Molecular function and a pathological role of LMTK1, a novel factor regulating spine formation

• Project/Area Number: 19K06942
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46030:Function of nervous system-related
• Research Institution: Tokyo Metropolitan University
• Principal Investigator: Hisanaga Shin-ichi 東京都立大学, 理学研究科, 客員教授 (20181092)
• Co-Investigator(Kenkyū-buntansha): 飯島 香奈絵 (安藤香奈絵) 東京都立大学, 理学研究科, 准教授 (40632500)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 神経細胞 / 小胞輸送 / エンドソーム / LMTK1 / 記憶形成 / アルツハイマー病 / BACE1 / APP / スパイン / リン酸化 / 高次脳機能 / Cdk5 / 神経回路 / 神経変性疾患 / LMTK

Outline of Research at the Start

神経細胞は軸索、樹状突起という長い突起を介して、回路を形成する。しかし、突起先端への膜成分の供給制御についての研究は少ない。申請者らはCdk5がエンドソームに結合する膜キナーゼあり、エンドソーム輸送を制御すること、そして、LMTK1という新規キナーゼを介して突起伸長やスパイン形成に関わることを明らかにした。LMTK1は認知症の危険因子であり、その変異は発達障害の原因にもなっていた。本研究では、LMTK1についての未解決な課題であるキナーゼ活性、アイソフォーム特異的役割、ノックアウトマウスを用いた行動解析や電気生理などを調べ、その生理的役割や認知症や発達障害との関連を分子レベルで明らかにする。

Outline of Final Research Achievements

We have been investigating the role of Lemur kinase 1 (LMTK1) in recycling endosome trafficking in neurons and reported previously that LMTK1 regulates axon outgrowth and spine formation via Rab11 activity. Here, we studied its in vivo function using LMTK1 knockout mouse and a pathological role in Alzheimer’s disease. We found that mice lacking LMTK1 show normal spatial and fear-conditioning memories, while the knockout of LMTK1 induced hyperactivity similar to those of Attention Deficient Hyperactivity Disorder (ADHD). We also observed that LMTK1 regulated the intracellular localization and trafficking of bata-secretase BACE1, but not amyloid precursor protein (APP), in COS-7 cells and primary neurons, resulting in the increased bata-cleavage of APP although amyloid beta peptide itself was not increased. We also found that LMTK1 was reduced in brains of Alzheimer’s disease patients, supporting the notion that LMTK1 and Rab11 are risk factors of neurodegenerative diseases.

Academic Significance and Societal Importance of the Research Achievements

神経細胞内における小胞輸送は軸索伸長やスパイン形成を介して、神経機能に影響を及ぼしているが詳細な分子機構は不明である。リサイクリングエンドソームの新規制御因子であるLMTK1の脳機能における生理的な役割と神経変性疾患にかかわる病理的な役割を探求した結果、LMTK1の欠失は記憶形成には影響を与えないが自閉症様の症状を示すこと、LMTK1活性はBACE1の細胞内輸送制御を介してアルツハイマー病発症に関わる可能性などが示唆された。LMTK1の変異は発達障害にも関わる可能性が示唆されており、今後その役割についてより詳細な研究が必要である。

