ER stress-mediated neuronal cell death (2015)
  • Author(s): Hasegawa T, Oshima R, Sugeno N, Tamai K, Kikuchi A, Takeda A, Tanaka N, Aoki M
  • Organizer: Neuroscience 2015
  • Place of Presentation: シカゴ、米国
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] CSF derived exosomal microRNA profile in patients with Parkinson’s disease (2015)
  • Author(s): Hasegawa T, Sugeno N, Akio Kikuchi1, Oshima R, Yoshida S, Takeda A, Aoki M
  • Organizer: The MDS 19th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: サンディエゴ、米国
  • Year and Date: 2015-06-14
  • Int'l Joint Research
• [Presentation] 教育講演：「αシヌクレインと細胞毒性発現メカニズム」αシヌクレインプリオン仮説の基礎－αシヌクレイン吸収・分泌のメカニズム (2015)
  • Author(s): 長谷川 隆文
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟コンベンションセンター（新潟）
  • Year and Date: 2015-05-20
  • Invited
• [Presentation] How does exogenous alpha-synuclein get access to the endogenous alpha-synuclein proteins? (2015)
  • Author(s): Hasegawa T
  • Organizer: 2015 MDS course Alpha-Synuclein: The Gateway to Parkinsonism
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 2015-02-11 – 2015-02-13
  • Invited
• [Presentation] Functional ESCRT machinery is required for the clearance of aggregate-prone proteins associated with neurodegenerative diseases. (2014)
  • Author(s): Hasegawa T
  • Organizer: th Asian and Oceanian Parkinson's disease and movement disorders congress
  • Place of Presentation: Pattaya, Thailand
  • Year and Date: 2014-11-28 – 2014-11-30
• [Presentation] Aberrant Vesicular Trafficking In Parkinson’s disease. (2014)
  • Author(s): Hasegawa T
  • Organizer: The 2nd East Asia German Alumni Symposia in Life Science
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2014-10-17 – 2014-10-19
  • Invited
• [Presentation] Role of ESCRT machinery in the clearance of aggregate-prone proteins associa ted with neurodegenerative diseases. (2014)
  • Author(s): Hasegawa T
  • Organizer: 第87回 生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Retromer dysfunction as an emerging mechanism of Parkinson's disease. (2014)
  • Author(s): Hasegawa T
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
  • Invited
• [Presentation] Vesicular trafficking defect in the pathogenesis of Parkinson’s disease. (2014)
  • Author(s): Hasegawa T
  • Organizer: 2014 ICME International Conference on Complex Medical Engineering
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2014-07-26 – 2014-07-29
  • Invited
• [Presentation] VPS35 dysfunction impairs lysosomal degradation of [alpha]-synuclein and exacerbates neurotoxicity in a drosophila model of Parkinson's disease. (2014)
  • Author(s): Hasegawa T
  • Organizer: The MDS 18th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-08 – 2014-06-12
• [Presentation] Nedd4 regulates internalization and endosomal targeting of alpha-synuclein. (2014)
  • Author(s): Hasegawa T, Sugeno N, Tanaka N, Fukuda M, Wakabayashi K, Oshima R, Konno M, Miura E, Kikuchi A, Baba T, Anan T, Nakao M, Geisler S, Takeda A, Aoki M
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-21 – 2014-05-24
• [Book] Annual Review神経2016 II.本年の動向 7)シヌクレイノパチーの新たな病態仮説・治療ターゲット-異常タンパク伝播 (2016)
  • Author(s): 長谷川 隆文
  • Total Pages: 275
  • Publisher: 中外医学社
• [Remarks] 小胞輸送制御因子ESCRTの異常が神経細胞死を引き起こす
  • URL: http://www.tohoku.ac.jp/japanese/2016/04/press20160425-04.html