Analysis of molecular mechanisms behind the prion hypothesis in synucleinopathy

• Project/Area Number: 23591228
• 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, 助教 (70361079)
• Co-Investigator(Kenkyū-buntansha): TAKEDA Atsushi 東北大学, 大学院医学系研究科, 准教授 (70261534)
• Co-Investigator(Renkei-kenkyūsha): NAGAI Yoshitaka 独立行政法人国立精神・神経医療研究センター, 神経研究所, 室長 (60335354)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: パーキンソン病 / 異常凝集タンパク / αシヌクレイン / プリオン仮説 / エキソソーム / 小胞輸送 / ダイナミン / エンドソーム / α-シヌクレイン / セルトラリン / 多系統萎縮症 / エンドサイトーシス / 神経細胞 / オリゴデンドログリア / 細胞間伝播

Research Abstract

The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration. In this study, we showed that unlike prion protein, extracellular alpha-synuclein (aS), a major constituent of intraneuronal inclusions in Parkinson's disease, was mainly recovered in the supernatant fraction rather than in exosome-containing pellets from the neuronal culture medium and cerebrospinal fluid. In addition, we identified that the extracellular secretion of aS was secreted via Rab11-mediated recycling pathway (Hasegawa T, et al., PloS One 2011). Furthermore, we demonstrated that aSwas taken up by neuronal and oligodendroglial cells bu dynamic-dependent endocytosis (Konno M, et al., Mol Neurodegener 2012).

Research Products

• [Journal Article] Hypometabolism in the supplementary and anterior cingulate cortices is related to dysphagia in Parkinson's disease: a cross-sectional and 3-year longitudinal cohort study (2013)
  • Author(s): Akio Kikuchi, Toru Baba, Takafumi Hasegawa, Michiko Kobayashi, Naoto Sugeno, Masatoshi Konno, Emiko Miura, Yoshiyuki Hosokai, Toshiyuki Ishioka, Yoshiyuki Nishio, Kazumi Hirayama, Kyoko Suzuki, Masashi Aoki, ShokiTakahashi, Hiroshi Fukuda, Yasuto Itoyama, Etsuro Mori, Atsushi Takeda
  • Journal Title: BMJ Open Volume: 3 Issue: 3 Pages: e002249-e002249
  • DOI: 10.1136/bmjopen-2012-002249
  • Peer Reviewed
• [Journal Article] Pathogenesis of Multiple system atrophy. (2013)
  • Author(s): Hasegawa T, Kikuchi A, Takeda A.
  • Journal Title: Neurol Clin Neurosci Volume: 1 (6) Issue: 6 Pages: 189-194
  • DOI: 10.1111/ncn3.57
  • Peer Reviewed
• [Journal Article] Anti-voltage-gated potassium channel antibody is associated with chronic autonomic and sensory neuropathy. (2013)
  • Author(s): Kaneko K, Tano O, Kikuchi A, Hasegawa T, Tateyama M, Yoshioka M, Saito H, Watanabe O, Takeda A, Aoki M.
  • Journal Title: J Neurol Volume: 260 Issue: 1 Pages: 315-317
  • DOI: 10.1007/s00415-012-6730-0
  • Peer Reviewed
• [Journal Article] Suppression of dynamin GTPase decreases alpha-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy. (2012)
  • Author(s): Konno M, Hasegawa T, Baba T, Miura E, Sugeno N, Kikuchi A, Fiesel FC, Sasaki T, Aoki M, Itoyama Y, Takeda A.
