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Elucidation of characters and neurotoxic mechanisms of alpha-synuclein oligomers and its application to molecular targeted therapy

Research Project

Project/Area Number 23591252
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), 准教授 (80242692)

Co-Investigator(Kenkyū-buntansha) MIZUNO Toshiki  京都府立医科大学, 医学(系)研究科(研究院), 教授 (30264782)
NAKAGAWA Masanori  京都府立医科大学, 医学(系)研究科(研究院), 教授 (50198040)
WATANABE Yoshihisa  京都府立医科大学, 医学(系)研究科(研究院), 講師 (50363990)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywordsα-シヌクレイン / オリゴマー / 神経細胞毒性 / パーキンソン病 / 分子標的治療 / アルファ・シヌクレイン / 神経細胞変性 / 原子間力顕微鏡 / A30P変異α-シヌクレイン
Research Abstract

We established the preparing method of alpha-synuclein (A-syn) oligomers and protofibrils by incubating high-concentration solution, 3 mg/mL, of recombinant A-syn with stirring for 7 days at 37 C. Although recombinant A-syn molecules and natural A-syn molecules derived from human CSF were eluted from gel-filtration chromatography at around fractions of 60-70 kDa, those molecules were not dissociated with 8M urea, and accordingly have been demonstrated to exist as monomers in aqueous solution. In cultured cells, intracellular aggregates were formed by adding mixture of recombinant A-syn oligomers and protofibrils into the culture medium, and their degradation was dependent on the autophagy pathway.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (50 results)

All 2013 2012 2011 Other

All Journal Article (17 results) (of which Peer Reviewed: 13 results) Presentation (27 results) (of which Invited: 10 results) Book (6 results)

  • [Journal Article] Biomarkers for the diagnosis and management of Parkinson's disease2013

    • Author(s)
      Waragai M、Sekiyama K、Fujita M、Tokuda T、Hashimoto M
    • Journal Title

      Expert Opin Med Diagn

      Volume: Vol.7 Pages: 71-83

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Correlation of Aβoligomer levels in matched cerebrospinal fluid and serum samples2013

    • Author(s)
      Kasai T、Tokuda T、Taylor M、Kondo M、Mann DM、Nakagawa M、Allsop D
    • Journal Title

      Neurosci Lett

      Volume: Vol.551 Pages: 17-22

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Corticobasal Syndrome : CBSのバイオマーカーと鑑別診断2013

    • Author(s)
      徳田隆彦
    • Journal Title

      BRAIN and NERVE

      Volume: Vol.65 Pages: 55-64

    • Related Report
      2013 Final Research Report
  • [Journal Article] Distribution of amyloid burden is different between idiopathic normal pressure hydrocephalus and Alzheimer’s disease2013

    • Author(s)
      Kondo M, Tokuda T, Itsukage M, Kuriyama N, Matsushima S, Yamada K, Nakanishi H, Ishikawa M, Nakagawa M
    • Journal Title

      Neuroradiol J

      Volume: 3 Pages: 129-134

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biomarkers for the diagnosis and management of Parkinson's disease2013

    • Author(s)
      Waragai M, Sekiyama K, Fujita M, Tokuda T, Hashimoto M
    • Journal Title

      Expert Opin Med Diagn

      Volume: 7 Issue: 1 Pages: 71-83

    • DOI

      10.1517/17530059.2013.733694

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Correlation of Aβ oligomer levels in matched cerebrospinal fluid and serum samples2013

    • Author(s)
      Kasai T, Tokuda T, Taylor M, Kondo M, Mann DM, Nakagawa M, Allsop D
    • Journal Title

      Neurosci Lett

      Volume: 551 Pages: 17-22

    • DOI

      10.1016/j.neulet.2013.06.029

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Corticobasal Syndrome: CBSのバイオマーカーと鑑別診断2013

    • Author(s)
      徳田隆彦
    • Journal Title

      BRAIN and NERVE

      Volume: 65 Pages: 55-64

    • Related Report
      2013 Annual Research Report
  • [Journal Article] Cerebrospinal fluid proteomic patterns discriminate Parkinson's disease and multiple system atrophy2012

    • Author(s)
      Ishigami N、Tokuda T、Ikegawa M、Komori M、Kasai T、Kondo T、Matsuyama Y、Nirasawa T、Thiele H、Tashiro K、Nakagawa M
    • Journal Title

      Movement Disorders

      Volume: Vol.27 Pages: 851-857

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Utilization of a multiple antigenic peptide as a calibration standard in the BAN50 single antibody sandwich ELISA for Aβoligomers2012

    • Author(s)
      Kasai T、Tokuda T、Taylor M、Nakagawa M、Allsop D
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: Vol.422 Pages: 375-380

