ＡＰＰとＡｌｃａｄｅｉｎによる膜小胞輸送制御機構と神経変性疾患

• Project Area: Intracellular logistics: interdisciplinary approaches to pathophysiology of membrane traffic
• Project/Area Number: 23113701
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: 鈴木 利治 北海道大学, 薬学研究科(研究院), 教授 (80179233)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2012: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2011: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 輸送モーター / 膜小胞輸送 / カーゴ / パターン認識 / 微小管

Outline of Annual Research Achievements

神経系に強く発現するAlcadeinは、Alcα、Alcβ、AlcγからなるI型膜タンパク質ファミリーである。Alcの細胞質ドメインは、キネシン-1モーターの軽鎖(KLC)に結合する短いペプチドWDモチーフを含み、軸索内の順行輸送を受ける。Alcは単なるカーゴ受容体ではなく、キネシン-1モーターを活性化できる分子であることを見いだして来た(EMBO J. [2007] 26, 1475-1486)。近年、キネシンー1などのモーター分子は、Alcの様なカーゴ受容体もしくはモーターとカーゴを繋ぐアダプター分子により活性が制御される報告が出始めたが、その詳細な分子機構は判っていない。今年度、Alcadeinがキネシンー1モーターを活性化する仕組みの解明を目指した。その結果、Alcadein細胞質ドメインのWDモチーフがキネシン-1モーターを活性化する必要十分条件を満たす事を報告した(Traffic　[2012] 13 834-848）。また、キネシンー1を活性化するアダプター分子として、JIP1が知られている 。JIPキネシンー1とJIP1の相互作用の詳細を解析した。また、異分野共同研究として、輸送小胞の自動追跡・解析法の開発を九大の内田教授と取り組んだ。輸送小胞のトレースは細胞生物学者にとって大変な作業であるが、パターン認識が専門の内田教授と共同で輝点追跡システムを作製している。そのうちの一つに自動カイモグラフ作製アプリケーションがある。これは、これまで手作業で行っていた輝点トレースをシングルムービーから直接に短時間で行えるソフトであり、論文公表後にオープンアクセスアプリとして公開を想定している。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A small peptide sequence is sufficient for initiating Kinesin-1 activation through part of TPR region of KLC1 (2012)
  • Author(s): Kawano T, Araseki M, Araki Y, Kinjo M, Yamamoto T, Suzuki T
  • Journal Title: Traffic Volume: (掲載確定) Issue: 6 Pages: 834-848
  • DOI: 10.1111/j.1600-0854.2012.01350.x
  • Peer Reviewed
• [Journal Article] Potential utility of soluble p3-alcadeinα plasma levels as a biomarker for sporadic Alzheimer's disease (2012)
  • Author(s): Kamogawa K, Kohara K, Tabara Y, Takita R, Miki T, Konno T, Hata S, Suzuki T
  • Journal Title: J Alzheimers Dis Volume: 31 Issue: 2 Pages: 421-8
  • DOI: 10.3233/jad-2012-120601
  • Peer Reviewed
• [Journal Article] Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects. (2012)
  • Author(s): Hata S
  • Journal Title: Mol Neurodegener. Volume: 16 Issue: 1 Pages: 16-16
  • DOI: 10.1186/1750-1326-7-16
  • Peer Reviewed
• [Journal Article] Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue (2012)
  • Author(s): Matsushima T
  • Journal Title: J Biol Chem Volume: 287 Issue: 23 Pages: 19715-19724
  • DOI: 10.1074/jbc.m111.334847
  • Peer Reviewed
• [Journal Article] Age-related modulation of γ-secretase activity in non-human primate brains (2012)
  • Author(s): Nishimura M
  • Journal Title: J Neurochem Volume: 123 Issue: 1 Pages: 21-28
  • DOI: 10.1111/j.1471-4159.2012.07884.x
  • Peer Reviewed
• [Journal Article] Costitutive cleavage of the single-pass transmembrane protein Alcadeinα prevents aberrant peripheral retention of kinesin-1. (2012)
  • Author(s): Maruta C.
