細胞内異常タンパク質の蓄積機構

• Project Area: Generation of synapse-neurocircuit pathology
• Project/Area Number: 25110738
• 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: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: 長谷川 成人 公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 分野長 (10251232)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Discontinued (Fiscal Year 2014)
• Budget Amount: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2014: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: αシヌクレイン / プリオン / 伝播 / タウ / アミロイド / 神経変性

Outline of Annual Research Achievements

試験管内で線維化したαシヌクレインを野生型マウスの黒質、線条体、嗅内野に接種し、接種後1ヶ月後に脳を固定して、免疫組織染色し、リン酸化αシヌクレイン病変の広がりを調べた。その結果、接種した部位によって全く異なる異常αシヌクレイン病変の出現と広がりを観察した。黒質に接種したマウスでは黒質、扁桃体、線条体の一部の神経細胞に病変が観察されたのに対し、線条体に接種したマウスでは大脳皮質の広い範囲と扁桃体、黒質の神経細胞に病変が観察された。また嗅内野に接種したマウスではその周辺、および扁桃体や海馬に病変がみられた。以上の結果は、異常αシヌクレインが神経回路を介して広がったことを強く示唆する。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] 3R and 4R tau isoforms in paired helical filaments in Alzheimer's disease. (2014)
  • Author(s): Hasegawa, M., S. Watanabe, H. Kondo, H. Akiyama, D. M. Mann, Y. Saito and S. Murayama
  • Journal Title: Acta Neuropathol Volume: 127 Issue: 2 Pages: 303-305
  • DOI: 10.1007/s00401-013-1191-9
  • Peer Reviewed
• [Journal Article] C9ORF72 repeat-associated non-ATG-translated polypeptides are distributed independently of TDP-43 in a Japanese patient with c9ALS. (2014)
  • Author(s): Konno T, Tada M, Shiga A, Tsujino A, Eguchi H, Masuda-Suzukake M, Hasegawa M, Nishizawa M, Onodera O, Kakita K, Takahashi H.
  • Journal Title: Neuropathol Appl Neurobiol Volume: 40 Pages: 783-788
  • Peer Reviewed
• [Journal Article] Differential diagnosis of amyotrophic lateral sclerosis from Guillain-Barré syndrome by quantitative determination of TDP-43 in cerebrospinal fluid. (2014)
  • Author(s): Hosokawa M, Arai T, Yamashita M, Tsuji H, Nonaka T, Masuda-Suzukake M, Tamaoka A, Hasegawa M, Akiyama H.
  • Journal Title: Int. J. Neurosci. Volume: 124 Issue: 5 Pages: 344-349
  • DOI: 10.3109/00207454.2013.848440
  • Peer Reviewed
• [Journal Article] Prion-like spreading of pathological alpha-synuclein in brain. (2013)
  • Author(s): Masuda-Suzukake M, Nonaka T, Hosokawa M., Oikawa T, Arai T, Akiyama H, Mann D, Hasegawa M
  • Journal Title: Brain Volume: 136 Issue: 4 Pages: 1128-38
  • DOI: 10.1093/brain/awt037
  • Peer Reviewed
• [Journal Article] Prion-like Properties of Pathological TDP-43 Aggregates from Diseased Brains. (2013)
  • Author(s): Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, Hasegawa M.
  • Journal Title: Cell Rep. Volume: 4 Issue: 1 Pages: 124-34
  • DOI: 10.1016/j.celrep.2013.06.007
  • Peer Reviewed
• [Journal Article] Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain. (2013)
  • Author(s): Dan A, Takahashi M, Masuda-Suzukake M, Kametani F, Nonaka T, Kondo H, Akiyama H, Arai T, Mann DMA, Saito Y, Hatsuta H, Murayama S, Hasegawa M.
  • Journal Title: Acta Neuropathol. Commun. Volume: 1 Issue: 1 Pages: 54-54
  • DOI: 10.1186/2051-5960-1-54
  • Peer Reviewed
• [Journal Article] Dipeptide repeat proteins are present in the p62 positive inclusions in patients with Frontotemporal Lobar Degeneration and Motor Neuron Disease associated with expansions in C9ORF72. (2013)
  • Author(s): Mann DMA, Rollinson S, Robinson AC, Callister J, Snowden JS, Gendron T, Petrucelli L, Masuda-Suzukake M, Hasegawa M, Davidson YS and Pickering-Brown S.
  • Journal Title: Acta Neuropathol. Commun. Volume: 1 Issue: 1 Pages: 68-68
  • DOI: 10.1186/2051-5960-1-68
  • Peer Reviewed
• [Journal Article] Kinase Inhibitor Screening Identifies Cyclin-Dependent Kinases and Glycogen Synthase Kinase 3 as Potential Modulators of TDP-43 Cytosolic Accumulation during Cell Stress. (2013)
