Dysfunction of RNA metabolism in TDP-43 proteinopathies: Elucidation of mechanism in stress granule formaion

• Project/Area Number: 23500424
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Hirosaki University
• Principal Investigator: MORI Fumiaki 弘前大学, 医学(系)研究科(研究院), 准教授 (60200383)
• Co-Investigator(Kenkyū-buntansha): TANJI Kunikazu 弘前大学, 大学院・医学研究科, 助教 (10271800) ; WAKABAYASHI Koichi 弘前大学, 大学院・医学研究科, 教授 (50240768)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 神経変性疾患 / ストレス顆粒 / 筋萎縮性側索硬化症 / TDP-43 / FUS / TDP43 / ALS / Optineurin / Ubiquilin2 / CHMP2B / ブニナ小体 / optineurin / TDP43プロテイノパチー

Research Abstract

Stress granules are dense aggregations in the cytosol composed of RNAs and RNA binding proteins that appear when the cell is under stress. To elucidate the significance of stress granule formation in the disease process of neurodegenerative diseases, we examined immunoreactivity for stress granule marker proteins in tauopathies, synucleinopathies, TDP-43 proteinopathies and polyglutamine diseases. Cytoplasmic and nuclear inclusions proved to be immunopositive for stress granule marker proteins, leading to the hypothesis that stress granules play important roles for disease mechanisms in the development of neurodegenerative diseases. These inclusions were also immunopositive for some proteins associated with familial amyotrophic lateral sclerosis (fALS), one of TDP-43 proteinopathies. These results suggested that stress granules marker proteins and fALS-associated proteins may be therapeutic targets to prevent neurodegenerative diseases.

Research Products

• [Journal Article] ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases. (2014)
  • Author(s): Kon T, Mori F, Yanji F, Miki Y, Toyoshima Y, Yoshida M, Sasaki H, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Issue: 1 Pages: 19-26
  • DOI: 10.1111/neup.12056
  • Peer Reviewed
• [Journal Article] Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases. (2014)
  • Author(s): Miki Y, Mori F, Kon T, Tanji K, Toyoshima Y, Yoshida M, Sasaki H, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 34 Issue: 2 Pages: 148-158
  • DOI: 10.1111/neup.12080
  • Peer Reviewed / Open Access
• [Journal Article] FUS colocalizes with polyglutamine, but not with TDP-43 in neuronal intranuclear inclusions in spinocerebellar ataxia type 2. (2014)
  • Author(s): Mori F, Toyoshima Y, Tanji K, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neuropathol Appl Neurobiol Volume: 40 Issue: 3 Pages: 351-355
  • DOI: 10.1111/nan.12075
  • Peer Reviewed / Open Access
• [Journal Article] Ubiquitin-negative, eosinophilic neuronal cytoplasmic inclusions associated with stress granules and autophagy : an immunohistochemical investigation of two cases (2014)
  • Author(s): Mori F, Watanabe Y, Miki Y, Tanji K, Odagiri S, Eto K, Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Pages: 140-147
  • Peer Reviewed
• [Journal Article] Ubiquitin-negative, eosinophilic neuronal cytoplasmic inclusions associated with stress granules and autophagy: an immunohistochemical investigation of two cases. (2014)
  • Author(s): Mori F, Watanabe Y, Miki Y, Tanji K, Eto K, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 34 Issue: 2 Pages: 140-147
  • DOI: 10.1111/neup.12075
  • Peer Reviewed / Open Access
• [Journal Article] Co-localization ofBunina bodies and TDP-43 inclusionsin lower motor neurons in amyotrophiclateral sclerosis (2013)
  • Author(s): Mori F, Kakita A, Takahashi H,Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Issue: 1 Pages: 71-76
