Spinal cord environment: elucidating the mechanism of neurodegeneration through glia-neuron interaction

• Project Area: Brain Environment
• Project/Area Number: 23111006
• 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: Nagoya University (2013-2015); The Institute of Physical and Chemical Research (2011-2012)
• Principal Investigator: Yamanaka Koji 名古屋大学, 環境医学研究所, 教授 (80446533)
• Co-Investigator(Kenkyū-buntansha): MISAWA Hidemi 慶應義塾大学, 薬学部, 教授 (80219617)
• Co-Investigator(Renkei-kenkyūsha): YAMASHITA Hirofumi 京都大学, 医学研究科, 講師 (60402913) ; MORIWAKI Yasuhiro 慶應義塾大学, 薬学部, 講師 (00392150)
• Research Collaborator: KOMINE Okiru 名古屋大学, 環境医学研究所, 助教 (00456211) ; WATANABE Seiji 名古屋大学, 環境医学研究所, 助教 (70633577) ; ENDO Fumito 名古屋大学, 環境医学研究所, 特任助教 (10713307)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥142,480,000 (Direct Cost: ¥109,600,000、Indirect Cost: ¥32,880,000); Fiscal Year 2015: ¥25,870,000 (Direct Cost: ¥19,900,000、Indirect Cost: ¥5,970,000); Fiscal Year 2014: ¥25,870,000 (Direct Cost: ¥19,900,000、Indirect Cost: ¥5,970,000); Fiscal Year 2013: ¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000); Fiscal Year 2012: ¥27,040,000 (Direct Cost: ¥20,800,000、Indirect Cost: ¥6,240,000); Fiscal Year 2011: ¥36,270,000 (Direct Cost: ¥27,900,000、Indirect Cost: ¥8,370,000)
• Keywords: 神経変性疾患 / グリア / 環境 / 脊髄環境 / 脊髄 / 細胞外環境

Outline of Final Research Achievements

We aimed to elucidate the mechanism for glial cells in recognition and response to neurodegeneration in amyotrophic lateral sclerosis (ALS). We identified an innate immune adaptor, TRIF and astrocyte derived cytokine, TGF-β1 as a detrimental factor of ALS related to glial cells. In addition, we found that osteopontin (OPN), known as a immune and inflammatory mediator, expressed specifically in motor neurons resistant to degeneration in ALS, and modified neuroinflammation through secretion to neighboring glial cells.

Research Products

• [Int'l Joint Research] スタンフォード大学/カリフォルニア大学サンディエゴ校(米国)
• [Journal Article] Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons. (2016)
  • Author(s): Lasiene J, Komine O, Fujimori-Tonou N, Powers B, Endo F, Watanabe S, Shijie J, Ravits J, Horner P, Misawa H, Yamanaka K
  • Journal Title: Acta Neuropathologica Communications Volume: 4 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s40478-016-0286-7
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neuroinflammation in Alzheimer’s disease. (2015)
  • Author(s): Heneka MT et al.
  • Journal Title: Lancet Neurology Volume: 14 Issue: 4 Pages: 388-405
  • DOI: 10.1016/s1474-4422(15)70016-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 aggresomes and is defective in an ALS mouse model. (2015)
  • Author(s): Chhangani D, Endo F, Amanullah A, Upadhyay A, Watanabe S, Mishra R, Yamanaka K, Mishra A
  • Journal Title: Neurobiology of Disease Volume: 86 Pages: 16-16
  • DOI: 10.1016/j.nbd.2015.11.017
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Astrocyte-Derived TGF-β1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells. (2015)
  • Author(s): Endo F, Komine O, et al.
  • Journal Title: Cell Reports Volume: 11 Pages: 592-604
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neuroinflammation in motor neuron disease. (2015)
  • Author(s): Komine O, Yamanaka K
  • Journal Title: Nagoya Journal of Medical Science Volume: 77 Pages: 537-549
  • NAID: 120005672307
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. (2014)
  • Author(s): Watanabe S, Ageta-Ishihara N, Nagatsu S, Takao K, Komine O, Endo F, Miyakawa T, Misawa H, Takahashi R, Kinoshita M, Yamanaka K.
  • Journal Title: Mol Brain Volume: 7 Issue: 1 Pages: 62-62
  • DOI: 10.1186/s13041-014-0062-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity. (2014)
  • Author(s): WATANABE Seiji, HAYAKAWA Tomoyo, Wakasugi Keisuke, YAMANAKA Koji
  • Journal Title: Cell Death & Disease Volume: 5 Issue: 10 Pages: e1497-e1497
  • DOI: 10.1038/cddis.2014.459
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis (2014)
  • Author(s): Nomura, T., Watanabe, S., Kaneko, K., Yamanaka, K., Nukina, N. & Furukawa, Y.