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] p62/SQSTM1-dependent autophagy of Lewy body-likeα-synuclein inclusions2012

    • Author(s)
      Watanabe Y、Tatebe H、Taguchi K、Endo Y、Tokuda T、Mizuno T、Nakagawa M、Tanaka M
    • Journal Title

      PLoS One

      Volume: Vol.7

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cerebrospinal fluid proteomic patterns discriminate Parkinson's disease and multiple system atrophy2012

    • Author(s)
      Ishigami N, Tokuda T, Ikegawa M, Tashiro K, Nakagawa M, 他
    • Journal Title

      Mov Disord.Peer-Reviewed papers

      Volume: 27(7) Issue: 7 Pages: 851-857

    • DOI

      10.1002/mds.24994

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Utilization of a multiple antigenic peptide as a calibration standard in the BAN50 single antibody sandwich ELISA for Aβ oligomers2012

    • Author(s)
      Kasai T, Tokuda T, Taylor M, Nakagawa M, Allsop D
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 422 Issue: 3 Pages: 375-380

    • DOI

      10.1016/j.bbrc.2012.04.146

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Knockdown of the Drosophila Fused in Sarcoma (FUS) homologue causes deficient locomotive behavior and shortening of motoneuron terminal branches.2012

    • Author(s)
      Sasayama, H., Shimamura, M., Tokuda, T., Azuma, Y., Yoshida, T., Mizuno, T., Nakagawa, M., Fujikake, N., Nagai, Y. and Yamaguchi, M
    • Journal Title

      PLoS ONE

      Volume: 7(6), Issue: 6 Pages: e39483-e39483

    • DOI

      10.1371/journal.pone.0039483

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] p62/SQSTM1-dependent autophagy of Lewy body-like α-synuclein inclusions2012

    • Author(s)
      Watanabe Y, Tatebe H, Taguchi K, Endo Y, Tokuda T, Mizuno T, Nakagawa M, Tanaka M
    • Journal Title

      PLoS One

      Volume: 7 Issue: 12 Pages: e52868-e52868

    • DOI

      10.1371/journal.pone.0052868

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Simultaneous impairment of intracranial and peripheral artery vasoreactivity in CADASIL patients.2012

    • Author(s)
      Fujiwara Y, Mizuno T, Okuyama C, Nagakane Y, Watanabe-Hosomi A, Kondo M, Kuriyama N, Tokuda T, Matsushima S, Nishimura T, Nakagawa M
    • Journal Title

      Cerebrovascular Diseases

      Volume: 33 Issue: 2 Pages: 128-134

    • DOI

      10.1159/000334185

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Correspondence : Detection of elevated levels ofα-synuclein oligomers in CSF from patients with parkinson disease2011

    • Author(s)
      El-Agnaf OMA、Tokuda T
    • Journal Title

      Neurology

      Volume: Vol.77 Pages: 510-511

    • Related Report
      2013 Final Research Report
  • [Journal Article] Correspondence: Detection of elevated levels of α-synuclein oligomers in CSF from patients with parkinson disease.2011

    • Author(s)
      El-Agnaf OMA, Tokuda T
    • Journal Title

      Neurology

      Volume: 77 Pages: 510-511

    • Related Report
      2011 Research-status Report
  • [Presentation] α-Synuclein is present as a monomer in the biological fluids2013

    • Author(s)
      Tatebe H、Tokuda T、Ishi R、Watanabe Y、Kasai T、Taguchi K、Mizuta I、Tanaka M、Mizuno T
    • Organizer
      The 20th World Congress on Parkinson's Disease and Related Disorders
    • Place of Presentation
      Geneva、Switzerland
    • Year and Date
      2013-12-11
    • Related Report
      2013 Final Research Report
  • [Presentation] Interference from heterophilic antibodies in A-Syn ELISA2013

    • Author(s)
      Ishii R、Tokuda T、Tatebe H、Kasai T、Mizuno T、Nakagawa M
    • Organizer
      The 20th World Congress on Parkinson's Disease and Related Disorders
    • Place of Presentation
      Geneva、Switzerland
    • Year and Date
      2013-12-11
    • Related Report
      2013 Final Research Report
  • [Presentation] 髄液,血清のα-synucleinなどの定量でパーキンソン病の発症は予測できるか?2013

    • Author(s)
      徳田隆彦
    • Organizer
      パーキンソン病・運動障害疾患コングレス(MDSJ :第7回)
    • Place of Presentation
      品川プリンスホテル(東京都)
    • Year and Date
      2013-10-12
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] CSBのバイオマーカーと鑑別診断2013

    • Author(s)
      徳田隆彦
    • Organizer
      日本神経学会学術大会(第54回)
    • Place of Presentation
      東京
    • Year and Date
      2013-06-01
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] Clinical application of ELISAs detecting pathogenic protein oligomers to the neurodegenerative disorders2013