  • Journal Title: Public Library of Science One Volume: 7
  • Peer Reviewed
• [Journal Article] Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Abeta generation in Alzheimer's disease (2012)
  • Author(s): Saito Y
  • Journal Title: Mol Neurodegener Volume: 7 Issue: 1 Pages: 50-50
  • DOI: 10.1186/1750-1326-7-50
  • Peer Reviewed
• [Journal Article] Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP(4) receptor (2012)
  • Author(s): Hoshino T, Namba T, Takehara M, Murao N, Matsushima T, Sugimoto Y, Narumiya S, Suzuki T, Mizushima T
  • Journal Title: J.Neurochem. Volume: 120 Issue: 5 Pages: 795-805
  • DOI: 10.1111/j.1471-4159.2011.07567.x
  • Peer Reviewed
• [Journal Article] FE65 as a link between VLDLR and APP to regulate their trafficking and processing. (2012)
  • Author(s): Dumanis, S., Chamberlain, K. A., Sohn, Y. J., Lee, Y. J., Guenette, S. Y., Suzuki, T., Mathews, P. W., Pak, D. T. S., Rebexk, G. W., Suh, Y-h., Park, H-S., Hoe, H-S.
  • Journal Title: Mol. Neurodegen Volume: 7 Issue: 1 Pages: 9-9
  • DOI: 10.1186/1750-1326-7-9
  • Peer Reviewed
• [Journal Article] Suppression of Alzheimer's disease-related phenotypes by expression of heat shock protein 70 in mice. (2011)
  • Author(s): Hoshino T, Murao N, Namba T, Takehara M, Adachi H, Katsuno M, Sobue G, Matsushima T, Suzuki T, Mizushima T.
  • Journal Title: J Neurosci. Volume: 31 Issue: 14 Pages: 5225-5234
  • DOI: 10.1523/jneurosci.5478-10.2011
  • Peer Reviewed
• [Journal Article] Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease : evidence for γ-secretase dysfunction (2011)
  • Author(s): Hata S
  • Journal Title: Ann.Neurol. Volume: 69 Issue: 6 Pages: 1026-1031
  • DOI: 10.1002/ana.22343
  • Peer Reviewed
• [Journal Article] Cystein-rich intestinal protein 2 (CRIP2) acts as a repressor of NFkB-mediated pro-angiogenic cytokins transcription to suppress tumorigenesis and angiogenesis (2011)
  • Author(s): Cheung, K.L., 7名略, Suzuki, T., 4名略
  • Journal Title: Proceeding of National Academy of Science USA Volume: 108 Issue: 20 Pages: 8390-8395
  • DOI: 10.1073/pnas.1101747108
  • Peer Reviewed
• [Journal Article] Intracellular trafficking of the amyloid β-protein precursor (APP) regulated by novel function of X11-like (2011)
  • Author(s): Saito Y
  • Journal Title: PLoS One Volume: 6 Issue: 7 Pages: e22108-e22108
  • DOI: 10.1371/journal.pone.0022108
  • Peer Reviewed
• [Journal Article] Effects of heparin and enoxaparin on APP processing and Ab production in primary cortical neurons from Tg2576 mouse (2011)
  • Author(s): Cui, H., Hung, A. C., Klaver, D. W., Suzuki, T., Freeman, C., Narkowicz, C., Jacobson, G. and Small, D. H.
  • Journal Title: PLoS One Volume: 6 Issue: 7 Pages: e23007-e23007
  • DOI: 10.1371/journal.pone.0023007
  • Peer Reviewed
• [Journal Article] Coordinated increase of y-secretase products in the plasma of some female Japanese sporadic Alzheimer's disease patients: quantitative analysis of p3-Alca with a new ELISA system (2011)
  • Author(s): Konno, et al.
  • Journal Title: Molecular Neurodegeneration Volume: 6 Issue: 1 Pages: 76-76
  • DOI: 10.1186/1750-1326-6-76
  • Peer Reviewed
• [Presentation] gamma-secretaseによるAlcadeinの膜内切断と孤発性アルツハイマー病ぼ発症機構の解明 (2012)
  • Author(s): Yi Piao
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] ヒト型ApolipoproteinEノックインマウスにおけるAlcadein代謝の解析 (2012)
  • Author(s): 木村彩乃
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] APP細胞質ドメインThr668のリン酸化によるAPP CTF の膜ラフト局在制御機構 (2012)
  • Author(s): 齋藤優実
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] X11Lの構造変換によるAPPの輸送・代謝制御機構 (2012)
  • Author(s): 本館利佳
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] Alcadein代謝産物による機能発現 (2012)
  • Author(s): 江波綾佳
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] てんかん発作、アルツハイマー病発症におけるX11/X11Lの関与 (2012)
  • Author(s): 木村尚紀
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] Alcadeinのリン酸化 (2012)
  • Author(s): 蘇武佑里子
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] Alcadeinによるkinesin-1活性と膜小胞輸送制御機構 (2012)
  • Author(s): 白木柚葉
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 （福岡）
  • Year and Date: 2012-12-14
• [Presentation] Function and metabolism of Alcadein in the relation with Alzheimer's disease. (2012)
  • Author(s): Suzuki, T.