  • Journal Title: Mol Neurodegener Volume: 7 Issue: 1 Pages: 38-38
  • DOI: 10.1186/1750-1326-7-38
  • Peer Reviewed
• [Journal Article] Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson's disease : a 3 year longitudinal study (2012)
  • Author(s): Baba T, Kikuchi A, Hirayama K, Nishio Y, Hosokai Y, Kanno S, Hasegawa T, Sugeno N, Konno M, Suzuki K, Takahashi S, Fukuda H, Aoki M, Itoyama Y, Mori E, Takeda A
  • Journal Title: Brain Volume: 135 Pages: 161-9
  • Peer Reviewed
• [Journal Article] Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson's disease : a 3-year longitudinal study (2012)
  • Author(s): BabaT, Kikuchi A, Hirayama K, Nishio Y, Hosokai Y, Kanno S, Hasegawa T, Sugeno N, Konno M, Suzuki K, et al
  • Journal Title: Brain Volume: 135 Issue: 1 Pages: 162-169
  • DOI: 10.1093/brain/awr321
  • Peer Reviewed
• [Journal Article] Differentiating Parkinson's disease from multiple system atrophy by [(123)I] meta-iodobenzylguanidine myocardial scintigraphy and olfactory test (2011)
  • Author(s): Kikuchi A, Baba T, Hasegawa T, Sugeno N, Konno M, Takeda A
  • Journal Title: Parkinsonism Relat Disord Volume: 17 Pages: 698-700
  • Peer Reviewed
• [Journal Article] The AAA-A TPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting of alpha-Synuclein (2011)
  • Author(s): Hasegawa T, Konno M, Baba T, Sugeno N, Kikuchi A, Kobayashi M, Miura E, Tanaka N, Tamai K, Furukawa K, Arai H, Mori F, Wakabayashi K, Aoki M, Itoyama Y, Takeda A
  • Journal Title: PLoS One Volume: 6 Issue: 12 Pages: 1-14
  • DOI: 10.1371/journal.pone.0029460
  • Peer Reviewed
• [Journal Article] Pathophysiology and clinical presentation of Parkinson's disease-up to date" pathomechanisms of Parkinson's disease. (2011)
  • Author(s): Hasegawa T
  • Journal Title: 臨床神経学 Volume: 51 Pages: 1165-1165
  • NAID: 130004504864
  • Peer Reviewed
• [Journal Article] Differentiating Parkinson's disease from multiple system atrophy by [123I] meta-iodobenzylguanidine myocardial scintigraphy and olfactory test (2011)
  • Author(s): Kikuchi A, Baba T, Hasegawa T, Sugeno N, Konno M, Takeda A
  • Journal Title: Parkinsonism & Related Disorders Volume: 17 Issue: 9 Pages: 698-700
  • DOI: 10.1016/j.parkreldis.2011.07.011
  • Peer Reviewed
• [Journal Article] Association of olfactory dysfunction and brain metabolism in Parkinson's disease (2011)
  • Author(s): Baba T, Takeda A, Kikuchi A, Hishio Y, Hosokai Y, Hirayama K, Hasegawa T, Sugeno N, Suzuki K, et al
  • Journal Title: Movement disorder Volume: 26 Issue: 4 Pages: 621-628
  • DOI: 10.1002/mds.23602
  • Peer Reviewed
• [Journal Article] A Case of Late Onset Riboflavin-responsive Multiple Acyl-CoA Dehydrogenase Deficiency Manifesting as Recurrent Rhabdomyolysis and Acute Renal Failure (2011)
  • Author(s): Izumi R, Suzuki N, Nagata M, Hasegawa T, Abe Y, Saito Y, Mochizuki H, Tateyama M, Aoki M
  • Journal Title: Internal Medicine Volume: 50 Pages: 2663-2668
  • NAID: 130001288632
  • Peer Reviewed
• [Presentation] ER stress and Parkinson’s disease: relevance to neurodegeneration. (2014)
  • Author(s): Hasegawa T
  • Organizer: The 87th Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Sendai, Japan
  • Invited
• [Presentation] RNAi-mediated silencing of VPS35 exacerbates phenotypic and locomotor abnormalities in alpha-synuclein transgenic drosophila (2013)
  • Author(s): Hasegawa T, Konno M, Miura E, Sugeno N, Nagai Y, Fujikake N, Suzuki M, Kikuchi A, Aoki M, Takeda A
  • Organizer: 17th International Congress of Parkinson's Disease and Related Disorders
  • Place of Presentation: シドニー,オーストラリア
  • Year and Date: 2013-06-17
• [Presentation] RNAi-mediated knockdown of VPS35 impairsα-synuclein degradation by inhibiting the maturation of cathepsin D (2013)
  • Author(s): Hasegawa T, Konno M, Miura E, Sugeno N, Nagai Y, Fujikake N, Suzuki M, Kikuchi A, Aoki M, Takeda A
  • Organizer: The 11th International Conference on Alzheimer's & Parkinson's Diseases (AD/PD 2013)
  • Place of Presentation: フローレンス,イタリア
  • Year and Date: 2013-03-07
• [Presentation] Regulation of alpha-synuclein internalization and secretion : what do we know, and where are we headed? (2013)
  • Author(s): Hasegawa T
  • Organizer: 7^<th> International Conference on alpha-Synuclein in Parkinson's Disease and Related Neurodegenerative Diseases : From Mechanisms to Therapeutic Strategies
  • Place of Presentation: ドバイ, UAE
  • Year and Date: 2013-03-02
• [Presentation] RNAi-mediated knockdown of VPS35 impairs α-synuclein degradation by inhibiting the maturation of cathepsin D (2013)
  • Author(s): Hasegawa T, Konno M, Miura M, Suzuki M, Sugeno N, Nagai Y, Fujikake N, Kikuchi A, Aoki M, Takeda A.
