Adult neurogenesis in the mouse models of ALS/FTLD

• Project/Area Number: 15K09310
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: Ishigaki Shinsuke 名古屋大学, 医学系研究科, 寄附講座助教 (40378170)
• Co-Investigator(Kenkyū-buntansha): 渡辺 宏久 名古屋大学, 脳とこころの研究センター, 特任教授 (10378177) ; 祖父江 元 名古屋大学, 医学系研究科, 特任教授 (20148315)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Adult neurogenesis / FTLD / ALS / tau / FUS / SFPQ / adult neurogenesis / 前頭側頭葉変性症 / タウ / 成体神経新生

Outline of Final Research Achievements

Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T specific silencing resulted in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of ALS/FTLD.

Research Products

• [Int'l Joint Research] University of Pittsburgh(米国)
• [Journal Article] Silencing of FUS in the common marmoset (Callithrix jacchus) brainvia stereotaxic injection of an adeno-associated virus encoding shRNA. (2018)
  • Author(s): Endo K, Ishigaki S, Masamizu Y, Fujioka Y, Watakabe A, Yamamori T, Hatanaka N, Nambu A, Okado H, Katsuno M, Watanabe H, Matsuzaki M, Sobue G
  • Journal Title: Neurosci Res Volume: in press Pages: 30183-9
  • DOI: 10.1016/j.neures.2017.08.006
  • Peer Reviewed
• [Journal Article] 3'UTR Length-Dependent Control of SynGAP Isoform α2 mRNA by FUS and ELAV-like Proteins Promotes Dendritic Spine Maturation and Cognitive Function. (2017)
  • Author(s): Yokoi S, Udagawa T, Fujioka Y, Honda D, Okado H, Watanabe H, Katsuno M.
  • Journal Title: Cell Rep Volume: 20(13) Issue: 13 Pages: 3071-3084
  • DOI: 10.1016/j.celrep.2017.08.100
  • Peer Reviewed / Open Access
• [Journal Article] Pathologic Involvement of Glutamatergic Striatal Inputs From the Cortices in TAR DNA-Binding Protein 43kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. (2017)
  • Author(s): Riku Y, Watanabe H, Yoshida M, Mimuro M, Iwasaki Y, Masuda M, Ishigaki S.
  • Journal Title: J Neuropathol Exp Neurol Volume: 76(9) Issue: 9 Pages: 759-768
  • DOI: 10.1093/jnen/nlx055
  • Peer Reviewed
• [Journal Article] Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania. (2017)
  • Author(s): Parekh PK, Becker-Krail D, Sundaravelu P, Ishigaki S, Okado H, Sobue G, Huang Y, McClung CA.
  • Journal Title: Biol Psychiatry Volume: S0006 Issue: 11 Pages: 31721-3
  • DOI: 10.1016/j.biopsych.2017.06.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Altered tau isoform ratio caused by loss of Fus and Sfpq function leads to FTLD-like phenotypes (2017)
  • Author(s): Ishigaki S, Fujioka Y, Okada Y, Riku Y, Udagawa T, Honda D, Yokoi S, Endo K, Ikenaka K, Takagi S, Iguchi Y, Sahara N, Takashima A, Okano H, Yoshida M, Warita H, Aoki M, Watanabe H, Okado H, Katsuno H, Sobue G.
  • Journal Title: Cell Reports Volume: 18 Issue: 5 Pages: 1118-1131
  • DOI: 10.1016/j.celrep.2017.01.013
  • Peer Reviewed / Open Access
• [Journal Article] Marked Involvement of the Striatal Efferent System in TAR DNA-Binding Protein 43 kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. (2017)
  • Author(s): Riku Y., Watanabe H., Yoshida M., Mimuro M., Iwasaki Y., Masuda M., Ishigaki S., Katsuno M., Sobue G.
