Amyotrophic lateral sclerosis and TDP-43 : elucidation of the entire neuropathological picture and molecular pathomechanism

2010 Fiscal Year Final Research Report

• Project/Area Number: 20240037
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Niigata University
• Principal Investigator: TAKAHASHI Hitoshi Niigata University, 脳研究所, 教授 (90206839)
• Co-Investigator(Kenkyū-buntansha): TAN ChenーFeng 新潟大学, 脳研究所, 助教 (40447610) ; TOYOSHIMA Yasuko 新潟大学, 脳研究所, 助教 (20334675) ; ONODERA Osamu 新潟大学, 脳研究所, 准教授 (20303167)
• Co-Investigator(Renkei-kenkyūsha): KAKITA Akiyoshi 新潟大学, 脳研究所, 准教授 (80281012) ; SAKIMURA Kenji 新潟大学, 脳研究所, 教授 (40162325) ; KUWANO Ryozo 新潟大学, 脳研究所, 教授 (20111734) ; YOKOYAMA Minesuke 新潟大学, 脳研究所, 教授 (40090930)
• Project Period (FY): 2008 – 2010
• Keywords: 神経変性疾患 / 筋萎縮性側索硬化症

Research Abstract

We examined clinicopathologically and immunohistochemically a large series of sporadic amyotrophic lateral sclerosis (SALS) cases, including those having long disease durations with artificial respiratory support. In each case, various brain regions were immunostained with an antibody against TDP-43, showing occurrence of TDP-43-positive neuronal (NCIs) and glial cytoplasmic inclusions in many regions, including the lower motor neuron nuclei. The results obtained indicate that SALS is a multisystem neuro-glial proteinopathy of TDP-43 and can show two pathological phenotypes (types 1 and 2 ; type 2 can be distinguished from type 1 by the presence of TDP-43-positive NCIs in the frontotemoral cortex, hippocampal formation, neostriatum and substantia nigra). We also generated a transgenic TDP-43 KO mouse model for further biochemical and molecular analyses on the pathomechanisms underlying SALS. The several data obtained strongly suggest that our next target is "splicing abnormalities of TDP-43".

