Disruption of mitochondria-associated membrane in neurodegenerative disease

• Project/Area Number: 25860252
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: Watanabe Seiji 名古屋大学, 環境医学研究所, 助教 (70633577)
• Co-Investigator(Renkei-kenkyūsha): YAMANAKA Koji 名古屋大学, 環境医学研究所, 教授 (80446533)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 筋萎縮性側索硬化症 / 小胞体・ミトコンドリア膜間領域 / SOD1 / σ1受容体

Outline of Final Research Achievements

We identified a homozygous p.L95fs mutation of Sigma 1 receptor (Sig1R) as a novel cause of ALS16. ALS‐linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5‐triphosphate receptor type 3 (IP3R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)‐mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP3R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R‐ and SOD1‐linked ALS. Furthermore, our discovery of the selective enrichment of IP3R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.

Research Products

• [Int'l Joint Research] ジョンホプキンス大学/テキサス大学医学部ヒューストン校/ヒューストンメソジスト病院(米国)
• [Journal Article] Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis (2017)
  • Author(s): Eiichi Tokuda, Itsuki Anzai, Takao Nomura, Keisuke Toichi, Masahiko Watanabe, Shinji Ohara, Seiji Watanabe, Koji Yamanaka, Yuta Morisaki, Hidemi Misawa, and Yoshiaki Furukawa
  • Journal Title: Molecular Neurodegeneration Volume: 12 Issue: 1 Pages: 2-2
  • DOI: 10.1186/s13024-016-0145-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. (2016)
  • Author(s): Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, Jin S, Mancias P, Kiyama H, *Yamanaka K.
  • Journal Title: EMBO Molecular Medicine Volume: 8 Issue: 12 Pages: 1421-1437
  • DOI: 10.15252/emmm.201606403
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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] 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, Fujimori-Tonou N, Katsuno M, Jin S, Watanabe S, Sobue G, Dezawa M, Wyss-Coray T, Yamanaka K
  • Journal Title: Cell Reports Volume: 11 Issue: 4 Pages: 592-604
  • DOI: 10.1016/j.celrep.2015.03.053
  • Peer Reviewed / Open Access / Int'l Joint Research / 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] 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] 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] Crucial roles of glu60 in human neuroglobin as a Guanine nucleotide dissociation inhibitor and neuroprotective agent. (2013)
  • Author(s): Takahashi N, Watanabe S, Wakasugi K
  • Journal Title: PLOS ONE Volume: 8 Issue: 12 Pages: e83698-e83698
  • DOI: 10.1371/journal.pone.0083698
  • Peer Reviewed
• [Presentation] Neuregulin 1 confers neuroprotection in SOD1-linked ALS mice via restoration of C-boutons of spinal motor neurons. (2016)
  • Author(s): Komine O, Lasiene J, Fujimori-Tonou N, Powers B, Endo F, Watanabe S, Jin S, Ravits J, Horner P, Misawa H, Yamanaka K.
  • Organizer: The 27th International Symposium on ALS/MND
  • Place of Presentation: アイルランド, ダブリン
  • Year and Date: 2016-12-07
  • Int'l Joint Research
• [Presentation] Disruption of Mitochondria-associated membrance is a common pathomechanism both in SOD1-and SIGMAR1-linked ALS. (2016)
  • Author(s): Watanabe S, Yamanaka K
  • Organizer: The 27th International Symposium on ALS/MND
  • Place of Presentation: アイルランド, ダブリン
  • Year and Date: 2016-12-07
  • Int'l Joint Research
• [Presentation] In vivo and in vitro characterization of SOD1 in early stages of ALS as a precursor to insoluble aggregates. (2016)
  • Author(s): Tokuda E, Anzai I, Nomura T, Ohara S, Watanabe S, Yamanaka K, Morisaki Y, Misawa H, Furukawa Y.
  • Organizer: The 27th International Symposium on ALS/MND
