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Identification of neurotoxic alpha-synuclein oligomers in Parkinson's disease and its application to molecular targeted therapy

Research Project

Project/Area Number 15K09322
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Tokuda Takahiko  京都府立医科大学, 医学(系)研究科(研究院), 教授 (80242692)

Co-Investigator(Kenkyū-buntansha) 建部 陽嗣  京都府立医科大学, 医学(系)研究科(研究院), 助教 (00637027)
渡邊 義久  京都府立医科大学, 医学(系)研究科(研究院), 講師 (50363990)
笠井 高士  京都府立医科大学, 医学(系)研究科(研究院), 講師 (70516062)
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsα-シヌクレイン / オリゴマー / パーキンソン病 / 脂質 / エクソソーム / リポ蛋白 / 分子篩クロマトグラフィー / シヌクレインオリゴマー
Outline of Final Research Achievements

It is known that extracellular α-synuclein (A-syn) oligomers are important as a pathogenic agent in Parkinson’s disease. In this research project, we first analyzed A-syn molecules in human plasma using gel-filtration chromatography. A-syn molecules in plasma were found in fraction with a molecular mass of 60 kDa and ~2,000 kDa. Furthermore, analyses of human plasma using lipid-adsorption columns demonstrated that A-syn molecules associated with lipids exist in the fractions corresponding to HDLs, and co-exist with ApoA1, ApoE, and ApoJ molecules. Some of those HDL-associated A-syn molecules were detected as oligomers. Our studies revealed that A-syn molecules in human plasma are mainly associated with HDL particles, and at least some part of them are oligomerized.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (48 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (9 results) Journal Article (17 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 17 results,  Open Access: 15 results,  Acknowledgement Compliant: 5 results) Presentation (17 results) (of which Int'l Joint Research: 6 results,  Invited: 11 results) Book (5 results)

  • [Int'l Joint Research] Hamad Bin Khalifa University(Qatar)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] University of Texas Medical School(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Lancaster University(英国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Hamad Bin Khalifa University(Qatar)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] University of Texas Medical School(米国)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Lancaster University(英国)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Neurological Disorders Center/Qatar Biomedical Research Institute/Hamad Bin Khalifa University(Qatar)

    • Related Report
      2015 Research-status Report
  • [Int'l Joint Research] Mitchell Center/University of Texas Medical School(米国)

    • Related Report
      2015 Research-status Report
  • [Int'l Joint Research]

    • Related Report
      2015 Research-status Report
  • [Journal Article] Increased levels of plasma total tau in adult Down syndrome2018

    • Author(s)
      Kasai T, Tatebe H, Kondo M, Ishii R, Ohmichi T, Yeung WTE, Morimoto M, Chiyonobu T, Terada N, Allsop D, Nakagawa M, Mizuno T, Tokuda T.
    • Journal Title

      Plos One

      Volume: 12 Issue: 11 Pages: e0188802-e0188802

    • DOI

      10.1371/journal.pone.0188802

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha-synuclein in patients diagnosed with probable Alzheimer's disease2017

    • Author(s)
      Majbour NK, Chiasserini D, Vaikath NN, Eusebi P, Tokuda T, van de Berg W, Parnetti L, Calabresi P, El-Agnaf OM
    • Journal Title

      Sci Rep.

      Volume: 7 Issue: 1 Pages: 40263-40263

    • DOI

      10.1038/srep40263

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid.2017

    • Author(s)
      Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, Trenkwalder, Mollenhauer B, Soto C C,
    • Journal Title

      JAMA Neurol

      Volume: 74 Issue: 2 Pages: 163-172

    • DOI

      10.1001/jamaneurol.2016.4547

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: Do PGK-1 mutations contribute to vulnerability to parkinsonism?2017

    • Author(s)
      Sakaue S, Kasai T, Osone S, Azuma Y, Imamura T, Mizuta I, Tokuda T, Kanno H, El-Agnaf OM, Morimoto M, Hosoi H, Mizuno T.
    • Journal Title

      npj Parkinson Disease

      Volume: 3 Issue: 1 Pages: 1-3

    • DOI

      10.1038/s41531-017-0014-4

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Abeta levels in the jugular vein and high molecular weight Abeta oligomer levels in CSF can be used as biomarkers to indicate the anti-amyloid effect of IVIg for Alzheimer's disease.2017