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 2 Pages: 1192-1202
  • DOI: 10.1074/jbc.m113.516492
  • Peer Reviewed / Open Access
• [Journal Article] Disease causing mutants of TDP-43 nucleic acid binding domains are resistant to aggregation and have increased stability and half-life. (2014)
  • Author(s): AUSTIN James J., WRIGHT Gareth S., WATANABE Seiji, GROSSMANN Gunter, ANTONYUK Svetlana V., YAMANAKA Koji, HASNAIN S. Samar
  • Journal Title: Proceedings of the National Academy of Sciences of U.S.A. Volume: 111 Issue: 11 Pages: 4309-4314
  • DOI: 10.1073/pnas.1317317111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Selective disruption of acetylcholine synthesis in subsets of motor neurons: A new model of late-onset motor neuron disease. (2014)
  • Author(s): Lecomte, M-J., Bertolus, C., Santamaria, J., Bauchet, A-L., Herbin, M., Saurini, F., Misawa, H., Maisonobe, T., Pradat, P-F. Nosten-Bertrand, M., Mallet, J. and Berrard S.
  • Journal Title: Neurobiology of Disease Volume: 65 Pages: 102-111
  • DOI: 10.1016/j.nbd.2014.01.014
  • Peer Reviewed / Open Access
• [Journal Article] E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity. (2013)
  • Author(s): MISHRA Amit, MAHESHIWARI Megha, CHHANGANI Deepak, FUJIMORI-TONOU Noriko, ENDO Fumito, JOSHI A.Prakashi, JANA N.Ranjan, YAMANAKA Koji
  • Journal Title: Neurobiology of Aging Volume: 34 Issue: 4 Pages: 1310.e11-1310.e23
  • DOI: 10.1016/j.neurobiolaging.2012.08.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intracellular seeded aggregation of mutant Cu,Zn-superoxide dismutase associated with amyotrophic lateral sclerosis (2013)
  • Author(s): Furukawa, Y., Kaneko, K., Watanabe, S., Yamanaka, K. & Nukina, N.
  • Journal Title: FEBS Lett. Volume: 587 Issue: 16 Pages: 2500-2505
  • DOI: 10.1016/j.febslet.2013.06.046
  • Peer Reviewed / Open Access
• [Journal Article] Spliceosome integrity is defective in the motor neuron diseases ALS and SMA (2013)
  • Author(s): Tsuiji H, Iguchi Y, Furuya A, Kataoka A, Hatsuta H, Atsuta N, Tanaka F, Hashizume Y, Akatsu H, Murayama S, Sobue G, Yamanaka K
  • Journal Title: EMBO Mol Med Volume: 5 Issue: 2 Pages: 221-234
  • DOI: 10.1002/emmm.201202303
  • Peer Reviewed / Open Access
• [Journal Article] Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins. (2013)
  • Author(s): Shoji Watanabe et al.
  • Journal Title: Journal of Biological Chemistry Volume: 288 Issue: 5 Pages: 3641-3654
  • DOI: 10.1074/jbc.m112.433615
  • Peer Reviewed
• [Journal Article] Critical roles of acetylcholine and the muscarinic and nicotinic acetylcholine receptors in the regulation of immune function (2012)
  • Author(s): 川島 紘一郎
  • Journal Title: Life Sciences Volume: 91 Issue: 21-22 Pages: 1027-1032
  • DOI: 10.1016/j.lfs.2012.05.006
  • Peer Reviewed
• [Journal Article] Osteopontin is an alpha motor neuron marker in the mouse spinal cord (2012)
  • Author(s): Misawa H., et al., 他5名
  • Journal Title: J.Neurosci.Res. Volume: 90 Issue: 4 Pages: 732-742
  • DOI: 10.1002/jnr.22813
  • Peer Reviewed
• [Journal Article] ALS病態におけるグリアの役割 (2012)
  • Author(s): 山下博史、山中宏二
  • Journal Title: 脳21 Volume: 15 Pages: 28-33
• [Journal Article] Substrate-induced internalization of the high-affinity choline transporter (2011)
  • Author(s): Okuda T., et al., 他3名
  • Journal Title: J.Neurosci. Volume: 31 Issue: 42 Pages: 14989-14997
  • DOI: 10.1523/jneurosci.2983-11.2011
  • Peer Reviewed
• [Journal Article] Sustained subcutaneous infusion of nicotine enhances cholinergic vasodilation in the cerebral cortex induced by stimulation of the nucleus basalis of Meynert in rats (2011)
  • Author(s): Uchida S., et al, 他3名
  • Journal Title: Eur.J.Pharmacol. Volume: 654 Issue: 3 Pages: 235-240
  • DOI: 10.1016/j.ejphar.2010.12.029
  • Peer Reviewed
• [Presentation] グリア細胞からみた運動神経変性機序 (2015)
  • Author(s): 山中宏二
  • Organizer: 第34回日本認知症学会学術集会 シンポジウム
  • Place of Presentation: 青森
  • Year and Date: 2015-10-03
  • Invited
• [Presentation] The active roles of glial cells in motor neuron disease. (2015)
  • Author(s): Yamanaka Koji
  • Organizer: The10th Annual GEO-PD(Genetic Epidemiology of Parkinson’s Disease).