  • Organizer: Asian Aging Core for Longevity Research (AACL) 2012 Seoul Conference. "On Aging, Metabolism and Neurobiology"
  • Place of Presentation: University of Seoul (Korea)
  • Year and Date: 2012-11-23
  • Invited
• [Presentation] Transplocation of APP cytoplasmic fragment regulated by phosphorylation of Thr668 residue. (2012)
  • Author(s): Suzuki, T.
  • Organizer: Neuroscience 2012
  • Place of Presentation: Morial Convention Center New Orleans (USA)
  • Year and Date: 2012-10-10
• [Presentation] Mechanism of intramembrane cleavage of neural Alcadein proteins by γ-secretase. (2012)
  • Author(s): Piao Y.
  • Organizer: Neuroscience 2012
  • Place of Presentation: Morial Convention Center New Orleans (USA)
  • Year and Date: 2012-10-10
• [Presentation] Role of Apolipoprotein E on Alcadeins metabolism. (2012)
  • Author(s): Kimura A.
  • Organizer: Neuroscience 2012
  • Place of Presentation: Morial Convention Center New Orleans (USA)
  • Year and Date: 2012-10-10
• [Presentation] γセクレターゼによるAlcadeinの膜内切断は、膜脂質組成によって変化する -孤発性アルツハイマー病の発症機構と予防への分子機構- (2012)
  • Author(s): 朴懿
  • Organizer: 第2回 日本認知症予防学会 学術集会
  • Place of Presentation: 北九州国際会議場（福岡）
  • Year and Date: 2012-09-07
• [Presentation] 血中p3-Alcαの定量によるアルツハイマー病のγセクレターゼ切断変化解析 (2012)
  • Author(s): 大森智織
  • Organizer: 第17回 日本病態プロテアーゼ学会学術集会
  • Place of Presentation: オークラアクトシティホテル浜松 （静岡）
  • Year and Date: 2012-08-10
• [Presentation] p3-Alcのアルツハイマー病早期診断マーカーとしての有用性の検証 (2012)
  • Author(s): 金子窓香
  • Organizer: 第17回 日本病態プロテアーゼ学会学術集会
  • Place of Presentation: オークラアクトシティホテル浜松 （静岡）
  • Year and Date: 2012-08-10
• [Presentation] Increased p3-Alc peptides in the CSF and plasma of sporadic Alzheimer's disease patients. (2012)
  • Author(s): Hata S.
  • Organizer: Alzheimer's Association International Conference 2012
  • Place of Presentation: Vancouver Convention Center (Canada)
  • Year and Date: 2012-07-14
• [Presentation] Membrane microdomain localization of APP C-terminal fragments regulated by the phosphorylation at cytoplasmic Thr668 residue. (2012)
  • Author(s): Matsushima T.
  • Organizer: Alzheimer's Association International Conference 2012
  • Place of Presentation: Vancouver Convention Center (Canada)
  • Year and Date: 2012-07-14
• [Presentation] Involvement of X11/X11L in Alzheimer's-related beta-amyloid generation and epileptogenesis. (2012)
  • Author(s): Kanada Y.
  • Organizer: Alzheimer's Association International Conference 2012
  • Place of Presentation: Vancouver Convention Center (Canada)
  • Year and Date: 2012-07-14
• [Presentation] Molecular pathogenesis of sporadic Alzheimer's disease. (2012)
  • Author(s): Suzuki T.
  • Organizer: Korea-Japan Joint Symposium for the 30th Anniversary of Hallym University: Aging and Neurodegenerative disease.
  • Place of Presentation: Hallym University Sacred Heart Hospital (Korea)
  • Invited
• [Presentation] Function and metabolism of Alcadein in the relation with Alzheimer's disease. (2012)
  • Author(s): Suzuki, T
  • Organizer: The 15th MNRC International Symposium "New avenue for developing disease-modifying therapies of Alzheimer's disease
  • Place of Presentation: Shiga University of Medical Science (Shiga)
  • Invited
• [Presentation] Increased levels of soluble p3-Alcadeinα in plasma of patients with Alzheimer's disease (2011)
  • Author(s): Kamogawa, K., Kohara, K., 10名略., Suzuki, T.
  • Organizer: American Academy of Neurology 63rd AAN Annualmeeting
  • Place of Presentation: Hawai'I Convention Center (USA)
• [Presentation] Malfunction of HCN chanels in X11/X11L doubly deficient mice (2011)
  • Author(s): Saito, Y., Inoue, T., Suzuki, T.