    • Author(s)
      Kasai T, Kondo M, Ishii R, Tanaka A, Ataka S, Shimada H, Tomiyama T, Mori H, Taylor M, Allsop D, Nakagawa M, Mizuno T, Tokuda T.
    • Journal Title

      Plos One

      Volume: 11 Issue: 4 Pages: e0174630-e0174630

    • DOI

      10.1371/journal.pone.0174630

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer’s disease and down syndrome2017

    • Author(s)
      Tatebe Harutsugu、Kasai Takashi、Ohmichi Takuma、Kishi Yusuke、Kakeya Tomoshi、Waragai Masaaki、Kondo Masaki、Allsop David、Tokuda Takahiko
    • Journal Title

      Molecular Neurodegeneration

      Volume: 12 Issue: 1 Pages: 1-11

    • DOI

      10.1186/s13024-017-0206-8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Subgroup differences in “brain-type” transferrin and alpha-synuclein in Parkinson's disease and multiple system atrophy2016

    • Author(s)
      A Yoshihara, M Fukatsu, K Hoshi, Y Hashimoto, et. al
    • Journal Title

      The Journal of Biochemistry

      Volume: 159 Issue: 2 Pages: 87-91

    • DOI

      10.1093/jb/mvw015

    • Description
      未定
    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Monoclonal antibody with conformational specificity for a toxic conformer of amyloid β42 and its application toward the Alzheimer's disease diagnosis2016

    • Author(s)
      Kazuma Murakami, Maki Tokuda, Takashi Suzuki, Yumi Irie, Mizuho Hanaki, Naotaka Izuo, Yoko Monobe, Ken-ichi Akagi, Ryotaro Ishii, Harutsugu Tatebe, Takahiko Tokuda, Masahiro Maeda, Toshiaki Kume, Takahiko Shimizu, Kazuhiro Irie
    • Journal Title

      Sci. Rep.

      Volume: 6 Issue: 1 Pages: 29038-29038

    • DOI

      10.1038/srep29038

    • NAID

      120005774689

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Longitudinal changes in CSF alpha-synuclein species reflect Parkinson’s disease progression2016

    • Author(s)
      Majbour NK, Vaikath NN, Eusebi P, Chiasserini D, Ardah M, Varghese S, Haque ME, Tokuda T, Auinger P, Calabresi P, Parnetti L, El-Agnaf OMA
    • Journal Title

      Mov Disord

      Volume: 31 Issue: 10 Pages: 1535-1542

    • DOI

      10.1002/mds.26754

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Serum albumin to globulin ratio is related to cognitive decline via reflection of homeostasis: a nested case-control study2016

    • Author(s)
      Koyama T, Kuriyama N, Ozaki E, Matsui D, Watanabe I, Miyatani F, Kondo M, Tamura A, Kasai T, Ohshima Y, Yoshida T, Tokuda T, Mizuta I, Mizuno S, Yamada K, Takeda K, Matsumoto S, Nakagawa M, Mizuno T, Watanabe Y
    • Journal Title

      BMC Neurol

      Volume: 16 Pages: 253-253

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease2016

    • Author(s)
      Majbour NK, Vaikath NN, van Dijk KD, Ardah MT, Varghese S, Vesterager LB, Montezinho LP, Poole S, Safieh-Garabedian B, Tokuda T, Teunissen CE, Berendse HW, van de Berg WD, El-Agnaf OM
    • Journal Title

      Mol Neurodegener

      Volume: 11 Issue: 1 Pages: 7-7

    • DOI

      10.1186/s13024-016-0072-9

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Serum Levels of Coenzyme Q10 in Patients with Multiple System Atrophy.2016

    • Author(s)
      Kasai T, Tokuda T, Ohmichi T, Ishii R, Tatebe H, Nakagawa M, Mizuno T
    • Journal Title

      Plos One

      Volume: 11 Issue: 1 Pages: e0147574-e0147574

    • DOI

      10.1371/journal.pone.0147574

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Diagnostic Accuracy of 123I-Meta-Iodobenzylguanidine Myocardial Scintigraphy in Dementia with Lewy Bodies: A Multicenter Study.2015

    • Author(s)
      Yoshita M, Arai H, Arai H, Arai T, Asada T, Fujishiro H, Hanyu H, Iizuka O, Iseki E, Kashihara K, Kosaka K, Maruno H, Mizukami K, Mizuno Y, Mori E, Nakajima K, Nakamura H, Nakano S, Nakashima K, Nishio Y, et al.
    • Journal Title