  • Place of Presentation: 東京
  • Year and Date: 2015-10-02
  • Int'l Joint Research / Invited
• [Presentation] The role of astrocyte-derived TGF-β in motor neuron disease. (2015)
  • Author(s): Yamanaka Koji
  • Organizer: 26th International Society for Neurochemistry Biennial Meeting
  • Place of Presentation: ケアンズ、豪州
  • Year and Date: 2015-08-23
  • Int'l Joint Research / Invited
• [Presentation] ALSモデルマウスにおける自然免疫TRIF経路の役割 (2015)
  • Author(s): 小峯 起、山下博史、藤森典子、森脇康博、三澤 日出巳、山中宏二
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] 運動ニューロンのサブタイプ選択的脆弱性におけるオステオポンチンとマトリックスメタロプロテアーゼ-9の役割 (2015)
  • Author(s): 森崎祐太、坪田充司、森脇康博、山中宏二、三澤日出巳
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] Pathomechanisms and therapeutic directions common to motor neuron diseases. (2015)
  • Author(s): 山中宏二
  • Organizer: 第56回日本神経学会学術大会 シンポジウム
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with neuroprotective functions of microglia and T cells. (2014)
  • Author(s): Fumito Endo et al.
  • Organizer: 9th Brain Research Conference-Neuroprotection
  • Place of Presentation: ワシントンD.C.（米国）
  • Year and Date: 2014-11-13
• [Presentation] 神経変性疾患ALSにおける自然免疫機構の役割. (2014)
  • Author(s): 山中宏二
  • Organizer: 第37回日本神経科学大会シンポジウム
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-12
  • Invited
• [Presentation] オステオポンチンはマウス脊髄におけるアルファー運動ニューロンサブタイプの新規マーカーである (2014)
  • Author(s): 森﨑 祐太、坪田 充司、森脇 康博、奥田 隆志、山中宏二、三澤 日出巳
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-11
• [Presentation] 筋萎縮性側索硬化症における神経炎症. (2014)
  • Author(s): 遠藤史人、山中宏二
  • Organizer: 第55回日本神経学会学術大会シンポジウム
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2014-05-24
  • Invited
• [Presentation] 筋萎縮性側索硬化症における細胞群特異的病態の解明 (2014)
  • Author(s): 山中宏二
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2014-05-23
  • Invited
• [Presentation] The roles of TGF-β1 in the disease progression of ALS mice. (2013)
  • Author(s): Fumito Endo et al.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego（米国）
  • Year and Date: 2013-11-11
  • Invited
• [Presentation] Motor neuron-derived osteopontin is an aggravation factor in the disease onset of ALS mice. (2013)
  • Author(s): Mamiko Niikura et al.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego（米国）
  • Year and Date: 2013-11-11
  • Invited
• [Presentation] Deletion of TLR-associated signaling adaptor TRIF significantly accelerates disease progression of ALS mice. (2013)
  • Author(s): Okiru Komine et al.
  • Organizer: 11th European Meeting on Glial Cells in Health and Disease
  • Place of Presentation: Berlin（ドイツ）
  • Year and Date: 2013-07-03 – 2013-07-06
  • Invited
• [Presentation] 中枢神経系に浸潤する免疫系細胞とグリア連関の神経変性病態への役割. (2013)
  • Author(s): 山中宏二
  • Organizer: 第36 回日本神経科学大会
  • Place of Presentation: 京都国際会議場（京都）
  • Year and Date: 2013-06-20
  • Invited
• [Presentation] The role of microglia-immune interaction in neurodegeneration of ALS mouse model. (2013)
  • Author(s): Koji Yamanaka
  • Organizer: 2013 conference of International Society for Neurochemistry
  • Place of Presentation: Cancun（メキシコ）
  • Year and Date: 2013-04-22
  • Invited
• [Presentation] Glial cells in experimental models of ALS: from a view of glia-immune communication. (2013)
  • Author(s): Koji Yamanaka
  • Organizer: 3rd Venusberg meeting on Neuroinflammation
  • Place of Presentation: Bonn, Germany
  • Year and Date: 2013-02-28
  • Invited
• [Presentation] 遺伝性ALSモデルにおけるSIRT1の関与 (2012)
  • Author(s): 永津真司ら
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-14
• [Presentation] Roles of TGF-β1 in the disease progression of ALS mice. (2012)
  • Author(s): Fumito Endo et al.