  • DOI: 10.1111/neup.12044
  • Peer Reviewed
• [Journal Article] An autopsy case of preclinical multiple system atrophy (MSA-C) (2013)
  • Author(s): Kon T, Mori F, Tanji K, Miki Y, Wakabayashi K
  • Journal Title: Neuropathology Volume: 33 Issue: 6 Pages: 667-672
  • DOI: 10.1111/neup.12037
  • Peer Reviewed
• [Journal Article] Valosin-containing protein immunoreactivity in tauopathies, synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease. (2013)
  • Author(s): Mori F, Tanji K, Toyoshima Y, Sasaki H, Yoshida M, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 33 Issue: 6 Pages: 637-644
  • DOI: 10.1111/neup.12050
  • Peer Reviewed
• [Journal Article] Brain expression level and activity of HDAC6 protein in neurodegenerative dementia. (2013)
  • Author(s): Odagiri S, Tanji K, Mori F, Miki Y, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Biochem Biophys Res Commun Volume: 430 Issue: 1 Pages: 397-399
  • DOI: 10.1016/j.bbrc.2012.11.034
  • Peer Reviewed
• [Journal Article] Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases (2013)
  • Author(s): Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: J Neuropathol Exp Neurol Volume: 72 Issue: 1 Pages: 18-28
  • DOI: 10.1097/nen.0b013e31827b5713
  • Peer Reviewed
• [Journal Article] Abnormal tau deposition in neurons, but not in glial cells in the cerebral tissue surrounding arteriovenous malformation (2012)
  • Author(s): Kon T, et al.
  • Journal Title: Neuropathology Volume: 32 Issue: 3 Pages: 267-271
  • DOI: 10.1111/j.1440-1789.2011.01249.x
  • Peer Reviewed
• [Journal Article] FUS immunoreactivity of neuronal and glial intranuclear inclusions in intranuclear inclusion body disease (2012)
  • Author(s): Mori F, et al.
  • Journal Title: Neuropathol Appl Neurobiol Volume: 38 Issue: 4 Pages: 322-328
  • DOI: 10.1111/j.1365-2990.2011.01217.x
  • Peer Reviewed
• [Journal Article] Status epilepticus associated with extensive axonal swelling in the unilateral cerebral cortex and hippocampus (2012)
  • Author(s): Mori F, et al.
  • Journal Title: Neuropathol Appl Neurobiol Volume: 38 Issue: 4 Pages: 387-390
  • DOI: 10.1111/j.1365-2990.2011.01223.x
  • Peer Reviewed
• [Journal Article] Ubiquitin-related proteins in neuronal and glial intranuclear inclusions in intranuclear inclusion body disease. (2012)
  • Author(s): Mori F, Tanji K, Odagiri S, Hattori M, Hoshikawa Y, Kono C, Yasui K, Yokoi S, Hasegawa Y, Kamitani T, Yoshida M, Wakabayashi K.
  • Journal Title: Pathol Int Volume: 62 Issue: 6 Pages: 407-411
  • DOI: 10.1111/j.1440-1827.2012.02812.x
  • Peer Reviewed
• [Journal Article] Ubiquilin immunoreactivity in cytoplasmic and nuclear inclusions in synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease. (2012)
  • Author(s): Mori F, Tanji K, Odagiri S, Toyoshima Y, Yoshida M, Ikeda T, Sasaki H, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Acta Neuropathol Volume: 124 Issue: 1 Pages: 149-151
  • DOI: 10.1007/s00401-012-0999-z
  • Peer Reviewed
• [Journal Article] Autophagy-related proteins (p62, NBR1 and LC3) in intranuclear inclusions in neurodegenerative diseases. (2012)
  • Author(s): Mori F, Tanji K, Odagiri S, Toyoshima Y, Yoshida M, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 522 Issue: 2 Pages: 134-138
  • DOI: 10.1016/j.neulet.2012.06.026
  • Peer Reviewed
• [Journal Article] Optineurin immunoreactivity in neuronal nuclear inclusions of polyglutamine diseases (Huntington's, DRPLA, SCA2, SCA3) and intranuclear inclusion body disease (2012)
  • Author(s): Mori F, et al.