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] Molecular mechanism of JIP1b-mediated APP association to kinesin-1 in APP transport and metabolic regulation (2011)
  • Author(s): Chiba, K., 4名略., Suzuki, T.
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] Enhanced amyloidogenic processing of APP in Alcadein-deficient mice (2011)
  • Author(s): Gotoh, N., 4名略., Suzuki, T.
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] Quantification of plasma p3-Alcα level with sELISA systems (2011)
  • Author(s): Fang, J., 6名略., Suzuki, T.
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] Alternative gamma-secretase processing in sporadic Alzheimer's disease suggested by p3-Alc peptide, metabolic product of Alcadein (2011)
  • Author(s): Hata, S., 4名略., Suzuki, T.
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] APP metabolism in brain of Alcadein alpha CTF transgenic mice (2011)
  • Author(s): Kimura, A., 3名略., Suzuki, T
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] Alcadeine epsilon-cleavage followed by gamma-cleavage (2011)
  • Author(s): Piao, Y., Hata, S., Suzuki, T.
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] Intracellular trafficking and metabolism of APP regulated by novel function of X11L (2011)
  • Author(s): Suzuki, T.
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Porte de Versailles (France)
• [Presentation] Altered processing of gamma-secretase substrates and clearance of peptide products (Abeta and p3-Alc) as a pathogenesis of sporadic Alzheimer's disease. in "Invited Symposium 2-The pathological mechanisms underlying Alzheimer's disease" (2011)
  • Author(s): Suzuki, T., Hata, S.
  • Organizer: Gerontology & Geriatrics 2011
  • Place of Presentation: Melbourne Convention and Exhibition Center (Australia)(招待講演)
• [Presentation] Intracellular Trafficking of the Amyloid β-Protein Precursor Regulated by PDZ domains of X11-Like (2011)
  • Author(s): Saito, Y., Suzuki, T.
  • Organizer: 51th The American society for cell biology annual meeting
  • Place of Presentation: Colorado Convention Center (USA)
• [Presentation] Molecular mechanism of kinesin-1 activation by Alcadeinα (2011)
  • Author(s): Araseki, M., 4名略., Suzuki, T.
  • Organizer: 51th The American society for cell biology annual meeting
  • Place of Presentation: Colorado Convention Center (USA)
• [Presentation] アルツハイマー病におけるγセクレターゼの機能変化を反映するAlcadein膜内の切断機構の解析 (2011)
  • Author(s): 朴懿、羽田沙緒里、鈴木利治
  • Organizer: 第16回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪)
• [Presentation] アルツハイマー病の新たな生化学的マーカー、p3-Alcの早期診断マーカーとしての可能性の検証 (2011)
  • Author(s): 羽田沙緒里、浦上克哉、谷口美也子、池内健、鈴木利治
  • Organizer: 第1回日本認知症予防学会学術集会
  • Place of Presentation: 米子コンベンションセンター(鳥取)
• [Presentation] Alcadeinのγセクレターゼによる膜内切断機構の解明 (2011)
  • Author(s): Piao Yi(朴懿)、羽田沙緒里、鈴木利治
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館(京都)
• [Presentation] リン酸化によるAPPの膜マイクロドメインへの移行制御機構の解析 (2011)
  • Author(s): 松島隆英、鈴木利治
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館(京都)
• [Presentation] アポリポタンパク質EによるAlcadein代謝への影響 (2011)
  • Author(s): 木村彩乃、羽田沙緒里、鈴木利治
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館(京都)
• [Presentation] JIP-KLC1結合によるAPP輸送の効率化 (2011)
  • Author(s): 千葉杏子、野澤啓輔、荒関雅彦、齋藤有紀、金城政孝、鈴木利治
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館(京都)
• [Book] Mechanism of Alzheimer amyloid β-protein precursor localization to membrane lipid rafts in "Understanding Alzheimer's Disease" (2013)
  • Author(s): Saito Y.
  • Total Pages: 15
  • Publisher: InTech(ISBN 978-953-51-1009-5)
• [Book] Alzheimer's disease as a membrane-associated enzymopathy of β-amyloid precursor protein (APP) secretases, in "Lipids and Cellular Membranes in Amyloid Disease"(Eds by Jelinek, R.) (2011)
  • Author(s): Hata, S., Saito, Y., Suzuki, T.
  • Publisher: Wiley-VCH (ISBN : 978-3-527-32860-4)
• [Remarks]
  • URL: http://www.pharm.hokudai.ac.jp/shinkei/index.html