  • Organizer: 23rd international symposium on ALS/MND
  • Place of Presentation: Chicago, USA
  • Year and Date: 2012-12-05
• [Presentation] Elimination of innate immune system adaptor TRIF significantly accelerates disease progression of ALS mice. (2012)
  • Author(s): Okiru Komine et al.
  • Organizer: Society for Neuroscience 2012
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2012-10-12
• [Presentation] The roles of microglia and immune system in neurodegeneration of ALS. (2012)
  • Author(s): Koji Yamanaka
  • Organizer: Neuro2012
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2012-09-18
  • Invited
• [Presentation] Non-autonomous cell deathは、神経変性疾患の共通機構か？ (2012)
  • Author(s): 山中宏二
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Year and Date: 2012-05-23
  • Invited
• [Presentation] Microarray Analysis in Spinal Cords of Sporadic ALS Patients with Cell-Type Specific Transcriptome. (2012)
  • Author(s): Hirofumi Yamashita et al.
  • Organizer: American Academy of Neurology 64th Annual Meeting
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2012-04-21
• [Presentation] The role of glia-immune communication in Amyotrophic Lateral Sclerosis. (2012)
  • Author(s): Koji Yamanaka
  • Organizer: 2012 The Korean Society for Neurodegenerative Disease Symposium
  • Place of Presentation: Seoul, Korea
  • Invited
• [Presentation] Elimination of innate immune system adaptor TRIF significantly accelerates disease progression of ALS mice (2011)
  • Author(s): Yamanaka K, et al, 他2名
  • Organizer: 22nd International Symposium on ALS/MND
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2011-11-30
• [Presentation] 細胞特異的トランスクリプトームを用いた孤発性ALS患者脊髄のDNAマイクロアレイによる解析 (2011)
  • Author(s): 山下博史, 他10名
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-16
• [Presentation] Active roles of glial cells in non-cell autonomous neurodegeneration in ALS (2011)
  • Author(s): Yamanaka K.
  • Organizer: 第34回日本神経科学大会シンポジウム
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2011-09-15
• [Presentation] Recent advances in motor neuron disease : from modeling disease in laboratory animals to understanding human neurodegenerative disease (2011)
  • Author(s): Yamanaka K.
  • Organizer: 2011 KALAS (Korea Association for Laboratory Animal Science) International Symposium
  • Place of Presentation: Muju, Korea(招待講演)
  • Year and Date: 2011-08-25
• [Book] すべてがわかるALS・運動ニューロン疾患 (2013)
  • Author(s): 山中宏二、小峯起
  • Publisher: 中山書店
• [Book] Animal Biotechnology: Models in Discovery and Translation (2013)
  • Author(s): Tsuiji Hitomi, Yamanaka Koji
  • Publisher: Elsevier
• [Book] 実験医学別冊「臓器円環による生体恒常性のダイナミクス」 (2013)
  • Author(s): 山中宏二
  • Publisher: 羊土社
• [Remarks] 名古屋大学環境医学研究所 病態神経科学分野
  • URL: http://www.riem.nagoya-u.ac.jp/4/mnd/index.html
• [Remarks] 名古屋大学プレスリリース：神経難病ALSの進行にグリア細胞由来のTGF-β1が関与
  • URL: http://www.nagoya-u.ac.jp/about-nu/public-relations/researchinfo/upload_images/20150417_riem.pdf
• [Remarks] ALS Research Forum
  • URL: http://www.alsresearchforum.org/in-als-astrocyte-tgf-1-pulls-rug-from-under-motor-neurons/
• [Remarks] 山中宏二研究室 名古屋大学環境医学研究所 病態神経科学分野
  • URL: http://www.riem.nagoya-u.ac.jp/4/mnd/index.html
• [Remarks] 山中宏二研究室 運動ニューロン変性研究チーム
  • URL: http://mnd.brain.riken.jp/index.html
• [Remarks]
  • URL: http://www.brain/.riken.jp/jp/faculty/details/52