      PLoS One

      Volume: 10 Issue: 3 Pages: 0-0

    • DOI

      10.1371/journal.pone.0120540

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Decrease in plasma levels of α-synuclein is evident in patients with parkinson’s disease after elimination of heterophilic antibody interference2015

    • Author(s)
      Ishii R, Tokuda T, Tatebe H, Ohmichi T, Kasai T, Nakagawa M, Mizuno T, El-Agnaf OMA
    • Journal Title

      PLoS ONE

      Volume: 10 Issue: 4 Pages: e0123162-e0123162

    • DOI

      10.1371/journal.pone.0123162

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Ventricular Temperatures in Idiopathic Normal Pressure Hydrocephalus (iNPH) Measured with DWI-based MR Thermometry2015

    • Author(s)
      Kuriyama N, Yamada K, Sakai K, Tokuda T, Akazawa K, Tomii Y, Tamura A, Kondo M, Watanabe I, Ozaki E, Matsui D, Nakagawa M, Mizuno T, Watanabe Y
    • Journal Title

      Magnetic Resonance in Medical Sciences

      Volume: 14 Issue: 4 Pages: 305-312

    • DOI

      10.2463/mrms.2014-0076

    • NAID

      130005109004

    • ISSN
      1347-3182, 1880-2206
    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The domestic cat as a natural animal model of Alzheimer’s disease2015

    • Author(s)
      Chambers JK, Tokuda T, Uchida K, Ishii R, Tatebe H, Takahashi E, Tomiyama T, Une Y, Nakayama H
    • Journal Title

      Acta Neuropathol Commun

      Volume: 3 Issue: 1 Pages: 78-78

    • DOI

      10.1186/s40478-015-0258-3

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Knockdown of the drosophila FIG4 induces deficient locomotive behavior, shortening of motor neuron, axonal targeting aberration, reduction of life span and defects in eye development2015

    • Author(s)
      Kyotani A, Azuma Y, Yamamoto I, Yoshida H, Mizuta I, Mizuno T, Nakagawa M, Tokuda T, Yamaguchi M
    • Journal Title

      Exp Neurol

      Volume: 277 Pages: 86-95

    • DOI

      10.1016/j.expneurol.2015.12.011

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Serum levels of coenzyme Q10 in patients with multiple system atrophy2017

    • Author(s)
      Kasai T, Tokuda T, Ohmichi T, Ishii R, Tatebe H, Nakagawa M, Mizuno T
    • Organizer
      The 13th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Progression of milestones by clinical types in progressive supranuclear palsy: a longitudinal observational study of a cohort of patients with PSP/CBD (the JALPAC project)2017

    • Author(s)
      Aiba I, Ikeuchi T, Takigawa H, Shimohata T, Tokuda T, Morita M, Onodera O, Murayama S, Hasegawa K, Nakashima K
    • Organizer
      The 21st International Congress of Parkinson's Disease and Movement Disorders (MDS)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] α-シヌクレインオリゴマーからα-シヌクレイノパチーを考える2017

    • Author(s)
      徳田隆彦
    • Organizer
      日本神経化学会大会(第60回)
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: Do PGK-1 mutations contribute to vulnerability to parkinsonism?2017

    • Author(s)
      Kasai T, Sakaue S, Mizuta I, Suematsu M, Osone S, Azuma Y, Imamura T, Tokuda T, Kanno H, El-Agnaf O, Morimoto M, Nakagawa M, Hosoi H, Mizuno T
    • Organizer
      The 23rd World Congress of Neurology 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 診断 AD BLD FTDの学際的アプローチ2017

    • Author(s)
      徳田隆彦
    • Organizer
      日本早期認知症学会学術大会 (第18回)
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] バイオマーカーからみたレビー小体病の多様性2017

    • Author(s)
      徳田隆彦
    • Organizer
      日本認知症学会学術集会(第36回)
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 前頭側頭型認知症のバイオマーカー2017

    • Author(s)
      徳田隆彦
    • Organizer
      日本認知症学会学術集会(第36回)
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] シンポジウム15:パーキンソン病におけるα-シヌクレインの役割: 遺伝子からその機能まで; 3. バイオマーカーとしてのα-シヌクレイン.2016

