Elucidation of the pathomechanism of neurodegeneration induced by TDP-43
| Project/Area Number |
15K08297
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Hashimoto Tadafumi 東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / TDP-43 / 神経変性疾患 / オートファジー / 神経変性 / ALS / 前頭側頭型認知症 |
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| Outline of Final Research Achievements |
To elucidate the pathomechanism of TDP-43, we carried out RNA-seq analysis and found that Atg1 and several authophgic geneswere upregulated in the brain of TDP-43 transgenic (tg) fly. Knockdown of Atg1 rescued the retinal degeneration of TDP-43 tg fly, suggesting that autophagic pathway is involved in the pathogenesis of TDP-43. Moreover, we found that TDP-43 specifically intedacted with ULK1 mRNA in Neuro-2a cells and that knockdown of TDP-43 reduced the expression level of ULK1 protein, suggesting that TDP-43 regulates autophagic pathway via regulating the expression of ULK1.
By the analysis of the ALS-related genes, we found that overexpression of CREST induced neurodegeneration in the retina of tg fly, that familial ALS-linked mutations in Profilin1 cause the neurodegenetaion through the sequestration of TDP-43 into cytoplasm, and that self-assembly of FUS via its lox-complexity domain contributes neurodegeneration induced by FUS.
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain.2017
Author(s)
Michal Arbel-Ornath, Eloise Hudry, Josiah R Bovine, Tadafumi Hashimoto, Shuko Takeda, Kishore V Kuchbhotla, Steven Hou, Carli R Lattarulo, Arianna M Belcher, Naomi Shakerdge, Pariss B Trujillo, Alona Muzikansky, Rebecca A Betensky, Bradley T Hyman, and Brian J Bacskai
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Journal Title
Molecular Neurodegeneration
Volume: 12
Issue: 1
Pages: 27-27
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Chronic optogenetic activation augments Aβ pathology in a mouse model of Alzheimer disease2015
Author(s)
Kaoru Yamamoto, Zen-ichi Tanei, Tadafumi Hashimoto, Tomoko Wakabayashi, Hiroyuki Okuno, Yasushi Naka, Ofer Yizhar, Lief E. Fenno, Masashi Fukayama, Haruhiko Bito, John R. Cirrito, David M. Holtzman, Karl Deisseroth, Takeshi Iwatsubo
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Journal Title
Cell reports
Volume: 11
Issue: 6
Pages: 859-865
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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