Molecular pathogenesis of ALS: approach from TDP-43 function.

2012 Fiscal Year Final Research Report

• Project/Area Number: 22249036
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Niigata University
• Principal Investigator: NISHIZAWA Masatoyo 新潟大学, 脳研究所, 教授 (80198457)
• Co-Investigator(Kenkyū-buntansha): ABE Manabu 新潟大学, 脳研究所, 准教授 (10334674) ; KUWANO Ryozo 新潟大学, 脳研究所, 教授 (20111734) ; ONODERA Osamu 新潟大学, 脳研究所, 教授 (20303167) ; KAKITA Akiyoshi 新潟大学, 脳研究所, 教授 (80281012) ; SATOU Toshiya 新潟大学, 脳研究所, 助教 (90359703)
• Project Period (FY): 2010 – 2012
• Keywords: ALS / GEM / TDP-43 / U12 snRNA

Research Abstract

Disappearance of TAR-DNA binding protein 43 kDa (TDP-43) from the nucleuscontributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclearfunction of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodiesincluding Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis ofuridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. Thenumber of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, alower motor neuron disease, suggesting that alteration of U snRNAs may also underliethe molecular pathogenesis of ALS. We investigated the number of GEMs andU11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry andthe level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMsdecreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALSpatients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y andU87MG cells. The level of U12 snRNA was decreased in tissues affected by ALS butnot in tissues unaffected by ALS. These findings suggest that loss of TDP-43 functiondecreases the number of GEMs, which is followed by a disturbance of pre-mRNAsplicing by the U11/U12 spliceosome in tissues affected by ALS.