  • Organizer: XX World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Geneva, Switzerland
• [Presentation] The E3 ubiquitin ligase Nedd4 facilitates the endosomal targeting of extracellular alpha-synuclein. (2013)
  • Author(s): Sugeno N, Hasegawa T, Konno M, Miura E, Oshima R, Kikuchi A, Aoki M, Takeda A.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, USA
• [Presentation] αSYN蓄積・神経変性におけるESCRT機能異常の関与 (2013)
  • Author(s): 大嶋龍司、長谷川隆文、田中伸幸、玉井恵一、菅野直人、三浦永美子、今野昌俊、菊池昭夫、青木正志、武田篤
  • Organizer: 第7回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 東京
• [Presentation] ショウジョウバエモデルを用いたVPS35遺伝子異常によるパーキンソン病発症機構の解析 (2013)
  • Author(s): 今野昌俊、長谷川隆文、鈴木マリ、藤掛伸宏、永井義隆、三浦永美子、菅野直人、大嶋龍司、菊池昭夫、青木正志、武田篤
  • Organizer: 第7回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 東京
• [Presentation] レトロマー障害はカテプシンD成熟障害を介しα-シヌクレイン蓄積を誘導する (2013)
  • Author(s): 三浦永美子、長谷川隆文、今野昌俊、菅野直人、大嶋龍司、菊池昭夫、青木正志、武田篤
  • Organizer: 第7回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 東京
• [Presentation] RNAi-mediated knockdown of VPS35 impairs α-synuclein degradation by inhibiting the maturation of cathepsin D (2013)
  • Author(s): Hasegawa T, Konno M, Miura M, Suzuki M, Sugeno N, Nagai Y, Fujikake N, Kikuchi A, Aoki M, Takeda A.
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] RNAi-mediated silencing of VPS35 exacerbates phenotypic and locomotor abnormalities in α-synuclein transgenic Drosophila. (2013)
  • Author(s): Hasegawa T, Konno M, Miura E, Sugeno N, Nagai Y, Fujikake N, Suzuki M, Kikuchi A, Aoki M, Takeda A.
  • Organizer: The MDS 17th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Sydney, Australia
• [Presentation] DNAJC6遺伝子異常によるパーキンソン病発症機序解析 (2013)
  • Author(s): 長谷川隆文、菅野直人、今野昌俊、三浦永美子、三好耕、浅沼幹人、菊池昭夫、青木正志、武田篤
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] Recent progress in multiple system atrophy-“Pathogenesis of multiple system atrophy.” (2013)
  • Author(s): Hasegawa T
  • Organizer: 54th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: Tokyo, Japan
  • Invited
• [Presentation] αシヌクレイン細胞内取り込みはダイナミン阻害により抑制される (2013)
  • Author(s): 長谷川隆文、今野昌俊、菅野直人、三浦永美子、菊池昭夫、青木正志、武田篤
  • Organizer: 平成24年度 運動失調症の病態解明と治療法開発に関する研究班班会議
  • Place of Presentation: 東京
• [Presentation] Regulation of alpha-synuclein internalization and secretion: what do we know, and where are we headed? (2013)
  • Author(s): Takafumi Hasegawa
  • Organizer: Alpha-Synuclein in Parkinson's Disease & Related Neurodegenerative Diseases: From Mechanisms to Therapeutic Strategies
  • Place of Presentation: ドバイ、UAE
  • Invited
• [Presentation] RNAi-mediated knockdown of VPS35 impairs α-synuclein degradation by inhibiting the maturation of cathepsin D (2013)
  • Author(s): Takafumi Hasegawa, Masatoshi Konno, Emiko Miura, Naoto Sugeno, Yoshitaka Nagai, Nobuhiro Fujikake, Mari Suzuki, Akio Kikuchi, Masashi Aoki, Atsushi Takeda
  • Organizer: AD/PD2013
  • Place of Presentation: フローレンス、イタリア
• [Presentation] Suppression of Dynamin GTPase Activity Decreasesα-synuclein Uptake in Neuronal and Oligodendroglial Cells (2012)
  • Author(s): Hasegawa T, Konno M, Sugeno N, Miura E, Baba T, Kikuchi A, Aoki M, Takeda A
  • Organizer: The 17th Takeda Science Foundation Symposium on Bioscience."Therapeutic Approach for Neurodegenerative Diseases : Focusing on Alzheimer & Parkinson Diseases"
  • Place of Presentation: 大阪
  • Year and Date: 2012-12-07
• [Presentation] The AAA-ATPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting ofα-synuclein (2012)
  • Author(s): Hasegawa T, Konno M, Baba T, Sugeno N, Kikuchi A, Miura E, Takeda A
  • Organizer: The 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: ダブリン,アイルランド