    • Author(s)
      徳田隆彦
    • Organizer
      日本認知症学会学術集会
    • Place of Presentation
      東京
    • Year and Date
      2016-12-02
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] シンポジウム9:Progressive Supranuclear Palsy: 基礎と臨床; 3. バイオマーカー; CBSとの鑑別を含めて.2016

    • Author(s)
      徳田隆彦
    • Organizer
      日本認知症学会学術集会
    • Place of Presentation
      東京
    • Year and Date
      2016-12-01
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] A longitudinal observational study of a cohort of patients with PSP/CBD: the JALPAC project2016

    • Author(s)
      Tokuda T, Ikeuchi T, Takigawa H, Aiba I, Shimohata T, Morita M, Onodera O, Murayama S, Nakashima K
    • Organizer
      The 20th International Congress of Parkinson's Disease and Movement Disorders (MDS)
    • Place of Presentation
      Berlin, Germany
    • Year and Date
      2016-06-20
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] レクチャーマラソン(教育講演)11:神経変性疾患とバイオマーカー; 国際的な現状と今後の展望.2016

    • Author(s)
      徳田隆彦
    • Organizer
      日本神経学会学術大会
    • Place of Presentation
      神戸
    • Year and Date
      2016-05-20
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 臨床症候学の立場から: 血液・脳脊髄液バイオマーカーの研究成果を含めて2016

    • Author(s)
      徳田隆彦
    • Organizer
      日本神経学会学術大会
    • Place of Presentation
      神戸
    • Year and Date
      2016-05-19
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Biomarker changes of plasma and CSF after the treatment of IVIg in patients with AD2015

    • Author(s)
      Kasai T, Kondo M, Ishii R, Mizuno T, Tokuda T
    • Organizer
      The 8th Clinical Trials on Alzheimer's Disease (CTAD) 2015
    • Place of Presentation
      Barcelona, Spain
    • Year and Date
      2015-11-06
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] アルツハイマー型認知症のバイオマーカーの現状と課題2015

    • Author(s)
      徳田隆彦
    • Organizer
      第21回北海道老年期認知症研究会
    • Place of Presentation
      札幌
    • Year and Date
      2015-10-24
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] Distribution of amyloid burden is different between idiopathic normal pressure hydrocephalus and Alzheimer’s disease2015

    • Author(s)
      Tokuda T, Kondo M, Kuriyama N, Matsushima S, Nakanishi H, Ishikawa M
    • Organizer
      The 7th Meeting of the International Society for Hydrocephalus & Cerebrospinal Fluid Disorders (Hydrocephalus 2015)
    • Place of Presentation
      Banff, Canada
    • Year and Date
      2015-09-21
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] パーキンソン病とその関連疾患の生化学的バイオマーカー: up to date.2015

    • Author(s)
      徳田隆彦
    • Organizer
      第56回日本神経学会学術大会
    • Place of Presentation
      新潟
    • Year and Date
      2015-05-20
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] 青年期以降のダウン症候群患者に出現する認知機能障害2015

    • Author(s)
      徳田隆彦
    • Organizer
      第118回日本小児科学会学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2015-04-17
    • Related Report
      2015 Research-status Report
    • Invited
  • [Book] 今日の治療指針 2017年版 私はこう治療している2017

    • Author(s)
      徳田隆彦
    • Publisher
      医学書院
    • Related Report
      2017 Annual Research Report
  • [Book] 実験医学2017年7月増刊号「認知症研究の新時代」2017

    • Author(s)
      徳田隆彦
    • Publisher
      羊土社
    • Related Report
      2017 Annual Research Report
  • [Book] アルツハイマー病 認知症疾患 臨床医のための実践ガイド2017

    • Author(s)
      大道卓摩, 徳田隆彦
    • Publisher
      朝倉書店
    • Related Report
      2017 Annual Research Report
  • [Book] 今日の治療指針 2017年版 私はこう治療している2017

    • Author(s)
      徳田隆彦; 医学書院編
    • Publisher
      医学書院
    • Related Report
      2016 Research-status Report
  • [Book] 前頭側頭葉変性症の療養の手引き2017

    • Author(s)
      徳田隆彦; 祖父江元・池田学・中島健二監修
    • Publisher
      神経変性疾患領域における基盤的調査研究班
    • Related Report
      2016 Research-status Report

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Published: 2015-04-16   Modified: 2022-06-16  

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