  • Journal Title: J Neuropathol Exp Neurol Volume: in press Issue: 8 Pages: 801-811
  • DOI: 10.1093/jnen/nlw053
  • Peer Reviewed
• [Journal Article] Gene Expression Profile of Inflammatory Myopathy with Malignancy is Similar to that of Dermatomyositis rather than Polymyositis (2016)
  • Author(s): Noda, T., Iijima, M., Noda, S., Maeshima, S., Nakanishi, H., Kimura, S., Koike, H., Ishigaki, S., Iguchi, Y., Katsuno, M., and Sobue, G.
  • Journal Title: Internal Medicine Volume: 55 Issue: 18 Pages: 2571-2580
  • DOI: 10.2169/internalmedicine.55.6706
  • NAID: 130005414859
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Involvement of the caudate nucleus head and its networks in sporadic amyotrophic lateral sclerosis-frontotemporal dementia continuum. (2016)
  • Author(s): Masuda, M., Senda, J., Watanabe, H., Epifanio, B., Tanaka, Y., Imai, K., Riku, Y., Li, Y., Nakamura, R., Ito, M., Ishigaki, S., Atsuta, N., Koike, H., Katsuno, M., Hattori, N., Naganawa, S., and Sobue, G.
  • Journal Title: Amyotroph Lateral Scler Frontotemporal Degener Volume: 17 Pages: 571-579
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5. (2016)
  • Author(s): Nakashima H., Ohkawara B., Ishigaki S., Fukudome T., Ito K., Tsushima M., Konishi H., Okuno T., Yoshimura T., Ito M., Masuda A., Sobue G., Kiyama H., Ishiguro N., Ohno K.
  • Journal Title: Sci Rep Volume: 22 Issue: 1 Pages: 28512-28512
  • DOI: 10.1038/srep28512
  • Peer Reviewed / Open Access
• [Journal Article] A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. (2016)
  • Author(s): Watanabe H, Atsuta N, Hirakawa A, Nakamura R, Nakatochi M, Ishigaki S, Iida A, Sobue G.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: in press Issue: 8 Pages: 851-8
  • DOI: 10.1136/jnnp-2015-311541
  • Peer Reviewed
• [Journal Article] FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. (2015)
  • Author(s): Udagawa, T., Fujioka, Y., Tanaka, M., Honda, D., Yokoi, S., Riku, Y., Ibi, D., Nagai, T., Yamada, K., Watanabe, H., Katsuno, M., Inada, T., Ohno, K., Sokabe, M., Okado, H., Ishigaki S*., and Sobue, G.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 7098-7098
  • DOI: 10.1038/ncomms8098
  • Peer Reviewed / Open Access
• [Journal Article] Position-specific binding of FUS to nascent RNA regulates mRNA length. (2015)
  • Author(s): Masuda A, Takeda J, Okuno T, Okamoto T, Ohkawara B, Ito M, Ishigaki S, Sobue G, Ohno K.
  • Journal Title: Genes Dev. Volume: 29(10) Issue: 10 Pages: 1045-57
  • DOI: 10.1101/gad.255737.114
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional and post-transcriptional regulation of transmembrane protein 132A. (2015)
  • Author(s): Oh-Hashi, K., Sone, A., Hikiji, T., Hirata, Y., Vitiello, M., Fedele, M., Ishigaki S., Sobue, G., and Kiuchi, K.
  • Journal Title: Mol Cell Biochem Volume: 405 Issue: 1-2 Pages: 291-299
  • DOI: 10.1007/s11010-015-2419-x
  • Peer Reviewed
• [Journal Article] A highly sensitive assay of IRE1 activity using the small luciferase NanoLuc: Evaluation of ALS-related genetic and pathological factors. (2015)
  • Author(s): Hikiji, T., Norisada, J., Hirata, Y., Okuda, K., Nagasawa, H., Ishigaki S., Sobue, G., Kiuchi, K., and Oh-hashi, K.
  • Journal Title: Biochem Biophys Res Commun Volume: 463 Issue: 4 Pages: 881-887
  • DOI: 10.1016/j.bbrc.2015.05.132
  • Peer Reviewed
• [Journal Article] Microglial keratan sulfate epitope elicits in central nervous tissues of transgenic model mice and patients with amyotrophic lateral sclerosis. (2015)
  • Author(s): Foyez T, Takeda-Uchimura Y, Ishigaki S, Narentuya, Zhang Z, Sobue G, Kadomatsu K, Uchimura K.