Research Products

• [Journal Article] Map7D2 and Map7D1 facilitate microtubule stabilization through distinct mechanisms in neuronal cells (2022)
  • Author(s): Kikuchi K, sakamoto S, Uezu A, Yamamoto H, Ishiguro K, Shimamura K, Saito T, Hisanaga S, Nakanishi H
  • Journal Title: Life Science Alliance Volume: 5(8) Issue: 8 Pages: e202201390-e202201390
  • DOI: 10.26508/lsa.202201390
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Valproic acid-induced anxiety and depression behaviors are ameliorated in p39 Cdk5 activator-deficient mice. (2022)
  • Author(s): Takahashi, M., Takasugi, T., Kawakami, A., Wei, R., Ando, K., Ohshima, T., Hisanaga, S.
  • Journal Title: Neurochem Res. Volume: 47 Issue: 9 Pages: 2773-2779
  • DOI: 10.1007/s11064-022-03642-9
  • Peer Reviewed
• [Journal Article] Cdk5-mediated JIP1 phosphorylation regulates axonal outgrowth through Notch1 inhibition. (2022)
  • Author(s): Im, D. S., Joselin, A., Svoboda, D., Takano, T., Rousseaux, M. W. C., Callaghan, S., Slack, R. S., Hisanaga, S., Davis, R. J., Park, D. S., Qu, D.
  • Journal Title: BMC Biol. Volume: 20 Issue: 1 Pages: 115-115
  • DOI: 10.1186/s12915-022-01312-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo analysis of the phosphorylation of tau and the tau protein kinases Cdk5-p35 and GSK3beta by using Phos-tag SDS-PAGE. (2022)
  • Author(s): Hisanaga, S., Krishnankutty, A., Kimura, T.
  • Journal Title: J. Proteomics, Volume: 262 Pages: 104591-104591
  • DOI: 10.1016/j.jprot.2022.104591
  • Peer Reviewed
• [Journal Article] Lemur tail kinase 1 (LMTK1) regulates the endosomal localization of β-secretase BACE1 (2021)
  • Author(s): Komaki Keisuke、Takano Tetsuya、Sato Yutaka、Asada Akiko、Ikeda Shikito、Yamada Kaoru、Wei Ran、Huo Anni、Fukuchi Aoi、Saito Taro、Ando Kanae、Murayama Shigeo、Araki Wataru、Kametani Fuyuki、Hasegawa Masato、Iwatsubo Takeshi、Tomomura Mineko、Fukuda Mitsunori、Hisanaga Shin-ichi
  • Journal Title: The Journal of Biochemistry Volume: 170 Issue: 6 Pages: 729-738
  • DOI: 10.1093/jb/mvab094
  • Peer Reviewed
• [Journal Article] Distinct phosphorylation profiles of tau in brains of patients with different tauopathies. (2021)
  • Author(s): Samimi, N., Sharma, G., Kimura, T., Matsubara, T., Huo, A., Saito, S., Murayama, M., Akatsu, H., Hashizume, Y., Hasegawa, M., Farjam, M., Shahpasand, K., Ando, K., Hisanaga, S.
  • Journal Title: Neurobiol. Aging Volume: 108 Pages: 72-79
  • DOI: 10.1016/j.neurobiolaging.2021.08.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] エンドソーム結合性プロテインキナーゼLMTK1によるRab11活性制御と神経機能． (2021)
  • Author(s): 高橋美由紀、友村美根子、久永眞市.
  • Journal Title: 生化学 Volume: 93 Pages: 765-769
  • NAID: 40022742860
  • Peer Reviewed
• [Journal Article] Hyperactive and impulsive behaviors of LMTK1 knockout mice (2020)
  • Author(s): Takahashi Miyuki、Sugiyama Arika、Wei Ran、Kobayashi Shizuka、Fukuda Kimiko、Nishino Hironori、Takahashi Roka、Tsutsumi Koji、Kita Ichiro、Ando Kanae、Manabe Toshiya、Kamiguchi Hiroyuki、Tomomura Mineko、Hisanaga Shin-ichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15461-15461
  • DOI: 10.1038/s41598-020-72304-z
  • Peer Reviewed / Open Access
• [Journal Article] α-synuclein strains that cause distinct pathologies differentially inhibit proteasome (2020)
  • Author(s): Suzuki Genjiro、Imura Sei、Hosokawa Masato、Katsumata Ryu、Nonaka Takashi、Hisanaga Shin-Ichi、Saeki Yasushi、Hasegawa Masato
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.56825
  • Peer Reviewed / Open Access
• [Journal Article] LMTK1, a Novel Modulator of Endosomal Trafficking in Neurons (2020)
  • Author(s): Hisanaga Shin-ichi、Wei Ran、Huo Anni、Tomomura Mineko
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 13 Pages: 112-112
  • DOI: 10.3389/fnmol.2020.00112
  • Peer Reviewed / Open Access
• [Journal Article] Isoform-dependent subcellular localization of LMTK1A and LMTK1B and their roles in axon outgrowth and spine formation (2020)
  • Author(s): Wei Ran、Sugiyama Arika、Sato Yuta、Nozumi Motohiro、Nishino Hironori、Takahashi Miyuki、Saito Taro、Ando Kanae、Fukuda Mitsunori、Tomomura Mineko、Igarashi Michihiro、Hisanaga Shin-ichi
  • Journal Title: The Journal of Biochemistry Volume: - Issue: 1 Pages: 23-32
  • DOI: 10.1093/jb/mvaa019
  • NAID: 40022279141
  • Peer Reviewed
• [Journal Article] Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT1A receptor via phosphorylation (2019)