Research Products

• [Journal Article] Decreased number of Gemini of coiledbodies and U12 snRNA level inamyotrophic lateral sclerosis (2013)
  • Author(s): Tomohiko Ishihara1, Yuko Ariizumi,Atsushi Shiga, Taisuke Kato,Chun-Feng Tan, Tatsuya Sato, YukariMiki, Mariko Yokoo, Takeshi Fujino,Akihide Koyama, Akio Yokoseki,Masatoyo Nishizawa, Akiyoshi Kakita,Hitoshi Takahashi, Osamu Onodera
  • Journal Title: Hum.Mol. Genet
  • DOI: doi:10.1093/hmg/ddt262
• [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
  • DOI: doi:10.1111/neup.12044.
• [Journal Article] Japanese amyotrophiclateral sclerosis patients withGGGGCC hexanucleotide repeatexpansion in C9ORF72 (2013)
  • Author(s): Konno T, Shiga A, Tsujino A, Sugai A,Kato T, Kanai K, Yokoseki A, Eguchi H,Kuwabara S, Nishizawa M, Takahashi H,Onodera O
  • Journal Title: J NeurolNeurosurg Psychiatry Volume: 84(4) Pages: 398-401
• [Journal Article] Transportin 1accumulates in FUS inclusions inadult-onset ALS without FUS mutation (2013)
  • Author(s): Takeuchi R, Toyoshima Y, Tada M, ShigaA, Tanaka H, Shimohata M, Kimura K,Morita T, Kakita A, Nishizawa M,Takahashi H
  • Journal Title: Neuropathol Appl Neurobiol
  • DOI: doi:10.1111/nan.12022.
• [Journal Article] Keap1 is localized inneuronal and glial cytoplasmicinclusions in variousneurodegenerative diseases (2013)
  • Author(s): Tanji K, Maruyama A, Odagiri S, MoriF, Itoh K, Kakita A, Takahashi H,Wakabayashi K
  • Journal Title: JNeuropathol Exp Neurol Volume: 72(1) Pages: 18-28
• [Journal Article] Coexistence ofHuntington's disease and amyotrophiclateral sclerosis: aclinicopathologic study (2012)
  • Author(s): Tada M, Coon EA, Osmand AP, Kirby PA,Martin W, Wieler M, Shiga A, ShirasakiH, Tada M, Makifuchi T, Yamada M,Kakita A, Nishizawa M, Takahashi H,Paulson HL
  • Journal Title: ActaNeuropathol Volume: 124(5) Pages: 749-60
• [Journal Article] Alteration of POLDIP3 splicingassociated with loss of function ofTDP-43 in tissues affected with ALS (2012)
  • Author(s): Shiga A, Ishihara T, Miyashita A,Kuwabara M, Kato T, Watanabe N,Yamahira A, Kondo C, Yokoseki A,Takahashi M, Kuwano R, Kakita A,Nishizawa M, Takahashi H,Onodera O
  • Journal Title: PLoS One Volume: 7(8) Pages: e43120
  • DOI: 10.1371/journal.pone.0043120
• [Journal Article] Profound downregulation of the RNAediting enzyme ADAR2 in ALS spinalmotor neurons (2012)
  • Author(s): Hideyama T, Yamashita T, Aizawa H,Tsuji S, Kakita A, Takahashi H, Kwak S
  • Journal Title: Neurobiol Dis Volume: 45(3) Pages: 1121-8
• [Journal Article] Co-occurrence of argyrophilic graindisease in sporadic amyotrophiclateral sclerosis (2012)
  • Author(s): Soma K, Fu YJ, Wakabayashi K, OnoderaO, Kakita A, Takahashi H
  • Journal Title: Neuropathol ApplNeurobiol Volume: 38(1) Pages: 54-60
• [Journal Article] Reduction rateof body mass index predicts prognosisfor survival in amyotrophic lateralsclerosis: a multicenter study inJapan (2012)
  • Author(s): Shimizu T, Nagaoka U, Nakayama Y,Kawata A, Kugimoto C, Kuroiwa Y, KawaiM,Shimohata T, Nishizawa M, Mihara B,Arahata H, Fujii N, Namba R, Ito H,Imai T,Nobukuni K, Kondo K, Ogino M,Nakajima T, Komori T
  • Journal Title: Amyotroph Lateral Scler Volume: 13(4) Pages: 363-6
• [Journal Article] Enhancement ofnative and phosphorylated TDP-43immunoreactivity by proteinase Ktreatment following autoclaveheating (2011)
  • Author(s): Mori F, Tanji K, Kakita A, TakahashiH, Wakabayashi K
  • Journal Title: Neuropathology Volume: 31(4) Pages: 401-4
• [Journal Article] Survival motor neuron (SMN) proteinin the spinal anterior horn cells ofpatients with sporadic amyotrophiclateral sclerosis (2011)
  • Author(s): Piao Y, Hashimoto T, Takahama S,Kakita A, Komori T, Morita T,Takahashi H, Mizutani T, Oyanagi K
  • Journal Title: Brain Res Volume: 4;1372 Pages: 152-9
• [Journal Article] FTLD/ALS as TDP-43proteinopathies (2010)
  • Author(s): Ishihara T, Ariizumi Y, Shiga A,Yokoseki A, Sato T, Toyoshima Y,Kakita A,Takahashi H, Nishizawa M,Onodera O
  • Journal Title: Rinsho Shinkeigaku Volume: 50(11) Pages: 1022-4
• [Journal Article] Clinical and pathological spectrumof TDP-43 associated ALS (2010)
  • Author(s): Onodera O, Yokoseki A, Tan CF,Ishihara T, Nishiira Y, Toyoshima Y,Kakita A, Nishizawa M, Takahashi H
  • Journal Title: RinshoShinkeigaku Volume: 50(11) Pages: 940-2
• [Journal Article] A case of amyotrophiclateral sclerosis/frontotemporallobar degeneration with apraxia ofeyelid opening (2010)
  • Author(s): Yajima R, Kasuga K, Sato T, Ikeuchi T,Nishizawa M
  • Journal Title: Rinsho Shinkeigaku Volume: 50(9) Pages: 645-50
