Generation of a new mouse model using neurons derived from iPS cells of Parkinson's disease patients

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 17H05700
• 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: Osaka University
• Principal Investigator: 望月 秀樹 大阪大学, 医学系研究科, 教授 (90230044)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: パーキンソン病 / iPS細胞 / αシヌクレイン / α-シヌクレイン / 動物モデル

Outline of Annual Research Achievements

我々はパーキンソン病（PD）の解明の為に、ヒトPD患者由来の異常折りたたみαシヌクレイン蛋白質をマウスに投与することで、よりヒトに近いPDの病態再現及び解明を目指す。平成30年度は、PD患者由来TH陽性神経細胞のマウス黒質への移植を予備的に行い、移植3か月後に解析を行ったが、殆ど移植細胞の生着を認めなかった。この結果について、移植細胞のin vitroでの解析の結果、PARK4患者由来TH陽性細胞はシヌクレインの蓄積を認めるが、分化後4週目をピークに減少していることが判明した。また、本邦で確認された点変異シヌクレインより作成した凝集体をマウス黒質に投与したところ緩徐進行性のリン酸化シヌクレイン陽性の凝集体形成と黒質TH陽性細胞の減少というパーキンソン病の病理学的特徴の再現に部分的に成功した。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Interaction of nectin-2α with the auxiliary protein of the voltage-gated A-type K(+) channel Kv4.2 dipeptidyl aminopeptidase-like protein at the boundary between the adjacent somata of clustered cholinergic neurons in the medial habenula (2019)
  • Author(s): Shiotani H, Miyata M, Mizutani K, Wang S, Mizoguchi A, Mochizuki H, *Mandai K, *Takai Y
  • Journal Title: Mol. Cell. Neurosci. Volume: 94 Pages: 32-40
  • DOI: 10.1016/j.mcn.2018.11.001
  • NAID: 120006850502
  • Peer Reviewed
• [Journal Article] In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson’s disease (2018)
  • Author(s): Uenaka Takeshi、Satake Wataru、Cha Pei-Chieng、Hayakawa Hideki、Baba Kousuke、Jiang Shiying、Kobayashi Kazuhiro、Kanagawa Motoi、Okada Yukinori、Mochizuki Hideki、Toda Tatsushi
  • Journal Title: Human Molecular Genetics Volume: 27 Pages: 3974-3985
  • DOI: 10.1093/hmg/ddy279
  • NAID: 120006549191
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing (2018)
  • Author(s): Murakami Tatsuya C.、Mano Tomoyuki、Saikawa Shu、Horiguchi Shuhei A.、Shigeta Daichi、Baba Kousuke、Sekiya Hiroshi、Shimizu Yoshihiro、Tanaka Kenji F.、Kiyonari Hiroshi、Iino Masamitsu、Mochizuki Hideki、Tainaka Kazuki、Ueda Hiroki R.
  • Journal Title: Nat Neurosci Volume: 21 Issue: 4 Pages: 627-637
  • DOI: 10.1038/s41593-018-0109-1
  • Peer Reviewed
• [Journal Article] Quantifying changes in nigrosomes using quantitative susceptibility mapping and neuromelanin imaging for the diagnosis of early-stage Parkinson's disease. (2018)
  • Author(s): Takahashi H, Watanabe Y, Tanaka H, Mihara M, Mochizuki H, Liu T, Wang Y, Tomiyama N
  • Journal Title: The British Journal of Radiology Volume: 2 Issue: 1086 Pages: 20180037-20180037
  • DOI: 10.1259/bjr.20180037
  • Peer Reviewed
• [Journal Article] Targeted knockdown of the mitochondria-localized protein p13 protects against experimental parkinsonism (2018)
  • Author(s): Inoue N, Ogura S, Kasai A, Nakazawa T, Ikeda K, Higashi S, Isotani A, Baba K, Mochizuki H, Fujimura H, Ago Y, Hayata-Takano A, Seiriki K, Shintani N, Hashimoto H
  • Journal Title: EMBO Reports Volume: 19(3) Issue: 3
  • DOI: 10.15252/embr.201744860