  • Place of Presentation: アイルランド, ダブリン
  • Year and Date: 2016-12-07
  • Int'l Joint Research
• [Presentation] Disruption of mitochondria associated membrane in amyotrophic lateral sclerosis. (2016)
  • Author(s): Watanabe S, Yamanaka K
  • Organizer: 第６回生理学研究所・名古屋大学医学系研究科合同シンポジウム
  • Place of Presentation: 名古屋大学鶴舞キャンパス
  • Year and Date: 2016-09-24
• [Presentation] ALSにおけるミトコンドリア・小胞体膜間領域の破綻 (2016)
  • Author(s): 渡邉征爾
  • Organizer: 第39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
  • Year and Date: 2016-07-20
  • Invited
• [Presentation] Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 and is defective in ALS mice. 26th International Symposium on ALS/MLD (2015)
  • Author(s): Chhangani D, Endo F, Amanullah A, Watanabe S, Mishra R, Mishra A, Yamanaka K
  • Organizer: 26th International Symposium on ALS/MLD
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] Calcium deregulation atmitochondria-associated membrane is important for motor neuronal degeneration in amyotrophic lateral sclerosis. (2015)
  • Author(s): Watanabe S, Yamanaka K
  • Organizer: BMB2015(第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会)
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] The role of innate immune TRIF pathway in amyotrophic lateral sclerosis. (2015)
  • Author(s): 小峯起、山下博史、藤森典子、森脇康博、遠藤史人、渡邊征爾、金世杰、三澤日出巳、山中宏二
  • Organizer: 第5回名古屋大学医学系研究科・生理学研究所合同シンポジウム
  • Place of Presentation: 生理学研究所
  • Year and Date: 2015-09-19
• [Presentation] アストロサイト由来TGF-β1はALSの疾患進行を規定する. (2015)
  • Author(s): 遠藤史人、小峯 起、金 世杰、渡邊征爾、山中宏二
  • Organizer: 第27回 日本神経免疫学会学術集会
  • Place of Presentation: 長良川国際会議場
  • Year and Date: 2015-09-15
• [Presentation] Sigma 1 receptor deficiency is involved in motor neuronal degeneration through calcium deregulation at mitochondria-associated membrane. (2015)
  • Author(s): 渡邊征爾、山中宏二
  • Organizer: 第58回 日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ
  • Year and Date: 2015-09-11
• [Presentation] Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by regulating the neuroprotective inflammatory response of microglia and T cells. (2015)
  • Author(s): 山中宏二、遠藤史人、小峯起、金世杰、渡邊征爾
  • Organizer: 第58回 日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ
  • Year and Date: 2015-09-11
• [Presentation] Coordinated activation of autophagy and Cathepsin-mediated proteolysis inhibition is essential for neuroprotection by Cystatin C against mutant SOD1-mediated toxicity. (2014)
  • Author(s): Watanabe S, Wakasugi K, Yamanaka K
  • Organizer: 25th International Symposium on ALS/MND
  • Place of Presentation: Brussels, Belgium
  • Year and Date: 2014-12-05 – 2014-12-07
• [Presentation] 変異SOD1由来の毒性に対するシスタチンCの神経細胞保護機構の解明 (2014)
  • Author(s): 渡邊征爾, 若杉桂輔, 山中宏二
  • Organizer: 第37回 日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Cystatin C protected neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity in vitro. (2013)
  • Author(s): Seiji Watanabe, Keisuke Wakasugi, Koji Yamanaka
  • Organizer: 24th International Symposium on ALS/MND
  • Place of Presentation: Milan, Italy
• [Presentation] 変異スーパーオキシドジスムターゼ1（SOD1）はSOD1（G93A）マウスにおいてミトコンドリア・小胞体膜間領域に蓄積する (2013)
  • Author(s): 渡邊征爾, 山中宏二
  • Organizer: Neuro2013（第36回 日本神経科学大会・第56回 日本神経化学会大会・第23回 日本神経回路学会大会 合同大会）
  • Place of Presentation: 国立京都国際会館
• [Remarks] 小胞体とミトコンドリア接触部の崩壊が神経難病 ALS の発症の鍵となる
  • URL: http://www.nagoya-u.ac.jp/about-nu/public-relations/researchinfo/upload_images/20161108_riem.pdf
• [Remarks] 長寿遺伝子産物 SIRT1の活性化で 神経難病 ALS マウスが延命（名古屋大学 プレスリリース）
  • URL: http://www.nagoya-u.ac.jp/about-nu/public-relations/researchinfo/upload_images/20140909_riem.pdf