    • Author(s)
      Tokuda T
    • Organizer
      3rd International Conference on Neurodegenerative Disorders : Immunotherapy and Biomarkers
    • Place of Presentation
      Uppsala、Sweden
    • Year and Date
      2013-05-23
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] Clinical application of ELISAs detecting pathogenic protein oligomers to the neurodegenerative disorders2013

    • Author(s)
      Tokuda T
    • Organizer
      3rd International Conference on Neurodegenerative Disorders: Immunotherapy and Biomarkers
    • Place of Presentation
      Uppsala, Sweden
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] CBSのバイオマーカーと鑑別診断2013

    • Author(s)
      徳田隆彦
    • Organizer
      日本神経学会学術大会(第54回)
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 髄液, 血清のα-synucleinなどの定量でパーキンソン病の発症は予測できるか?2013

    • Author(s)
      徳田隆彦
    • Organizer
      パーキンソン病・運動障害疾患コングレス(MDSJ: 第7回)
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] α-Synuclein is present as a monomer in the biological fluids2013

    • Author(s)
      Tatebe H, Tokuda T, Ishi R, Watanabe Y, Kasai T, Taguchi K, Mizuta I, Tanaka M, Mizuno T
    • Organizer
      The 20th World Congress on Parkinson’s Disease and Related Disorders
    • Place of Presentation
      Geneva, Switzerland
    • Related Report
      2013 Annual Research Report
  • [Presentation] Interference from heterophilic antibodies in A-Syn ELISA2013

    • Author(s)
      Ishii R, Tokuda T, Tatebe H, Kasai T, Mizuno T, Nakagawa M
    • Organizer
      The 20th World Congress on Parkinson’s Disease and Related Disorders
    • Place of Presentation
      Geneva, Switzerland
    • Related Report
      2013 Annual Research Report
  • [Presentation] パーキンソニズム患者の髄液プロテオーム解析2012

    • Author(s)
      徳田隆彦、石神紀子、中川正法、池川雅哉、近藤誉之、小森美華
    • Organizer
      第6回パーキンソン病・運動障害疾患コングレス(Movement Disorder Society of Japan)
    • Place of Presentation
      京都
    • Year and Date
      2012-10-12
    • Related Report
      2013 Final Research Report
  • [Presentation] パーキンソン病のバイオマーカーの開発を目指して2012

    • Author(s)
      徳田隆彦
    • Organizer
      日本神経学会学術大会(第53回)
    • Place of Presentation
      東京
    • Year and Date
      2012-05-25
    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Invited
  • [Presentation] パーキンソン病とその関連疾患のバイオマーカー2012

    • Author(s)
      徳田隆彦
    • Organizer
      第20回日本神経学会近畿地区生涯教育講演会(招待講演)
    • Place of Presentation
      京都教育文化センター(京都府)
    • Related Report
      2011 Research-status Report
  • [Presentation] 教育講演:パーキンソン病biomarker最新知見2011

    • Author(s)
      徳田隆彦
    • Organizer
      第5回パーキンソン病・運動障害疾患コングレス(MDSJ)
    • Place of Presentation
      品川プリンスホテル(東京都)
    • Year and Date
      2011-10-07
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] パーキンソン病とALSのバイオマーカー:現状と展望: 1)パーキンソン病2011

    • Author(s)
      徳田隆彦
    • Organizer
      神経変性疾患に関する調査研究班平成23年度ワークショップ
    • Place of Presentation
      都市センターホテル(東京都)
    • Year and Date
      2011-07-15
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] ヒト髄液中のAβオリゴマーを定量するELISA系の開発と臨床応用2011

    • Author(s)
      徳田隆彦、笠井高士、石神紀子、近藤正樹、中川正法
    • Organizer
      第52回日本神経学会学術大会
    • Place of Presentation
      名古屋国際会議場(愛知県)
    • Year and Date
      2011-05-20
    • Related Report
      2013 Final Research Report
  • [Presentation] ヒト髄液中のAβオリゴマーを定量するELISA系の開発と臨床応用2011

    • Author(s)
      徳田隆彦,笠井高士,石神紀子,近藤正樹,中川正法
    • Organizer
      第52回日本神経学会学術大会
    • Place of Presentation
      名古屋国際会議場(愛知県)
    • Related Report
      2011 Research-status Report
  • [Presentation] パーキンソン病とALSのバイオマーカー:現状と展望: 1) パーキンソン病2011

    • Author(s)
      徳田隆彦
    • Organizer
      神経変性疾患に関する調査研究班平成23年度ワークショップ(招待講演)
    • Place of Presentation
      都市センターホテル(東京都)
    • Related Report
      2011 Research-status Report
  • [Presentation] Intravenous immunoglobulin improved cognitive functions in patients with Alzheimer’s disease without any changes in PIB retention in the brain.2011

