Molecular pathogenesis of ALS: approach from TDP-43 function.
| Project/Area Number |
22249036
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Niigata University |
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Principal Investigator |
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| 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)
横関 明男 新潟大学, 医歯(薬)学総合研究科, 特任准教授 (90515719)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥48,880,000 (Direct Cost: ¥37,600,000、Indirect Cost: ¥11,280,000)
Fiscal Year 2012: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2011: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2010: ¥28,080,000 (Direct Cost: ¥21,600,000、Indirect Cost: ¥6,480,000)
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| Keywords | ALS / GEM / TDP-43 / U12 snRNA / SMN / 核内小体 / Cajal小体 |
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| 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.
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Report
(4 results)
Research Products
(60 results)
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[Journal Article] Japanese amyotrophiclateral sclerosis patients withGGGGCC hexanucleotide repeatexpansion in C9ORF722013
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
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Journal Title
J NeurolNeurosurg Psychiatry
Volume: 84(4)
Pages: 398-401
Related Report
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[Journal Article] Transportin 1accumulates in FUS inclusions inadult-onset ALS without FUS mutation2013
Author(s)
Takeuchi R, Toyoshima Y, Tada M, ShigaA, Tanaka H, Shimohata M, Kimura K,Morita T, Kakita A, Nishizawa M,Takahashi H
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Journal Title
Neuropathol Appl Neurobiol
Volume: Epub
Issue: 5
Pages: 580-584
DOI
Related Report
Peer Reviewed
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[Journal Article] Coexistence ofHuntington's disease and amyotrophiclateral sclerosis: aclinicopathologic study2012
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
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Journal Title
ActaNeuropathol
Volume: 124(5)
Pages: 749-60
Related Report
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[Journal Article] Reduction rateof body mass index predicts prognosisfor survival in amyotrophic lateralsclerosis: a multicenter study inJapan2012
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
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Journal Title
Amyotroph Lateral Scler
Volume: 13(4)
Pages: 363-6
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[Journal Article] Primary lateral sclerosis : Upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration-immunohistochemical and biochemical analyses of TDP-432011
Author(s)
Kosaka T, Fu YJ, Shiga A, Ishidaira H, Tan CF, Tani T, Koike R, Onodera O, Nishizawa M, Kakita A, Takahashi H
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Journal Title
Neuropathology. 2011
Volume: 32
Issue: 4
Pages: 373-384
DOI
Related Report
Peer Reviewed
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[Presentation] Aberrant splicing ofPOLDIP3 gene in motor neuron with ALS2011
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
Related Report
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[Presentation] Aberrant splicing of POLDIP3 gene in motor neuron with ALS2011
Author(s)
A.SHIGA, T.ISHIHARA, A.MIYASHITA, T.KATO, M.KUWABARA, A.YOKOSEKI, R.KUWANO, A.KAKITA, H.TAKAHASHI, M.NISHIZAWA, O.ONODERA
Organizer
Neuroscience 2011
Place of Presentation
Washington, D.C.
Year and Date
2011-11-13
Related Report
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[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
Related Report
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[Presentation] Aberrant splicing of POLDIP3 gene in motor neuron with ALS2011
Author(s)
A.SHIGA, T.ISHIHARA, A. MIYASHITA, T.KATO, M.KUWABARA, A.YOKOSEKI, R.KUWANO, A.KAKITA, H.TAKAHASHI, M.NISHIZAWA, O.ONODERAI
Organizer
6th Brain Research Conference : RNA-Binding Proteins in Neurological Disease
Place of Presentation
Washington, D.C.
Year and Date
2011-11-10
Related Report
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