Establishment of ALS model by artificial RNA-binding proteins related to ALS proteinopathies.

• Project/Area Number: 18K07534
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Keio University
• Principal Investigator: ITO Daisuke 慶應義塾大学, 医学部(信濃町), 准教授 (80286450)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 筋萎縮性側索硬化症 / 前頭側頭型認知症 / TDP-43 / FUS / 遺伝子改変マウス / 筋萎縮性側策硬化症 / RNA結合蛋白

Outline of Final Research Achievements

The aim of this study was to generate a novel ALS model, knocked-in mouse of artificially designing cDNA harboring with the characteristics of the ALS causative genes causing ALS and introducing into the ROSA26 locus to examined their cytotoxicity in vivo.
We were able to obtain a line of ALS artificial gene knock-in mice. Currently, we are planning to breed them. On the other hand, from the analysis of our established ALS model mouse (△NLS-FUS transgenic), we found that a wide variety of splicing changes were observed in the brain and spinal cord and also that semaphorin 3G, which is required for synaptic plasticity, was upregulated in this mouse.

Academic Significance and Societal Importance of the Research Achievements

本研究により、ALS病態誘導人工遺伝子が神経変性のトリガーとなることをin vivoで証明するとともに、運動ニューロンの選択的変性の分子機構をin vivoレベルで解析が可能となり、新規治療戦略の確立、薬剤の評価への利用が期待できる.
また、△NLS-FUSトランスジェニックマウスより見出されたSemaphorin 3Gは、バイオマーカーへの応用や治療ターゲットにつながることが期待される.