  • Journal Title: Am J Pathol Volume: 185 Issue: 11 Pages: 3053-3065
  • DOI: 10.1016/j.ajpath.2015.07.016
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 3’UTR length-dependent control of SynGAP isoform α2 mRNA by FUS and ELAV-like proteins promotes dendritic spine maturation and cognitive function. (2017)
  • Author(s): Yokoi S, Udagawa T, Fujioka Y, Honda D, Okado H, Watanabe H, Katsuno M, Ishigaki S, Sobue G.
  • Organizer: WCN 2017
  • Int'l Joint Research
• [Presentation] Silencing of FUS in the brain of non-human primates via stereotaxic injection of an adeno-associated virus encoding shRNA. (2017)
  • Author(s): Endo K, Ishigaki S, Fujioka Y, Watanabe H, Katsuno M, Sobue G.
  • Organizer: WCN 2017
  • Int'l Joint Research
• [Presentation] Silencing of FUS in the non-human primate brain via stereotaxic injection of an adeno-associated virus encoding shRNA. (2017)
  • Author(s): Endo K, Ishigaki S, Fujioka Y, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 47th Society for Neuroscience annual meeting
  • Int'l Joint Research
• [Presentation] FUS and ELAV-like proteins cooperatively control SynGAP isoform α2 in a 3'UTR length-dependent manner to promote dendritic spine maturation and cognitive function. (2017)
  • Author(s): Yokoi S, Udagawa T, Fujioka Y, Honda D, Okado H, Watanabe H, Katsuno M, Ishigaki S, Sobue G.
  • Organizer: The 47th Society for Neuroscience annual meeting
  • Int'l Joint Research
• [Presentation] Aberrant interaction between FUS and SFPQ in 4R-tau dominant tauopathy brains. (2017)
  • Author(s): Ishigaki S, Riku Y, Fujioka Y, Honda D, Yokoi S, Endo K., Kawai K, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 47th Society for Neuroscience annual meeting
  • Int'l Joint Research
• [Presentation] ALS/FTLDにおけるFUSの機能の重要性 (2017)
  • Author(s): 石垣 診祐
  • Organizer: 2017年度 生命科学系学会合同年次大会
  • Invited
• [Presentation] Accumulation of phosphorylated tau in neurons in FUS-silenced mice. (2016)
  • Author(s): 27.Ishigaki S, Fujioka Y, Honda D, Yokoi S, Endo K., Okado H, Watanabe H, Katsuno M, Takashima A., Sobue G.
  • Organizer: The 46th Society for Neuroscience annual meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Loss of SFPQ, an intra-nuclear counterpart of FUS causes FTLD-like phenotypes. (2016)
  • Author(s): 28.Fujioka Y, Ishigaki S, Yokoi S, Honda D, Okado H, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 46th Society for Neuroscience annual meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Loss of PSF/SFPQ, an intra-nuclear counterpart of FUS causes FTLD-like phenotypes (2016)
  • Author(s): Fujioka Y, Ishigaki S, Yokoi S, Honda D, Okado H, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 39th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市)
  • Year and Date: 2016-07-20
• [Presentation] 石垣 診祐、藤岡 祐介、本田 大祐、横井 聡、岡戸 晴生、渡辺 宏久、勝野 雅央、祖父江 元 (2016)
  • Author(s): Loss of FUS causes phosphorylated tau accumulation in aged mice
  • Organizer: 第57回神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター(兵庫県 神戸市)
  • Year and Date: 2016-05-18
• [Presentation] 藤岡 祐介、石垣 診祐、本田 大祐、横井 聡、岡戸 晴生、渡辺 宏久、勝野 雅央、祖父江 元 (2016)
  • Author(s): Loss of PSF/SFPQ, an intra-nuclear counterpart of FUS causes FTLD-like phenotypes
  • Organizer: 第57回神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター(兵庫県 神戸市)