Research Products

• [Journal Article] An inducer of VGF protecs cells against ER stress-induced cell death and prolongs survival in the mutant SOD1 animal models of familial ALS. (2010)
  • Author(s): Shimazawa M, Tanaka H, Ito Y, Morimoto N, Tsurumi K, Kadokura M, Tamura S, Inoue T, Yamada M, Takahashi H, Warita H, Aoki M, Hara H.
  • Journal Title: PLos One 5 Pages: e15307
  • Peer Reviewed
• [Journal Article] Involvement of Onuf's nucleus in Machado-Joseph disease : a morphometric and immunohistochemical study. (2010)
  • Author(s): Shimizu H, Yamada M, Toyoshima Y, Ikeuchi T, Onodera O, Takahashi H.
  • Journal Title: Acta Neuropathol 120 Pages: 439-448
  • Peer Reviewed
• [Journal Article] Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease : a distinct clinicopathological and biochemical disease entity. (2010)
  • Author(s): Fu Y-J, Nishihira Y, Kuroda S, Toyoshima Y, Ishihara T, Shinozaki M, Miyashita A, Piao Y-S, Tan C-F, Tani T, Koike R, Iwanaga K, Tsujihata M, Onodera O, Kuwano R, Nishizawa M, Kakita A, Ikeuchi T, Takahashi H.
  • Journal Title: Acta Neuropathol 120 Pages: 21-32
  • Peer Reviewed
• [Journal Article] Relationship between Bunina bodies and TDP-43 inclusins in spinal anterior horn in amyotrophic lateral sclerpsis. (2010)
  • Author(s): Mori F, Tanji K, Miki Y, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neuropathol Appl Neurobiol 36 Pages: 345-352
  • Peer Reviewed
• [Journal Article] Increased expression and activation of cytosolic phospholipase A_2 in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. (2010)
  • Author(s): Shibata N, Kakita A, Takahashi H, Ihara Y, Nobukuni K, Fujinami H, Sakoda S, Kobayashi M.
  • Journal Title: Acta Neuropathol 119 Pages: 345-354
  • Peer Reviewed
• [Journal Article] Involvement of CHOP, an ER-stress apoptotic mediator, in both human sporadic ALS and ALS model mice. (2009)
  • Author(s): Ito Y, Yamada M, Tanaka H, Aida K, Tsuruma K, Shimazawa M, Hozumi I, Inuzuka T, Takahashi H, Hara H.
  • Journal Title: Neurobiol Dis 36 Pages: 470-476
  • Peer Reviewed
• [Journal Article] Persistent cleavage and nuclear translocation of apoptosis-inducing factor in motor neurons in the spinal cord of sporadic amyotrophic lateral sclerosis patients. (2009)
  • Author(s): Shibata N, Kakita A, Takahashi H, Ihara Y, Nobukuni K, Fujumura H, Sakoda S, Sasaki S, Yamamoto T, Kobayashi M.
  • Journal Title: Acta Neuropathol 118 Pages: 755-762
  • Peer Reviewed
• [Journal Article] Sporadic amyotrophic lateral sclerosis : widespread multisystem degeneration with TDP-43 pathology in a patient after long-term survival on a respirator. (2009)
  • Author(s): Nishihira Y, Tan C-F, Toyoshima Y, Yonemochi Y, Kondo H, Nakajima T, Takahashi H.
  • Journal Title: Neuropathology 29 Pages: 689-696
  • Peer Reviewed
• [Journal Article] Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease. (2009)
  • Author(s): Tan C-F, Yamada M, Toyoshima Y, Yokseki A, Miki Y, Hoshi Y, Kaneko H, Ikeuchi T, Onodera O, Kakita A, Takahashi H.
  • Journal Title: Acta Neuropathol 118 Pages: 553-560
  • Peer Reviewed
• [Journal Article] Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. (2009)
  • Author(s): Nishihira Y, Tan C-F, Hoshi Y, Iwanaga K, Yamada M, Kawachi I, Tsujihata M, Hozumi I, Morita T, Onodera O, Nishizawa M, Kakita A, Takahashi H.
  • Journal Title: Acta Neuropathol 117 Pages: 45-53
  • Peer Reviewed
• [Journal Article] Spinal anterior horn cells in sporadic amyotrophic lateral sclerosis show ribosomal detachment from, and cisternal distention of the rough endoplasmic reticulum. (2008)
  • Author(s): Oyanagi K, Yamazaki M, Takahashi H, Watabe K, Wada M, Komori T, Morita T, Mizutani T.
  • Journal Title: Neuropathol Appl Neurobiol 34 Pages: 650-658
  • Peer Reviewed
• [Journal Article] The expression of metallothioneins is diminished in the spinal cords of patients with sporadic amyotrophic lateral sclerosis. (2008)