  • Journal Title: Acta Neuropathol Volume: 123 Issue: 5 Pages: 747-749
  • DOI: 10.1007/s00401-012-0956-x
  • Peer Reviewed
• [Journal Article] Amyotrophic lateral sclerosis with demyelinating neuropathy (2012)
  • Author(s): Nishijima H, Tomiyama M, Suzuki C, Kon T, Funamizu Y, Ueno T, Haga R, Miki Y, Arai A, Kimura T, Mori F, Wakabayashi K, Baba M
  • Journal Title: Intern Med Volume: 51 Pages: 1917-1921
  • NAID: 130002062234
  • URL: http://DN/JST.JSTAGE/internalmedicine/51.7246
  • Peer Reviewed
• [Journal Article] Immunohistochemical analysis of Marinesco bodies, using antibodies against proteins implicated in the ubiquitin-proteasome system, autophagy and aggresome formation (2012)
  • Author(s): Odagiri S, et al.
  • Journal Title: Neuropathology Volume: 32 Issue: 3 Pages: 261-266
  • DOI: 10.1111/j.1440-1789.2011.01267.x
  • Peer Reviewed
• [Journal Article] Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in α-synucleinopathy (2012)
  • Author(s): Odagiri S, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Acta Neuropathol Volume: (in press) Issue: 2 Pages: 173-186
  • DOI: 10.1007/s00401-012-0975-7
  • NAID: 110009614141
  • Peer Reviewed
• [Journal Article] Endosomal sorting related protein CHMP2B is localized in Lewy bodies and glial cytoplasmic inclusions in alpha-synucleinopathy. (2012)
  • Author(s): Tanikawa S, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 527 Issue: 1 Pages: 16-21
  • DOI: 10.1016/j.neulet.2012.08.035
  • Peer Reviewed
• [Journal Article] Alteration of autophagosomal proteins in the brain of multiple system atrophy. (2012)
  • Author(s): Tanji K, Odagiri S, Maruyama A, Mori F, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neurobiol Dis Volume: 49C Pages: 190-198
  • DOI: 10.1016/j.nbd.2012.08.017
  • Peer Reviewed
• [Journal Article] p62/sequestosome 1 binds to TDP-43 in the brains of frontotemporal lobar degeneration with TDP-43 inclusions (2012)
  • Author(s): Tanji K, et al.
  • Journal Title: J Neurosci Res Volume: 90(印刷中) Issue: 10 Pages: 2034-2042
  • DOI: 10.1002/jnr.23081
  • Peer Reviewed
• [Journal Article] Amyotrophic lateral sclerosis with demyelinating neuropathy. (2012)
  • Author(s): Nishijima H, Tomiyama M, Suzuki C, Kon T, Funamizu Y, Ueno T, Haga R, Miki Y, Arai A, Kimura T, Mori F, Wakabayashi K, Baba M.