    • Author(s)
      Tokuda T, Kondo M, Kasai T, Oishi Y, Ataka S, Shimada H, Miki T, Mori H, Nakagawa M
    • Organizer
      The 11th Alzheimer's Association International Conference on Alzheimer’s Disease 2011 (AAICAD)
    • Place of Presentation
      Paris Porte de Versailles Convention and Exhibition Center, Paris
    • Related Report
      2011 Research-status Report
  • [Presentation] 教育講演:パーキンソン病biomarker最新知見2011

    • Author(s)
      徳田隆彦
    • Organizer
      第5回パーキンソン病・運動障害疾患コングレス(MDSJ)(招待講演)
    • Place of Presentation
      品川プリンスホテル(東京都)
    • Related Report
      2011 Research-status Report
  • [Presentation] シンポジウム2:認知症のバイオマーカー:その現状と展望2011

    • Author(s)
      徳田隆彦
    • Organizer
      第31回日本精神科診断学会(招待講演)
    • Place of Presentation
      信州大学附属病院大会議室(長野県)
    • Related Report
      2011 Research-status Report
  • [Presentation] Cardiomyopathy in a Japanese family with the Glu61Lys transthyretin variant: a new phenotype.2011

    • Author(s)
      Tokuda T, Noto Y, Shiga K, Tsuchiya A, Yazaki M, Matoba S, Nakagawa M
    • Organizer
      The 8th International Symposium on Familial Amyloidotic Polyneuropathy
    • Place of Presentation
      The Kumamoto City Medical Association hall(熊本県)
    • Related Report
      2011 Research-status Report
  • [Presentation] アルツハイマー型認知症患者5例に対するIVIg療法と治療後経過の検討

    • Author(s)
      徳田隆彦, 近藤正樹, 笠井高士, 田中章浩, 中川正法, 安宅鈴香, 嶋田裕之, 三木隆己, 森啓
    • Organizer
      日本神経学会学術大会(第53回)
    • Place of Presentation
      東京
    • Related Report
      2012 Research-status Report
  • [Presentation] パーキンソニズム患者の髄液プロテオーム解析

    • Author(s)
      徳田隆彦, 石神紀子, 中川正法, 池川雅哉, 近藤誉之, 小森美華
    • Organizer
      第6回パーキンソン病・運動障害疾患コングレス(Movement Disorder Society of Japan)
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report
  • [Presentation] The usefulness of the Convexity APPArent Hyperperfusion (CAPPAH) sign in the perfusion SPECT study for the diagnosis of iNPH

    • Author(s)
      Tokuda T, Koizumi H, Kondo M, Kuriyama N, Okuyama C, Ishii K, Mori E, Nakagawa M
    • Organizer
      The 4th Meeting of the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report
  • [Presentation] アルツハイマー型認知症患者に対するIVIg療法の短期及び長期効果の検討

    • Author(s)
      徳田隆彦, 近藤正樹, 笠井高士, 田中章浩, 中川正法, 安宅鈴香, 嶋田裕之, 三木隆己, 森啓
    • Organizer
      日本認知症学会学術集会(第31回)
    • Place of Presentation
      筑波
    • Related Report
      2012 Research-status Report
  • [Presentation] 神経変性疾患のバイオマーカーの現状と課題

    • Author(s)
      徳田隆彦
    • Organizer
      日本臨床薬理学会学術総会(第33回)
    • Place of Presentation
      宜野湾
    • Related Report
      2012 Research-status Report
    • Invited
  • [Book] アクチュアル脳・神経疾患の臨床2013

    • Author(s)
      笠井高士、徳田隆彦
    • Publisher
      中山書店
    • Related Report
      2013 Final Research Report
  • [Book] アクチュアル脳・神経疾患の臨床2013

    • Author(s)
      徳田隆彦、中川正法
    • Publisher
      中山書店
    • Related Report
      2013 Final Research Report
  • [Book] アクチュアル 脳・神経疾患の臨床2013

    • Author(s)
      笠井高士, 徳田隆彦
    • Publisher
      中山書店
    • Related Report
      2013 Annual Research Report
  • [Book] アクチュアル 脳・神経疾患の臨床2013

    • Author(s)
      徳田隆彦, 中川正法
    • Publisher
      中山書店
    • Related Report
      2013 Annual Research Report
  • [Book] ガイドライン外来診療20122012

    • Author(s)
      徳田隆彦、中川正法
    • Publisher
      日経メディカル開発社
    • Related Report
      2013 Final Research Report
  • [Book] ガイドライン外来診療20122012

    • Author(s)
      徳田隆彦, 中川正法
    • Publisher
      日経メディカル開発社
    • Related Report
      2012 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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