名古屋大学環境医学研究所

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病態神経科学分野(病態神経科学

教員紹介

教授
YAMANAKA Koji
講師
KOMINE Okiru
講師
WATANABE Seiji
特任講師
ENDO Fumito
特任助教
SOBUE Akira
特任助教
KAWADE Noe
特任助教
SHIMOHATA Atsushi
特任助教
大岩 康太郎
OIWA Kotaro
特任助教
SHINNO Kanako
メンバー

研究内容

多くの遺伝性神経変性疾患の病因遺伝子が同定されていますが, その発症や疾患進行機序に関してはいまだ解明されていません. 当研究室では, 神経変性疾患の病態解明を目標として,特に筋萎縮性側索硬化症(ALS)とアルツハイマー病(AD)について研究を行っています. 当研究室でのこれまでの研究により, ALSの発症に必要な病的変化は運動ニューロンに起因し, 疾患の進行に関しては非神経細胞であるグリア細胞に起こる病的変化が寄与していることが明らかになりました. 当研究室では, 神経細胞内で起こる病的変化(タンパク質のフォールディングや分解の異常、RNA代謝異常など)とグリア細胞で起こる病的変化(神経炎症の異常など)の両面から神経変性疾患の病態を解明し, 新たな治療戦略を構築することを目指しています

研究実績

発表論文
  1. Wang T, Sobue A, Watanabe S, Komine O, Saido TC, Saito T, and Yamanaka K. Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer's disease. Journal of Neuroinflammation 21(1), 55, 2024.
  2. Komine O, Ohnuma S, Hinohara K, Hara Y, Shimada M, Akashi T, Watanabe S, Sobue A, Kawade N, Ogi T, and Yamanaka K. Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice. iScience 27(2), 108872, 2024.
  3. Watanabe S, Murata Y, Oka Y, Horiuchi M, Iguchi Y, Komine O, Sobue A, Okada Y, Katsuno M, Ogi T, and Yamanaka K. Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS. Proceedings of the National Academy of Sciences of the United States of America 120(47): e2315347120, 2023.
  4. Oiwa K, Watanabe S, Onodera K, Iguchi Y, Kinoshita Y, Komine O, Sobue A, Okada Y, Katsuno M, and Yamanaka K. Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis. Science Advances 9(31): eadf6895, 2023.
  5. Hashimoto K, Watanabe S, Akutu M, Mukai N, Kamishina H, Furukawa Y, and Yamanaka K. Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy-linked E40K mutation. Journal of Biological Chemistry 299(6): 104798, 2023.
  6. Watanabe S, Horiuchi M, Murata Y, Komine O, Kawade N, Sobue A, and Yamanaka K. Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis. Neurobiology of Disease 2: 179 106031, 2023.
  7. Sakai S, Watanabe S, Komine O, Sobue A, and Yamanaka K. Novel reporters of mitochondria-associated membranes (MAM), MAMtrackers, demonstrate MAM disruption as a common pathological feature in amyotrophic lateral sclerosis. The FASEB Journal e21688, 2021.
  8. Sobue A, Komine O, Hara Y, Endo F, Mizoguchi H, Watanabe S, Murayama S, Saito T, Saido T, Sahara N, Higuchi M, Ogi T and Yamanaka K. Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease. Acta Neuropathologica Communications 9: 1, 2021.
  9. Watanabe S, Inami H, Oiwa K, Murata Y, Sakai S, Komine O, Sobue A, Iguchi Y, Katsuno M, Yamanaka K. Aggresome formation and liquid–liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43. Cell Death & Disease 11: 909, 2020.
  10. Watanabe S, Oiwa K, Murata Y, Komine O, Sobue A, Endo F, Takahashi E and Yamanaka K. ALS-linked TDP-43M337V knock-in mice exhibit splicing deregulation without neurodegeneration. Molecular Brain 13: 8, 2020.
  11. Nishino K, Watanabe S, Jin S, Murata Y, Oiwa K, Komine O, Endo F, Tsuiji H, Abe M, Sakimura K, Mishra A, Yamanaka K. Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway. Acta Neuropathologica Communications 7(1): 118, 2019.
  12. Komine O, Yamashita H, Fujimori-Tonou N, Koike M, Jin S, Moriwaki Y, Endo F, Watanabe S, Uematsu S, Akira S, Uchiyama Y, Takahashi R, Misawa H, Yamanaka K. Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes. Cell Death & Differentiation 25: 2130-2146, 2018.
  13. Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, Jin S, Mancias P, Kiyama H, Yamanaka K. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mololecular Medicine 8(12): 1421-1437, 2016.
  14. Endo F, Komine O, Fujimori-Tonou N, Jin S, Watanabe S, Katsuno M, Sobue G, Dezawa M, Wyss-Coray T, Yamanaka K. Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Reports 11: 592, 2015.
  15. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, & Cleveland DW. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neuroscience 11: 251-253, 2008.
  16. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, KassiotisG, KolliasG, Cleveland DW. Onset and Progression in Inherited ALS determined by Motor Neurons and Microglia. Science 312: 1389-1392, 2006.
著書・総説
  1. 山中宏二. ミクログリアと神経変性疾患. 実験医学増刊「神経免疫 メカニズムと疾患 神経系と免疫系を結ぶ分子機構の解明からバイオマーカー・治療標的の探索まで」(羊土社) 39(15): 109-114, 2021.
  2. 渡邊征爾,山中宏二.筋萎縮性側索硬化症におけるMAMの破綻.実験医学増刊 「ミトコンドリアと疾患・老化」,37(12):138-144, 2019.
  3. Yamanaka K, Komine O. The multi-dimensional roles of astrocytes in ALS. Neuroscience Research 126: 31-38, 2018.
  4. Endo F, Komine O, Yamanaka K. Neuroinflammation in motor neuron disease. Clinical and Experimental Neuroimmunology 7: 126-138, 2016.
  5. Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurology 14: 388-405, 2015.