  • Author(s): Moujalled D, James JL, Parker SJ, Lidgerwood GE, Duncan C, Meyerowitz J, Nonaka T, Hasegawa M, Kanninen KM, Grubman A, Liddell JR, Crouch PJ, White AR.
  • Journal Title: PLoS One Volume: 8 Issue: 6 Pages: e67433-e67433
  • DOI: 10.1371/journal.pone.0067433
  • Peer Reviewed
• [Journal Article] Isomerase Pin1 Stimulates Dephosphorylation of Tau Protein at Cyclin-dependent Kinase (Cdk5)-dependent Alzheimer Phosphorylation Sites (2013)
  • Author(s): Taeko Kimura, Koji Tsutsumi, Masato Taoka, Taro Saito, Masami Masuda-Suzukake, Koichi Ishiguro, Florian Plattner, Takafumi Uchida, Toshiaki Isobe, Masato Hasegawa, and Shin-ichi Hisanaga
  • Journal Title: THE JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 288 Issue: 11 Pages: 7968-7977
  • DOI: 10.1074/jbc.m112.433326
  • Peer Reviewed
• [Journal Article] Pathological features of FTLD-FUS in a Japanese population: Analyses of nine cases. (2013)
  • Author(s): Kobayashi Z, Kawakami I, Arai T, Yokota O, Tsuchiya K, Kondo H, Shimomura Y, Haga C, Aoki N, Hasegawa M, Hosokawa M, Oshima K, Niizato K, Ishizu H, Terada S, Onaya M, Ikeda M, Oyanagi K, Nakano I, Murayama S, Akiyama H, Mizusawa H.
  • Journal Title: Neurol. Sci. Volume: 335 Issue: 1-2 Pages: 89-95
  • DOI: 10.1016/j.jns.2013.08.035
  • Peer Reviewed
• [Journal Article] A longitudinal study on alpha-synuclein in blood plasma as a biomarker for Parkinson’s disease. (2013)
  • Author(s): Foulds PG, Diggle P, Mitchell D, Parker A, Hasegawa M, Masuda-Suzukake M, Mann DMA, Allsop D.
  • Journal Title: Sci. Rep. Volume: 3 Issue: 1 Pages: 2540-2540
  • DOI: 10.1038/srep02540
  • Peer Reviewed
• [Presentation] 活性型カゼインキナーゼ１デルタの共発現によるTDP-43の局在変化および細胞内蓄積 (2014)
  • Author(s): 長谷川成人、野中隆
  • Organizer: 第87回 日本生化学会大会
  • Place of Presentation: 国立京都国際会館・グランドプリンスホテル京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] αシヌクレイン (2014)
  • Author(s): 長谷川成人
  • Organizer: 第8回 パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都ホテルオークラ
  • Year and Date: 2014-10-02 – 2014-10-04
  • Invited
• [Presentation] Molecular Mechanisms underlying Parkinson Disease (2014)
  • Author(s): 長谷川成人
  • Organizer: 第37回 日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-12
  • Invited
• [Presentation] 神経変性疾患における細胞内異常タンパク質の伝播 (2014)
  • Author(s): 長谷川成人
  • Organizer: 第2回 日本アミロイドーシス研究会学術集会
  • Place of Presentation: KKRホテル東京
  • Year and Date: 2014-08-22
  • Invited
• [Presentation] αシヌクレインの伝播について (2014)
  • Author(s): 長谷川成人
  • Organizer: 第8回 進行期パーキンソン病研究会
  • Place of Presentation: 名古屋マリオットアソシアホテル
  • Year and Date: 2014-05-30
  • Invited
• [Presentation] Insoluble TDP-43 prepared from diseased brains has prion-like properties.
  • Author(s): Nonaka T, Masuda-Suzukake M, Tetsuaki Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DMA, Akiyama H and Hasegawa M;
  • Organizer: Alzheimer's Association International Conference (AAIC2013); Boston, USA,
  • Place of Presentation: Boston, USA
• [Presentation] 3R and 4R tau isoforms in paired helical filaments in Alzheimer’s disease.
  • Author(s): Hasegawa M, Dan A, Watanabe S, Kondo H, Akiyama H, Mann DM, Saito Y, Murayama S
  • Organizer: International symposium "New Frontier of Molecular Neuropathology 2014";
  • Place of Presentation: Tokyo, Japan
• [Presentation] 神経変性疾患の原因となるタンパク質の構造異常とその伝播
  • Author(s): 長谷川成人
  • Organizer: 第４回神経科学と構造生物学の融合研究会,
  • Place of Presentation: 岡崎
  • Invited
• [Presentation] 神経変性疾患の細胞病理を形成する蛋白質のプリオン様特性
  • Author(s): 長谷川成人
  • Organizer: 第８回臨床ストレス応答学会
  • Place of Presentation: 松本
  • Invited
• [Presentation] 神経変性疾患の分子基盤と進行機序 ―患者脳の解析から導かれた新しい考え方とその検証―
  • Author(s): 長谷川成人
  • Organizer: 平成２５年度 文部科学省 新学術領域研究 生命科学系３分野 がん・ゲノム・脳 支援活動合同シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Remarks] ALS患者脳に出現する原因タンパク質TDP-43の異常凝集物が自身を鋳型として細胞内で増殖・蓄積
  • URL: http://www.igakuken.or.jp/research/topics/2013/0704.html