Analysis of molecular mechanisms behind the prion hypothesis in synucleinopathy

2013 Fiscal Year Final Research Report

• 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
• 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

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): Kikuchi A, Baba T, Hasegawa T, Kobayashi M, Sugeno N, Konno M, Miura E, Hosokai Y, Ishioka T, Nishio Y, Hirayama K, Suzuki K, Aoki M, Takahashi S, Fukuda H, Itoyama Y, Mori E, Takeda A
  • Journal Title: BMJ Open Volume: 3 Pages: (3)
  • DOI: 10.1136/bmjopen-2012-002249
  • 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(1) Pages: 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] 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-ATPase 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(12) Pages: e29460
  • DOI: 10.1371/journal.pone.0029460
  • Peer Reviewed
• [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] 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
• [Remarks]
  • URL: http://www.neurol.med.tohoku.ac.jp