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

• Project/Area Number: 15K09322
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyoto 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: ¥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)
• Keywords: α-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.

Research Products

• [Int'l Joint Research] Hamad Bin Khalifa University(Qatar)
• [Int'l Joint Research] University of Texas Medical School(米国)
• [Int'l Joint Research] Lancaster University(英国)
• [Int'l Joint Research] Hamad Bin Khalifa University(Qatar)
• [Int'l Joint Research] University of Texas Medical School(米国)
• [Int'l Joint Research] Lancaster University(英国)
• [Int'l Joint Research] Neurological Disorders Center/Qatar Biomedical Research Institute/Hamad Bin Khalifa University(Qatar)
• [Int'l Joint Research] Mitchell Center/University of Texas Medical School(米国)
• [Int'l Joint Research]
• [Journal Article] Increased levels of plasma total tau in adult Down syndrome (2018)
  • 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
  • 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 disease (2017)
  • 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
  • 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
  • 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
  • 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
  • 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 syndrome (2017)
  • 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
  • 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 atrophy (2016)
  • 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
  • Peer Reviewed
• [Journal Article] Monoclonal antibody with conformational specificity for a toxic conformer of amyloid β42 and its application toward the Alzheimer's disease diagnosis (2016)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Longitudinal changes in CSF alpha-synuclein species reflect Parkinson’s disease progression (2016)
  • 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
  • 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 study (2016)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease (2016)
  • 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
  • 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
  • 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
  • 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 interference (2015)
  • 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
  • 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 Thermometry (2015)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The domestic cat as a natural animal model of Alzheimer’s disease (2015)
  • 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
  • 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 development (2015)
  • 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
  • Peer Reviewed / Open Access
• [Presentation] Serum levels of coenzyme Q10 in patients with multiple system atrophy (2017)
  • 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)
  • 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)
  • 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)
  • 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
  • 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)
  • 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)
  • 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)
  • 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
  • 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
  • Invited
• [Presentation] A longitudinal observational study of a cohort of patients with PSP/CBD: the JALPAC project (2016)
  • 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
  • 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
  • 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
  • Invited
• [Presentation] Biomarker changes of plasma and CSF after the treatment of IVIg in patients with AD (2015)
  • 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
  • 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
  • Invited
• [Presentation] Distribution of amyloid burden is different between idiopathic normal pressure hydrocephalus and Alzheimer’s disease (2015)
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [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