  • Year and Date: 2016-05-18
• [Presentation] Functional linkage between FUS and tau in ALS/FTLD (2016)
  • Author(s): Ishigaki S, Fujioka Y, Honda D, Yokoi S, Okado H, Watanabe H, Katsuno M, Sobue G
  • Organizer: The 39th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市)
  • Invited
• [Presentation] Quality loss of FUS and SFPQ alters the ratio of Tau isoforms, which recapitulates FTLD accompanied with aberrant adult neurogenesis. (2015)
  • Author(s): Ishigaki S, Fujioka Y, Honda D, Yokoi S, Okado H, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 45th Society for Neuroscience annual meeting
  • Place of Presentation: Chicago, IL USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Loss of FUS causes a decrease in brain volume accompanied with neuronal loss (2015)
  • Author(s): Fujioka Y, Ishigaki S, Yokoi S, Honda D, Udagawa T, Okado H, Yoshikawa M, Takashima A, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 45th Society for Neuroscience annual meeting
  • Place of Presentation: Chicago, IL USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] FTLD-like phenotypes accompanied with aberrant adult neurogenesis are regulated by altered Tau isoforms in FUS-silenced mice (2015)
  • Author(s): Ishigaki S, Fujioka Y, Honda D, Yokoi S, Okado H, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 10th brain research conference
  • Place of Presentation: Chicago, IL USA
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] Loss of FUS causes a decrease in brain volume accompanied with neuronal loss (2015)
  • Author(s): Fujioka Y, Ishigaki S, Yokoi S, Honda D, Udagawa T, Okado H, Yoshikawa M, Takashima A, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 10th brain research conference
  • Place of Presentation: Chicago, IL USA
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] FUSの機能喪失はTau isoform依存的にadult neurogenesis抑制を引き起こす (2015)
  • Author(s): 石垣 診祐、 藤岡 祐介、本田 大祐、横井 聡、渡辺 宏久、勝野 雅央、祖父江 元
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: 青森県 青森市 リンクステーション青森
  • Year and Date: 2015-10-02
• [Presentation] Aberrant adult neurogenesis in FUS-knockdown mice which exhibited FTLD-like phenotypes (2015)
  • Author(s): Ishigaki S, Fujioka Y, Honda D, Yokoi S, Okado H, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 38th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 兵庫県 神戸市 神戸国際会議場
  • Year and Date: 2015-07-28
• [Presentation] The loss of FUS leads to brain atrophy accompanied with neuronal loss. (2015)
  • Author(s): Fujioka Y, Ishigaki S, Yokoi S, Honda D, Udagawa T, Okado H, Watanabe H, Katsuno M, Sobue G.
  • Organizer: The 38th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 兵庫県 神戸市 神戸国際会議場
  • Year and Date: 2015-07-28
• [Presentation] FUS knockdown causes the morphologic abnormities of dendritic spines (2015)
  • Author(s): Yokoi S, Ishigaki S, Honda D, Fujioka Y, Udagawa T, Katsuno M, Sobue G.
  • Organizer: The 38th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 兵庫県 神戸市 神戸国際会議場
  • Year and Date: 2015-07-28
• [Presentation] FUS regulates AMPA receptor function and FTLD/ALS-associated behavior via GluA1 mRNA stabilization (2015)
  • Author(s): Honda D, Udagawa T, Fujioka Y, Tanaka M, Yokoi S, Nagai T, Yamada K, Ishigaki S, Watanabe H, Katsuno M, Ohno K, Sokabe M, Okado H, Sobue G.
