Autoreguation of TDP-43 in ALS
| Project/Area Number |
25253065
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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) |
ONODERA Osamu 新潟大学, 脳研究所, 教授 (20303167)
ISHIHARA Tomohiko 新潟大学, 脳研究所, 助教 (70612232)
KAKITA Akiyoshi 新潟大学, 脳研究所, 教授 (80281012)
SATO Toshiya 北里大学, 医学部, 助教 (90359703)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥45,890,000 (Direct Cost: ¥35,300,000、Indirect Cost: ¥10,590,000)
Fiscal Year 2015: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
Fiscal Year 2014: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
Fiscal Year 2013: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000)
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| Keywords | 筋萎縮性側索硬化症 / 神経病態 |
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| Outline of Final Research Achievements |
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. We show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons; especially neurons with mislocalized TDP-43; the amount of TARDBP mRNA is increased in the cytoplasm. Our observations suggests that that the absence of nuclear TDP-43 induces an abnormal autoregulation.
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Report
(4 results)
Research Products
(21 results)
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[Journal Article] Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia.2015
Author(s)
Takeuchi R, Toyoshima Y, Tada M, Tanaka H, Shimizu H, Shiga A, Miura T, Aoki K, Aikawa A, Ishizawa S, Ikeuchi T, Nishizawa M, Kakita A, Takahashi H.
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Journal Title
Brain Pathology
Volume: in press
Issue: 1
Pages: 82-94
DOI
Related Report
Peer Reviewed
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[Journal Article] Sporadic ALS with compound heterozygous mutation in the SQSTM1 gene.2013
Author(s)
Shimizu H, Toyoshima Y, Shiga A, Yokoseki A, Arakawa K, Sekine Y, Shimohata T, Ikeuchi T, Nishizawa M, Kakita A, Onodera O, Takahashi H
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Journal Title
Acta Neuropathol
Volume: 126
Issue: 3
Pages: 453-459
DOI
Related Report
Peer Reviewed
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[Presentation] Update in amyotrophic lateral sclerosis2014
Author(s)
Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi
Organizer
The XVIII International Congress of Neuropathology. ICN 2014
Place of Presentation
Rio de Janeiro, Brazil
Year and Date
2014-09-14 – 2014-09-18
Related Report
Invited
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