  • Author(s): Hozumi I, Yamada M, Uchida Y, Ozawa K, Takahashi H, Inuzuka T.
  • Journal Title: Amyotroph Lateral Scler 9 Pages: 294-298
  • Peer Reviewed
• [Journal Article] Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. (2008)
  • Author(s): Mori F, Tanji K, Zhang H-X, Nishihira Y, Tan C-F, Takahashi H, Wakabayashi K.
  • Journal Title: Acta Neuropathol 116 Pages: 193-203
  • Peer Reviewed
• [Journal Article] Sporadic amyotrophic lateral sclerosis : two pathological patterns shown by analysis of distribution of TDP-43-immunreactive neuronal and glial cytoplasmic inclusions. (2008)
  • Author(s): Nishihira Y, Tan C-F, Onodera O, Toyoshima Y, Yamada M, Morita T, Nishizawa M, Kakita A, Takahashi H.
  • Journal Title: Acta Neuropathol 116 Pages: 169-182
  • Peer Reviewed
• [Journal Article] TDP-43 mutation in familial amyotrophic lateral sclerosis. (2008)
  • Author(s): Yokoseki A, Shiga A, Tan C-F, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A, Okamoto K, Nishizawa M, Takahashi H, Onodera O.
  • Journal Title: Ann Neurol 63 Pages: 538-542
  • Peer Reviewed
• [Journal Article] TDP-43-immunoreactive neuronal and glial inclusions in the neostriatum in amyotrophic lateral sclerosis with and without dementia. (2008)
  • Author(s): Zhang H, Tan C-F, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Acta Neuropathol 115 Pages: 115-122
  • Peer Reviewed
• [Journal Article] Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis.
  • Author(s): Soma K, Fu J-Y, Wakabayashi K, Onodera O, Kakita A, Takahashi H.
  • Journal Title: Neuropathol Appl Neurobiol in press
  • Peer Reviewed
• [Presentation] Pathological TDP-43 in a case of primary lateral sclerosis. (2010)
  • Author(s): 付永娟, et al.
  • Organizer: 7th International Conference on Frontotemporal Dementias
  • Place of Presentation: Indianapolis, USA
  • Year and Date: 2010-10-06
• [Presentation] An autopsy case of amyotrophic lateral sclerosis showing an upper-motor predominant form with frontotemporal lobar degeneration. (2010)
  • Author(s): 付永娟, et al.
  • Organizer: 17th International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
  • Year and Date: 2010-09-12
• [Presentation] 前頭側頭葉変性症(FTLD)に属する新規4リピートタウオパチー:3剖検例におけるその臨床病理と生化学所見 (2010)
  • Author(s): 付永娟, ほか
  • Organizer: 第51回日本神経病理学会総会学術研究会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-24
• [Presentation] 前頭側頭葉変性を伴う上位運動神経系優位型の筋萎縮性側索硬化症の1剖検例 (2009)
  • Author(s): 付永娟, ほか
  • Organizer: 第50回日本神経病理学会総会学術研究会
  • Place of Presentation: 高松
  • Year and Date: 2009-06-06
• [Presentation] Machado-Joseph 病におけるTDP-43の異常発現 (2009)
  • Author(s): 豊島靖子, ほか
  • Organizer: 第50回日本神経病理学会総会学術研究会
  • Place of Presentation: 高松
  • Year and Date: 2009-06-06
• [Presentation] 孤発性ALSをめぐる最近の知見-病理学から見たALS (2009)
  • Author(s): 高橋均, ほか
  • Organizer: 第50回日本神経病理学会総会学術研究会
  • Place of Presentation: 高松(招待講演)
  • Year and Date: 2009-06-04
• [Presentation] Dementia lacking distinctive histology (DLDH)とTDP-43:1剖検例の再検討 (2008)
  • Author(s): 譚春鳳, ほか
  • Organizer: 第49回日本神経病理学会総会学術研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-20
• [Presentation] 長期の臨床経過を示した孤発性筋萎縮性側索硬化症におけるTDP-43異常発現とその分布に関する免疫組織化学検討 (2008)
  • Author(s): 西平靖, ほか
  • Organizer: 第49回日本神経病理学会総会学術研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-20
• [Presentation] 孤発性筋萎縮性側索硬化症におけるTDP-43異常発現とその分布に関する免疫組織化学検討 (2008)
  • Author(s): 西平靖, ほか
  • Organizer: 第49回日本神経病理学会総会学術研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-20
• [Remarks] Yokoseki A, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 2008 ; 63 : 538-542 本論文発表内容については、「ALS:新たな原因遺伝子新潟大チーム発見」の見出しで毎日新聞(2008, 4, 29)に掲載された。
• [Remarks] Nishihira Y, et al. Sporadic amyotrophic lateral sclerosis : two pathological patterns shown by analysis of distribution of TDP-43-immunreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 2008 ; 116 : 169-182 本論文発表内容については、「Research Brief : Redefining ALS-Time to Think Laterally?」のタイトルで国際的研究者ネットである ALZHEIMER RESEARCH FORUM に掲載、討論(May 2008)された。