Research Products

• [Journal Article] Alpha‐synuclein dynamics in induced pluripotent stem cell‐derived dopaminergic neurons from a Parkinson’s disease patient ( PARK4 ) with SNCA triplication (2021)
  • Author(s): Fukusumi Hayato、Togo Kazuyuki、Sumida Miho、Nakamori Masayuki、Obika Satoshi、Baba Kousuke、Shofuda Tomoko、Ito Daisuke、Okano Hideyuki、Mochizuki Hideki、Kanemura Yonehiro
  • Journal Title: FEBS Open Bio Volume: 11 Issue: 2 Pages: 354-366
  • DOI: 10.1002/2211-5463.13060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A diagnostic strategy for Parkinsonian syndromes using quantitative indices of DAT SPECT and MIBG scintigraphy: an investigation using the classification and regression tree analysis (2021)
  • Author(s): Iwabuchi Yu、Kameyama Masashi、Matsusaka Yohji、Narimatsu Hidetoshi、Hashimoto Masahiro、Seki Morinobu、Ito Daisuke、Tabuchi Hajime、Yamada Yoshitake、Jinzaki Masahiro
  • Journal Title: European Journal of Nuclear Medicine and Molecular Imaging Volume: - Issue: 6 Pages: 1833-1841
  • DOI: 10.1007/s00259-020-05168-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extensive splicing changes in an ALS/FTD transgenic mouse model overexpressing cytoplasmic fused in sarcoma. (2020)
  • Author(s): Ito D, Taguchi R, Deguchi M, Ogasawara H, Inoue E.
  • Journal Title: Sci Rep Volume: 10(1) Issue: 1 Pages: 4857-4857
  • DOI: 10.1038/s41598-020-61676-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The utility of simple questions to evaluate cognitive impairment. (2020)
  • Author(s): Date Y, Sugiyama D, Tabuchi H, Saito N, Konishi M, Eguchi Y, Momota Y, Yoshizaki T, Mashima K, Mimura M, Nakahara J, Ito D.
  • Journal Title: PLoS One Volume: 5 Issue: 5 Pages: 0233225-0233225
  • DOI: 10.1371/journal.pone.0233225
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Disclosure of Amyloid Status for Risk of Alzheimer Disease to Cognitively Normal Research Participants With Subjective Cognitive Decline: A Longitudinal Study (2020)
  • Author(s): Wake T, Tabuchi H, Funaki K, Ito D, Yamagata B, Yoshizaki T, Nakahara T, Jinzaki M, Yoshimasu H, Tanahashi I, Shimazaki H, Mimura M
  • Journal Title: American journal of Alzheimer's disease and other dementias Volume: 35 Pages: 1-9
  • DOI: 10.1177/1533317520904551
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Can we predict amyloid deposition by objective cognition and regional cerebral blood flow in patients with subjective cognitive decline? (2019)
  • Author(s): Funaki K, Nakajima S, Noda Y, Wake T, Ito D, Yamagata B, Yoshizaki T, Kameyama M, Nakahara T, Murakami K, Jinzaki M, Mimura M, Tabuchi H.
  • Journal Title: Psychogeriatrics Volume: AOP Issue: 4 Pages: 325-332
  • DOI: 10.1111/psyg.12397
  • Peer Reviewed / Open Access
• [Journal Article] Impact of a combination of quantitative indices representing uptake intensity, shape, and asymmetry in DAT SPECT using machine learning: comparison of different volume of interest settings (2019)
  • Author(s): Iwabuchi Yu、Nakahara Tadaki、Kameyama Masashi、Yamada Yoshitake、Hashimoto Masahiro、Matsusaka Yohji、Osada Takashi、Ito Daisuke、Tabuchi Hajime、Jinzaki Masahiro
  • Journal Title: EJNMMI Research Volume: 9 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s13550-019-0477-x
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative evaluation of the tracer distribution in dopamine transporter SPECT for objective interpretation (2018)
  • Author(s): Iwabuchi Yu、Nakahara Tadaki、Kameyama Masashi、Yamada Yoshitake、Hashimoto Masahiro、Ogata Yuji、Matsusaka Yohji、Katagiri Mari、Itoh Kazunari、Osada Takashi、Ito Daisuke、Tabuchi Hajime、Jinzaki Masahiro
  • Journal Title: Annals of Nuclear Medicine Volume: Epub ahead of print Issue: 5 Pages: 363-371
  • DOI: 10.1007/s12149-018-1256-x
  • Peer Reviewed
• [Presentation] Dementia screening using simple questions and symptoms-News, Consciousness, and Pleasure simple screening questionnaires for dementia (Neucop-Q). (2021)
  • Author(s): Date Y, Sugiyama D, Tabuchi H, Saito N, Konishi M, Eguchi Y, Momota Y, Yoshizaki T, Mashima K, Mimura M, Nakahara J, Ito D
  • Organizer: The 15th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders
  • Int'l Joint Research
• [Presentation] Phase 1/2a, Double-blind, Placebo-controlled Study of Ropinirole Hydrochloride Remedy for ALS (ROPALS trial) Based On The iPSC Drug Repositioning. (2021)
  • Author(s): Takahashi S, Morimoto S, Okada K, Date Y, Ito D, Nakahara J, Okano H.
  • Organizer: American Academy of Neurology
  • Int'l Joint Research
• [Presentation] iPS細胞創薬に基づいた筋萎縮性側索硬化症（ALS）治療薬候補ロピニロールの第1/2a相試験 (2020)
  • Author(s): 伊東大介, 森本悟, 髙橋愼一 , 伊達悠岳, 岡田健佑, 岡野栄之 , 中原仁
  • Organizer: 第61回日本神経学会学術大会
  • Invited
• [Presentation] Evaluation of the novel tau tracer, [18F] PI-2620, for the assessment of Alzheimer’s disease (AD) and non-AD tauopathies including pathological correlation. (2020)
  • Author(s): Tezuka T, Takahata K, Tabuchi H, Ueda R, Miura E, Okita H, Takao M, Mashima K, Kubota M, Seki M, Yoshizaki T, Nakahara T, Yamamoto Y, Sano Y, Momota Y, Shiraiwa M, Suzuki N, Shibata M, Jinzaki M, Mimura M, Nakahara J, Ito D
  • Organizer: Alzheimer's Association International Conference
  • Int'l Joint Research
• [Presentation] The utility of simple questions to evaluate cognitive impairment (2020)
  • Author(s): 伊達 悠岳, 杉山 大典, 田渕 肇, 齊藤 菜穂, 小西 海香, 江口 洋子, 百田 友紀, 吉崎 崇仁, 馬島 恭子, 三村 將, 中原 仁, 伊東 大介
  • Organizer: 第39回日本認知症学会
• [Presentation] Tau-PET IMAGING OF ALZHEIMER AND NON-ALZHEIMER DEMENTIA USING 18F-PI 2620. (2019)
  • Author(s): Mimura M, Tabuchi H, Ito D.
  • Organizer: . Alzheimer's & Parkinson's Diseases Congress.
  • Int'l Joint Research
• [Presentation] De novo design of a cytoplasmic rna-binding protein with a prion-like domain related to als/ftd proteinopathies. (2018)
  • Author(s): Ito D, Mitsuhashi K, Suzuki N.
  • Organizer: 5th RNA Metabolism in Neurological Disease Conference.
  • Int'l Joint Research
• [Presentation] Disclosure of amyloid status for risk of Alzheimer’s disease to cognitively normal persons with subjective cognitive decline (2018)
  • Author(s): Wake T, Tabuchi H, Funaki K, Ito D, Yamagata B, Yoshizaki T, Kameyama M, Nakahara T, Murakami K, Jinzaki M, Mimura M
  • Organizer: Alzheimer's Association International Conference
  • Int'l Joint Research