  • Organizer: The 38th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 兵庫県 神戸市 神戸国際会議場
  • Year and Date: 2015-07-28
• [Presentation] ALS/FTLDの病態におけるFUSの役割 Quality loss of function of FUS in ALS/FTLD (2015)
  • Author(s): 石垣 診祐、祖父江 元
  • Organizer: 第15回日本蛋白質科学会年会 ワークショップ
  • Place of Presentation: 徳島県 徳島市 あわぎんホール
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] FUSの質的機能喪失によるALS/FTLDの病態機構 Quality loss of FUS is involved in the pathogenesis of ALS/FTLD. (2015)
  • Author(s): Ishigaki S, Sobue G
  • Organizer: 第56回神経学会学術大会 シンポジウム
  • Place of Presentation: 新潟県 新潟市 朱鷺メッセ
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] Suppression of FUS induces the morphologic abnormities of dendritic spines (2015)
  • Author(s): 横井 聡、石垣 診祐、宇田川 剛、本田 大祐、藤岡 祐介、勝野 雅央、祖父江 元
  • Organizer: 第56回神経学会学術大会
  • Place of Presentation: 新潟 新潟市 朱鷺メッセ
  • Year and Date: 2015-05-20
• [Presentation] Loss of FUS affects adult neurogenesis by modulating Tau isoforms (2015)
  • Author(s): 石垣 診祐、藤岡 祐介、本田 大祐、横井 聡、岡田 洋平、岡戸 晴生、渡辺 宏久、勝野 雅央、祖父江 元
  • Organizer: 第56回神経学会学術大会
  • Place of Presentation: 新潟 新潟市 朱鷺メッセ
  • Year and Date: 2015-05-20
• [Presentation] Striatum is systematically affected in TDP-43-related FTLD; a pathological study (2015)
  • Author(s): 陸 雄一、渡辺 宏久、吉田 眞理、三室 マヤ、岩崎 靖、桝田 道人、勝野 雅央、石垣 診祐、祖父江 元
  • Organizer: 第56回神経学会学術大会
  • Place of Presentation: 新潟 新潟市 朱鷺メッセ
  • Year and Date: 2015-05-20
• [Presentation] Loss of FUS causes a decrease in brain volume accompanied with neuronal loss (2015)
  • Author(s): 藤岡 祐介、石垣 診祐、横井 聡、本田 大祐、宇田川 剛、岡戸 晴生、渡辺 宏久、勝野 雅央、祖父江 元
  • Organizer: 第56回神経学会学術大会
  • Place of Presentation: 新潟 新潟市 朱鷺メッセ
  • Year and Date: 2015-05-20
• [Presentation] FUS regulates AMPA receptor function and FTLD-associated behavior (2015)
  • Author(s): 本田 大祐、宇田川 剛、藤岡 祐介、田中 基樹、永井 拓、山田 清文、横井 聡、石垣 診祐、渡辺 宏久、勝野 雅央、大野 欽司、曽我部 正博、岡戸 晴生、祖父江 元
  • Organizer: 第56回神経学会学術大会
  • Place of Presentation: 新潟 新潟市 朱鷺メッセ
  • Year and Date: 2015-05-20
• [Presentation] Involvement of caudate nucleus head connectivities in ALS (2015)
  • Author(s): 渡辺 宏久、桝田 道人、千田 譲、Bagarinao, Epifanio、田中 康博、陸 雄一、中村 良一、渡辺 はづき、伊藤 瑞規、石垣 診祐、熱田 直樹、勝野 雅央、長縄 慎二、祖父江 元
  • Organizer: 第56回神経学会学術大会
  • Place of Presentation: 新潟 新潟市 朱鷺メッセ
  • Year and Date: 2015-05-20
• [Book] 【認知症の予防と対策】 前頭側頭型認知症への新しいアプローチ (2016)
  • Author(s): 石垣 診祐, 祖父江 元
  • Publisher: Medical Science Digest
• [Patent(Industrial Property Rights)] ＴＤＰ－４３の発現量を調節するアンチセンスオリゴヌクレオチド及びその用途 (2017)
  • Inventor(s): 祖父江元、石垣診祐、他7名
  • Industrial Property Rights Holder: 名古屋大学、大阪大学、神戸天然物化学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] 細胞内容物の回収方法および回収装置 (2017)
  • Inventor(s): 宇理須恒雄、石垣診祐、宇野秀隆、高村禅
  • Industrial Property Rights Holder: 名古屋大学、北陸先端科学技術大学院大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] 疾患モデル動物および疾患治療剤 (2016)
  • Inventor(s): 祖父江元、石垣診祐、横井聡
  • Industrial Property Rights Holder: 国立大学法人名古屋大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-139308
  • Filing Date: 2016-07-14