  • Journal Title: Intern Med Volume: 51 Pages: 1917-1921
  • NAID: 130002062234
  • Peer Reviewed
• [Journal Article] Dysfunction of extrasynaptic GABAergic transmission in PRIP-1 KO mice is associated with an epilepsy phenotype (2011)
  • Author(s): Zhu G., Yoshida S., Migita K., Yamada J., Ueno S
  • Journal Title: J Pharmacol Exp Ther Volume: 340(3) Issue: 3 Pages: 520-8
  • DOI: 10.1124/jpet.111.182386
  • URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22128345
  • Peer Reviewed
• [Journal Article] The AAA-A TPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting of alpha-Synuclein (2011)
  • Author(s): Hasegawa T, Konno M, Baba T, Sugeno N, Kikuchi A, Kobayashi M, Miura E, Tanaka N, Tamai K, Furukawa K, Arai H, Mori F, Wakabayashi K, Aoki M, Itoyama Y, Takeda A
  • Journal Title: PLoS One Volume: 6 Issue: 12 Pages: 1-14
  • DOI: 10.1371/journal.pone.0029460
  • Peer Reviewed
• [Journal Article] Immunohistochemical study of microscopic globular bodies of normal human brain (2011)
  • Author(s): Odagiri S, Mori F, Tanji K, Kuroda N, Wakabayashi K
  • Journal Title: Biomed Res Volume: 32 Pages: 337-342
  • NAID: 130004724060
  • URL: http://JST.JSTAGE/biomedres/32.337
  • Peer Reviewed
• [Journal Article] Syinpilin 1-binding protein NUB1 is colocalized with nonfibrillar, proteinase K-resistant・-synuclein in presynapses in Lewy Body disease (2011)
  • Author(s): Tanji K, Mori F, Kito K, Kakita A, Mimura J, Itoh K, Takahashi H, Kamitani T, Wakabayashi K
  • Journal Title: J Neuropathol Exp Neurol Volume: 70 Issue: 10 Pages: 879-889
  • DOI: 10.1097/nen.0b013e3182303745
  • Peer Reviewed
• [Journal Article] Ubiquitin-related proteins in neuronal and glial intranuclear inclusions in intranuclear inclusion body disease (2011)
  • Author(s): Mori F, Tanji K, Odagiri S, Hattori M, Hoshikawa Y, Kono C, Yasui K, Yokoi S, Hasegawa Y, Kamitani T, Yoshida M, Wakabayashi K
  • Journal Title: Pathol Int Volume: 印刷中
  • Peer Reviewed
• [Journal Article] 筋萎縮性硬化症とTDP43 (2011)
  • Author(s): 森 文秋、丹治邦和、若林孝一
  • Journal Title: Cognition and Dementia Volume: 10 Pages: 113-120
• [Journal Article] Alteration of autophagosomal protein (LC3, GABARAP and GATE-16) in Lewy body disease (2011)
  • Author(s): Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neurobiol Dis Volume: 43 Issue: 3 Pages: 690-697
  • DOI: 10.1016/j.nbd.2011.05.022
  • Peer Reviewed
• [Presentation] 神経変性疾患におけるユビキリンの免疫組織化学的検討 (2013)
  • Author(s): 森 文秋, 丹治邦和, 豊島靖子, 佐々木秀直, 吉田眞理, 柿田明美, 高橋 均, 若林孝一
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: 東京
• [Presentation] 神経変性疾患におけるvalosin-containing protein の免疫組織化学的検討 (2013)
  • Author(s): 森 文秋, 丹治邦和, 豊島靖子, 佐々木秀直, 吉田眞理, 柿田明美, 高橋均, 若林孝一
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: 東京
• [Presentation] 神経変性疾患におけるユビキリンの免疫組織化学的検討 (2013)
  • Author(s): 森 文秋、丹治邦和、豊島靖子、佐々木秀直、吉田眞理、柿田明美、高橋均、若林孝一．
  • Organizer: 日本神経病理学会
  • Place of Presentation: 東京
• [Presentation] 神経変性疾患におけるvalosin-containing proteinの免疫組織化学的検討 (2013)