  • Author(s): Takahashi Miyuki、Kobayashi Yuki、Ando Kanae、Saito Yumiko、Hisanaga Shin-ichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 510 Issue: 3 Pages: 370-375
  • DOI: 10.1016/j.bbrc.2019.01.093
  • Peer Reviewed / Open Access
• [Journal Article] CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway (2019)
  • Author(s): Furusawa K, Takasugi T, Chiu YW, Hori Y, Tomita T, Fukuda M, Hisanaga SI
  • Journal Title: J. Biol. Chem. Volume: 294(28) Issue: 28 Pages: 10886-10899
  • DOI: 10.1074/jbc.ra118.005385
  • Peer Reviewed / Open Access
• [Journal Article] Tau isoform expression and phosphorylation in marmoset brains (2019)
  • Author(s): Sharma Govinda、Huo Anni、Kimura Taeko、Shiozawa Seiji、Kobayashi Reona、Sahara Naruhiko、Ishibashi Minaka、Ishigaki Shinsuke、Saito Taro、Ando Kanae、Murayama Shigeo、Hasegawa Masato、Sobue Gen、Okano Hideyuki、Hisanaga Shin-ichi
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 30 Pages: 11433-11444
  • DOI: 10.1074/jbc.ra119.008415
  • Peer Reviewed / Open Access
• [Journal Article] The LMTK1-TBC1D9B-Rab11A cascade regulates dendritic spine formation via endosome trafficking. (2019)
  • Author(s): Nishino, H., Saito. T., Wei, R., Takano, T., Tsutsumi, T., Taniguchi, M., Ando, K., Tomomura, M., Fukuda, M., Hisanaga, S.
  • Journal Title: J. Neurosci. Volume: 39 Pages: 9491-9502
  • Peer Reviewed
• [Presentation] Cellular and in vivo function of LMTK1 in mouse neurons (2023)
  • Author(s): Hisanaga, S.
  • Organizer: 1st LMTK International Virtual Meeting
  • Int'l Joint Research
• [Presentation] GSK3bとタウのin vivoリン酸化のPhos-tag電気泳動法による解析 (2021)
  • Author(s): 久永眞市、木村妙子、Ambika Krishnankutty、 Nastaran Samimi
  • Organizer: 第72回日本電気泳動学会
  • Invited
• [Presentation] Distinct phosphorylation profiles of tau in brains of patients with different tauopathies (2021)
  • Author(s): Nastaran Samimi, Taeko Kimura, Tomoyasu Matsubara, Yuko Saito, Shigeo Murayama, Masato Hasegawa, Kanae Ando, Shin-ichi Hisanaga
  • Organizer: 第６４回日本神経化学会大会
• [Presentation] The role of Cdk5 activity in valproic acid-induced anxiety- and depression-like behaviors. (2021)
  • Author(s): 高橋美由紀、Ran Wei、安藤香奈絵、大島登志男、久永眞市
  • Organizer: 第６４回日本神経化学会大会
• [Presentation] Analysis of the phosphorylation of neurodegenerative disease protein Tau by Phos-tag phosphoaffinity SDS-PAGE. (2021)
  • Author(s): Shin-ichi Hisanaga, Taeko Kimura, Masato Hasegawa
  • Organizer: The International Chemical Congress of Pacific Basin Societies
  • Int'l Joint Research
• [Presentation] 脳に高発現するキナーゼLMTK1のアイソフォーム依存的な機能解析 (2020)
  • Author(s): 魏冉、西野尋紀、佐藤勇太、杉山亜梨華、高橋美由紀、浅田明子、福田光則、五十嵐道弘、友村美根子、久永真市
  • Organizer: 第６３回日本神経化学会年会
• [Presentation] Disease-dependent phosphorylation of tau in tauopathies (2020)
  • Author(s): Samimi, N., Sharma, G., Kimura, T., Huo, A., Chiba, K., Murayama, S., Akatsu, H., Hashizume, Y., Hasegawa, M., Farjam, M., Shahpasand, K., Ando, K., Hisanaga, S.
  • Organizer: 第６３回日本神経化学会年会
• [Presentation] Hyperactive and impulsive behaviors of LMTK1 knockout mice (2020)
  • Author(s): Takahashi, M., Takahashi, R., Sugiyama, A., Kobayashi, S., Fukuda, K., Nishino, H., Wei, R., Kita, I., Ando, K., Manabe, T., Kamiguchi, H., Tomomura, M., Hisanaga, S.
  • Organizer: 第６３回日本神経化学会年会
• [Presentation] CD2-associated protein (CD2AP) sorts amyloid precursor protein (APP) to late endosomes from early endosomes. (2019)
  • Author(s): Furusawa, K., Takasugi, T., Fukuda, M., Hisanaga, S.
  • Organizer: AD/PD 2019
  • Int'l Joint Research
• [Presentation] Tau in marmoset brains, its isoform expression and phosphorylation. (2019)
  • Author(s): Sharma, G., Huo, A., Kimura, T., Shiozawa, S., Kobayashi, R., Sahara, N., Ishibashi, M., Ishigaki, S., Saito, T., Ando, K., Murayama, S., Hasegawa, H., Sobue, G., Okano, H., Hisanaga, S.
  • Organizer: AD/PD 2019
  • Int'l Joint Research
• [Presentation] Tau phosphorylation at AT8 pathological site during brain development. (2019)
  • Author(s): T. Dilina, K. Furusawa, T. Takasugi, S. Ishigaki, K. Ando, G. Sobue, S. Hisanaga.
  • Organizer: Neuro2019
• [Presentation] Tau phosphorylation at AT8 pathological site during brain development. (2019)
  • Author(s): T. Dilina, K. Furusawa, T. Takasugi, S. Ishigaki, K. Ando, G. Sobue, S. Hisanaga.
  • Organizer: ISN/ASN2019
  • Int'l Joint Research
• [Book] Bio Clinica (2020)
  • Author(s): 木村妙子、久永眞市、長谷川成人
  • Total Pages: 5
  • Publisher: 北隆館