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death. (2018)
  • Author(s): Hirata Y, Sasaki T, Kanki H, Choong CJ, Nishiyama K, Kubo G, Hotei A, Taniguchi M, Mochizuki H, Uesato S.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1400-1400
  • DOI: 10.1038/s41598-018-19664-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neurofeedback-induced facilitation of the supplementary motor area affects postural stability. (2017)
  • Author(s): Fujimoto H, Mihara M, Hattori N, Hatakenaka M, Yagura H, Kawano T, Miyai I, Mochizuki H.
  • Journal Title: Neurophotonics Volume: 4 Issue: 04 Pages: 045003-045003
  • DOI: 10.1117/1.nph.4.4.045003
  • Peer Reviewed
• [Journal Article] Evidence that glial cells attenuate G47R transthyretin accumulation in the central nervous system. (2017)
  • Author(s): Sumi-Akamaru H, Etoh M, YamauchiA, Uehara T, Kakuda K, Obayashi K, Kato S, Naka T, Mochizuki H
  • Journal Title: Neuropathology Volume: 38 Issue: 1 Pages: 11-21
  • DOI: 10.1111/neup.12412
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Structural variations in alpha synuclein (αSyn) fibrils of Parkinson’s disease and related disorders. (2017)
  • Author(s): Kensuke Ikenaka, Katsuya Araki, Masatomo So, Cesar Aguirre, Kousuke Baba, Yuji Goto, Hideki Mochizuki.
  • Organizer: American Neurological Association 2017 SAN DIEGO OCTOBER 15-17 2017
  • Int'l Joint Research
• [Presentation] A novel method for behavioral assessments of the common marmoset Marmodetector, detects general natural movement and changes in motor behavior. (2017)
  • Author(s): Taiki Yabumoto, Fumiaki Yoshida, Kousuke Baba, Hideki Hayakawa, Hiroki Hamanaka, Masayuki Hirata, Hideki Mochizuki.
  • Organizer: XXIII World Congress of Neurology (WCN 2017), Kyoto, Japan
  • Int'l Joint Research
• [Presentation] Small-molecule inhibitors of p53/negative regulator-interaction protect dopaminergic neurons against MPP+/MPTP-induced neurotoxicity. (2017)
  • Author(s): Choong CJ, Sasaki T, Hayakawa H, Baba K, Hirata Y, Uesato S, Mochizuki H.Small-molecule inhibitors of p53/negative regulator-interaction protect dopaminergic neurons against MPP+/MPTP-induced neurotoxicity.
  • Organizer: XXIII World Congress of Neurology (WCN 2017)
  • Int'l Joint Research
• [Presentation] Gapmer型Amido-bridged nucleic acids搭載核酸医薬によるα-シヌクレイン抑制の検討. (2017)
  • Author(s): 上原拓也, Choong Chi-Jing, 早川英規, 笠原勇矢, 永田哲也, 横田隆徳, 馬場孝輔, 中森雅之, 小比賀聡, 望月秀樹.
  • Organizer: 第10回パーキンソン病・運動障害疾患コングレス 2017年10月 東京
• [Presentation] Antisense oligonucleotides containing amido-bridged nucleic acid downregulate SNCA expression and improve motor function in Parkinson's disease mouse models. (2017)
  • Author(s): Takuya Uehara, Chi-Jing Choong, Hideki Hayakawa, Yuuya Kasahara, Tetsuya Nagata, Takanori Yokota, Kousuke Baba, Masayuki Nakamori, Satoshi Obika, Hideki Mochizuki.
  • Organizer: MDS 2017 Vancouver, BC, Canada Vancouver Convention Centre VANCOUVER JUNE 4-8 2017
  • Int'l Joint Research