  • Author(s): 森 文秋、丹治邦和、豊島靖子、佐々木秀直、吉田眞理、柿田明美、高橋均、若林孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: 東京
• [Presentation] 筋萎縮性側索硬化症における TDP43と Bunina 小体との関わり (2012)
  • Author(s): 森 文秋, 柿田 明美, 高橋 均, 若林孝一
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] ポリグルタミン病と核内封入体病におけるオートファジー関連蛋白の発現 (2012)
  • Author(s): 森 文秋, 丹治邦和, 小田桐紗織, 豊島靖子, 柿田明美, 吉田眞理, 高橋 均, 若林孝一
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] ポリグルタミン病と核内封入体病におけるoptineurin の発現 (2012)
  • Author(s): 森 文秋, 丹治邦和, 豊島靖子, 柿田明美, 吉田眞理, 高橋 均, 若林孝一
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] 核内封入体病におけるユビキチン関連蛋白の免疫組織化学的検討 (2012)
  • Author(s): 森 文秋, 丹治邦和, 小田桐紗織, 服部 学, 星川恭子, 河野親夫, 安井敬三, 横井聡, 長谷川康博, 神谷 哲, 吉田真理, 若林孝一
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] TDP-43 と Bunina小体の関わり (2012)
  • Author(s): 森 文秋、柿田 明美、高橋 均、若林 孝一
  • Organizer: 第５３回 日本神経病理学会
  • Place of Presentation: 新潟
  • Invited
• [Presentation] ポリグルタミン病と核内封入体病におけるoptineurin の発現 (2012)
  • Author(s): 森 文秋、丹治邦和、豊島靖子、柿田明美、吉田眞理、高橋 均、若林孝一
  • Organizer: 第５３回 日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] ポリグルタミン病と核内封入体病におけるオ－トファジー関連蛋白の発現 (2012)
  • Author(s): 森 文秋、丹治邦和、小田桐紗織、豊島靖子、柿田明美、吉田眞理、高橋 均、若林孝一
  • Organizer: 第５３回 日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] Immunoreactivity of ubiquitin-related proteins in neuronal and glial intranuclear inclusions in intranuclear inclusion body disease (2011)
  • Author(s): Fumiaki Mori, Kunikazu Tanji, Saori Odagiri, Manabu Hattori, Yasuko Hoshikawa, Chikao Kono, Keizo Yasui, Satoshi Yokoi, Yasuhiro Hasegawa, Mari Yoshida, and Koichi Wakabayashi
  • Organizer: The 2nd Cngress of Asian Society of Neuropathology
  • Place of Presentation: Bejin, China
• [Presentation] 軸索腫脹を伴う層状壊死を左大脳半球優位に認めた痙攣重積の 1 剖検例 (2011)
  • Author(s): 森 文秋, 丹治邦和, 三木 康生, 西嶌 春生, 馬場 正之, 黒滝 日出一, 若林孝一
  • Organizer: 第52回日本神経病理学会
  • Place of Presentation: 京都
• [Presentation] 核内封入体病における FUS の免疫組織化学的検討 (2011)
  • Author(s): 森 文秋, 丹治邦和, 今 智矢, 小田桐紗織, 服部 学, 星川恭子, 河野親夫, 安井敬三, 横井聡, 長谷川康博, 吉田真理, 若林孝一
  • Organizer: 第52回日本神経病理学会
  • Place of Presentation: 京都
• [Presentation] Immunoreactivity of ubiquitin-related proteins in neuronal and glial intranuclear inclusions in intranuclear inclusion body disease (2011)
  • Author(s): Mori F, Tanji K, Odagiri S, Hattori M, Hoshikawa Y, Kono C, Yasui K, Yokoi S, Hasegawa Y, Kamitani T, Yoshida M, Wakabayashi K
  • Organizer: The Second Congress of Asian Society of Neuropathology
  • Place of Presentation: Beijing, China
• [Presentation] 熱処理後proteinase K処理によるTDP-43免疫染色性の増強 (2011)
  • Author(s): 森 文秋、丹治 邦和、柿田 明美、高橋 均、若林 孝一
  • Organizer: 第52回日本神経病理学会
  • Place of Presentation: 京都
• [Presentation] 核内封入体病におけるFUSの免疫組織化学的検討 (2011)
  • Author(s): 森 文秋、丹治邦和、今 智矢、小田桐紗織、服部 学、星川恭子、河野親夫、安井敬三、横井聡、長谷川康博、吉田真理、若林孝一
  • Organizer: 第52回日本神経病理学会
  • Place of Presentation: 京都
• [Presentation] 軸索腫脹を伴う層状壊死を左大脳半球優位に認めた痙攣重積の1剖検例 (2011)
  • Author(s): 森 文秋、丹治 邦和、三木 康生、西嶌 春生、馬場 正之、黒滝 日出一、若林 孝一
  • Organizer: 第52回日本神経病理学会
  • Place of Presentation: 京都