• [Journal Article] Relationship between Bunina bodiesand TDP-43 inclusions in spinalanterior horn in amyotrophic lateralsclerosis (2010)
  • Author(s): Mori F, Tanji K, Miki Y, Kakita A,Takahashi H, Wakabayashi K
  • Journal Title: Neuropathol ApplNeurobiol Volume: 36(4) Pages: 345-52
• [Presentation] TDP-43 Q343Rノックインマウスの生化学的 (2013)
  • Author(s): 廣川祥子
  • Organizer: 神経病理学的解析第118回日本解剖学会総会
  • Place of Presentation: 香川
  • Year and Date: 2013-03-28
• [Presentation] レーザーマイクロダイセクション法による脊髄運動ニューロンの単離方法の確立 (2013)
  • Author(s): 近藤千草
  • Organizer: 第118回日本解剖学会総会
  • Place of Presentation: 香川
  • Year and Date: 2013-03-28
• [Presentation] c9FTD/ALS is rare in Japanesefamilial and sporadic amyotrophiclateral sclerosis patients (2012)
  • Author(s): Konno T
  • Organizer: Neuorscience 2012
  • Place of Presentation: New Orlens
  • Year and Date: 2012-10-17
• [Presentation] Reduction of U12 snRNAs innervous tissues with TDP-43 pathologyin amyotrophic lateral sclerosis (2012)
  • Author(s): Ishihara T
  • Organizer: Neuorscience 2012
  • Place of Presentation: New Orleans
  • Year and Date: 2012-10-17
• [Presentation] 本邦の9FTD/ALSのまとめと展望神経変性疾患に関する調査研究班 (2012)
  • Author(s): 小野寺理
  • Organizer: 平成24年度ワークショッフ(招待講演)
  • Place of Presentation: 東京
  • Year and Date: 2012-07-20
• [Presentation] RNA代謝からTDP-43 proteinopathyの病態に迫る (2012)
  • Author(s): 小野寺理
  • Organizer: 第53回神経病理学会総会学術研究会(招待講演)
  • Place of Presentation: 新潟
  • Year and Date: 2012-06-30
• [Presentation] ALS患者神経組織ではスプライシング関連機能性RNAか低下する (2012)
  • Author(s): 石原智彦
  • Organizer: 第53回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-23
• [Presentation] 筋萎縮性側索硬化症の克服を目指して (2012)
  • Author(s): 小野寺理
  • Organizer: 新潟医学会特別例会(招待講演)
  • Place of Presentation: 新潟
  • Year and Date: 2012-05-19
• [Presentation] Tardbp欠損マウスのmRNA選択的スプライシングと組織特異的な多様性Tardbp alternatively spliced mRNA andtissue-specific variation inheterozygous Tardbp-deficient mice (2011)
  • Author(s): 廣川祥子,佐藤俊哉,石原知彦,藤野赳至,近藤千草,横山峯介,崎村健司,西澤正豊,小野寺理
  • Organizer: 分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-14
• [Presentation] ALS関連蛋白TDP-43の自己発現調節機能に関与するスプライシング因子の検討Splicing factors involved in anautoregulation of the ALS-associated protein TDP-43 (2011)
  • Author(s): 桑原美咲,石原智彦,志賀篤,今野卓哉,小山哲秀,西澤正豊,小野寺理
  • Organizer: 分子生物学
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-14
• [Presentation] Aberrant splicing ofPOLDIP3 gene in motor neuron with ALS (2011)
  • Author(s): A. SHIGA1, T. ISHIHARA1, A.MIYASHITA1, T. KATO1, M. KUWABARA1, A. YOKOSEKI2, R. KUWANO1, A. KAKITA1,H. TAKAHASHI1, M. NISHIZAWA1, O.ONODERA1
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington, D. C.
  • Year and Date: 2011-11-13
• [Presentation] Alteration of snRNAs inamyotrophic lateral sclerosis (2011)
  • Author(s): T. ISHIHARA, A. SHIGA, A. KAKITA A.YOKOSEKI, M. NISHIZAWA, H. TAKAHASHI, O. ONODERA
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington, D. C.
  • Year and Date: 2011-11-12
• [Presentation] Alteration of snRNAs inamyotrophic lateral sclerosis (2011)
  • Author(s): T. ISHIHARA, A. SHIGA, A. KAKITA A.YOKOSEKI, M. NISHIZAWA, H. TAKAHASHI,O. ONODERA
  • Organizer: 6th Brain Research Conference RNA-Binding Proteins in Neurological Disease
  • Place of Presentation: Washington, D. C.
  • Year and Date: 2011-11-10
• [Presentation] Aberrant splicing ofPOLDIP3 gene in motor neuron with ALS. (2011)
  • Author(s): A. SHIGA1, T. ISHIHARA1, A.MIYASHITA1, T. KATO1, M. KUWABARA1, A. YOKOSEKI2, R. KUWANO1, A. KAKITA1,H. TAKAHASHI1, M. NISHIZAWA1, O. ONODERA1
  • Organizer: 6th Brain Research Conference RNA-Binding Proteins in NeurologicalDisease
  • Place of Presentation: Washington, D. C.
  • Year and Date: 2011-11-10
• [Presentation] Alteration of snRNAs inAmyotrophic Lateral Sclerosis (2010)
  • Author(s): Ishihara, T. Shiga, A. Kakita A.Yokoseki A. Nishizawa M. Takahashi, H.Onodera O
  • Organizer: AAN 2010
  • Place of Presentation: Toronto
  • Year and Date: 20100410-17
• [Presentation] Cytoplasmic C-Terminus TDP-43 Aggregate Leads to Increased Phosphorylation of Full-LengthTDP-43 in Culture Cell (2010)
  • Author(s): Ariizumi, Y. Ishihara, T. Yokoo, M.Shiga, A. Yokoseki A. Onodera O.Nishizawa M
  • Organizer: AAN
  • Place of Presentation: Toronto
  • Year and Date: 20100410-17
• [Presentation] TDP-43 depletion causes splicingdefects in the genes associated withendomembrane system (2010)
  • Author(s): A. SHIGA, T. ISHIHARA, A. MIYASHITA,M. YOKOO, Y. ARIIZUMI, A. YOKOSEKI,R. KUWANO, M. NISHIZAWA, O. ONODERA
  • Organizer: Neuroscience 2010 Saturday
  • Place of Presentation: SanDiego
  • Year and Date: 2010-11-13