  • Year and Date: 2012-06-18
• [Presentation] The AAA-ATPase VPS4 regulates Extracellular Secretion and Lysosomal Targeting of Alpha-synuclein (2012)
  • Author(s): Hasegawa T., Konno M, Baba T, Sugeno N, Kikuchi A, Miura E, Takeda A
  • Organizer: NRF-JSPS Asian Science Seminar
  • Place of Presentation: ソウル,韓国
  • Year and Date: 2012-02-14
• [Presentation] α-synuclein細胞間伝播に関与する細胞内小胞輸送系の解明 (2012)
  • Author(s): 長谷川隆文
  • Organizer: 第19回カテコールアミンと神経疾患研究会
  • Place of Presentation: 東京
• [Presentation] αシヌクレインのリソソーム移行および細胞外分泌はAAA型ATPase VPS4により制御される (2012)
  • Author(s): 長谷川隆文、今野昌俊、三浦永美子、馬場徹、菅野直人、菊池昭夫、青木正志、武田篤
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] The AAA-ATPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting of α-synuclein (2012)
  • Author(s): Takafumi Hasegawa, Masatoshi Konno, Toru Baba, Naoto Sugeno, Akio Kikuchi, Emiko Miura, Atsushi Takeda
  • Organizer: 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: ダブリン、アイルランド
• [Presentation] α-synucleinの細胞間Propagationの機序 (2012)
  • Author(s): 長谷川隆文
  • Organizer: 厚労科研神経変性疾患に関する調査研究班 H24年度ワークショップ
  • Place of Presentation: 東京
  • Invited
• [Presentation] α-synuclein細胞間伝播に関与する細胞内小胞輸送系の解明 (2012)
  • Author(s): 長谷川隆文
  • Organizer: 平成24年度 第6回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都
  • Invited
• [Presentation] ショウジョウバエモデルを用いたVps35遺伝子異常によるパーキンソン病病態の解析 (2012)
  • Author(s): 長谷川隆文、今野昌俊、三浦永美子、菅野直人、永井義隆、藤掛伸宏、鈴木マリ、菊池昭夫、馬場徹、青木正志、武田篤
  • Organizer: 平成24年度 第6回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都
• [Presentation] αシヌクレイン細胞間伝播はダイナミン機能阻害により抑制される (2012)
  • Author(s): 長谷川隆文、今野昌俊、三浦永美子、菅野直人、菊池昭夫、青木正志、武田篤
  • Organizer: 第30回 日本神経治療学会総会
  • Place of Presentation: 北九州
• [Presentation] Suppression of Dynamin GTPase Activity Decreases α-synuclein Uptake in Neuronal and Oligodendroglial Cells (2012)
  • Author(s): Takafumi Hasegawa, Masatoshi Konno, Naoto Sugeno, Emiko Miura, Toru Baba, Akio Kikuchi, Masashi Aoki, Atsushi Takeda
  • Organizer: 第17回武田科学振興財団 生命科学シンポジウム
  • Place of Presentation: 大阪
• [Presentation] Suppression of dynamin GTPase decreases alpha-Synuclein uptake by neuronal and oligodendroglial Cells (2012)
  • Author(s): Takafumi Hasegawa
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] The AAA-ATPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting of Alpha-synuclein (2012)
  • Author(s): Hasegawa T, Konno M, Baba T, Sugeno N, Kikuchi A, Miura E, Takeda A
  • Organizer: NRF-JSPS Asian Science Seminar 2012
  • Place of Presentation: ソウル、韓国
• [Presentation] 培養細胞系を用いたα-synucleinプリオン仮説の分子病態解析 (2011)
  • Author(s): 長谷川隆文、今野昌俊、馬場徹、菅野直人、菊池昭夫、武田篤
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
• [Presentation] MVB sorting機構はα-synuclein分泌・ライソゾーム移行に関与する (2011)
  • Author(s): 長谷川 隆文、今野 昌俊、馬場 徹、菅野 直人、菊池 昭夫、若林 孝一、武田 篤
  • Organizer: 第5回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 東京
• [Presentation] アルファシヌクレインの細胞外分泌・ライソゾーム移行を制御する細胞内膜動輸送系の探索 (2011)
  • Author(s): 長谷川隆文、今野 昌俊、馬場 徹、菅野 直人、菊池 昭夫、武田 篤
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] シンポジウム パーキンソン病ー病態ー (2011)
  • Author(s): 長谷川隆文
  • Organizer: 第52回日本神経学会学術大会(招待講演)
  • Place of Presentation: 名古屋
• [Presentation] Role of TPPP/p25 on alpha-synuclein-mediated oligodendroglial degeneration and the protective effect of SIRT2 inhibition in a cellular model of multiple system atrophy (2011)
  • Author(s): Hasegawa T, Baba T, Michiko Kobayashi, Konno M, Sugeno N, Kikuchi A, Takeda A
  • Organizer: 15th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: トロント、カナダ
• [Remarks]
  • URL: http://www.neurol.med.tohoku.ac.jp