Investigation of ALS/FTLD pathogenesis based on translational deterioration due to ribosome dysfunction in axons
Project/Area Number |
16K09690
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Neurology
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Research Institution | Osaka University |
Principal Investigator |
NAGANO Seiichi 大阪大学, 医学系研究科, 准教授 (40362727)
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Co-Investigator(Kenkyū-buntansha) |
永井 義隆 大阪大学, 医学系研究科, 寄附講座教授 (60335354)
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Project Period (FY) |
2016-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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Keywords | TDP-43 / 軸索輸送 / 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / リボソーム蛋白質 / 局所翻訳 / mRNA / リボソーム蛋白質mRNA |
Outline of Final Research Achievements |
In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), abnormal deposition of the RNA-binding protein TDP-43 in neurons was observed, suggesting a relationship with the pathogenesis. We hypothesized that impairment of TDP-43-mediated mRNA transport to neuronal axons would cause ALS/FTLD, and identified ribosomal protein (Rp) mRNA as its target. It was suggested that Rp mRNA is transported by binding and colocalizing with TDP-43 in axons, and the transported Rp mRNA is locally translated in axons and assembled into endogenous ribosomes. In the axons in which TDP-43 was down-regulated, local translational ability by ribosomes and axonal outgrowth was impaired, while the disturbance was ameliorated by overexpression of each Rp.
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Academic Significance and Societal Importance of the Research Achievements |
筋萎縮性側索硬化症(ALS)、前頭側頭葉変性症(FTLD)は根本的治療法のない重篤な神経変性疾患であり、一刻も早い効果的治療法の開発が切望されている。ALS/FTLDではRNA結合蛋白質TDP-43の神経細胞での局在異常が知られているが、我々は独自に開発した神経細胞区画培養法を用いて神経軸索を選択的に解析する手法を確立し、それによりTDP-43による軸索輸送標的としてリボソーム蛋白質(Rp)mRNAを同定した。Rp mRNAの発現を増加させる薬剤により、ALS/FTLDの新たな治療法が開発されることが期待される。
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Report
(5 results)
Research Products
(38 results)
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[Journal Article] Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis.2020
Author(s)
Ikenaka K, Ishigaki S, Iguchi Y, Kawai K, Fujioka Y, Yokoi S, Abdelhamid RF, Nagano S, Mochizuki H, Katsuno M, Sobue G.
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Journal Title
J Neuropathol Exp Neurol
Volume: 79
Issue: 4
Pages: 370-377
DOI
Related Report
Peer Reviewed
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[Journal Article] Critical role of CRAG, a splicing variant of centaurin-γ3/AGAP3, in ELK1-dependent SRF activation at PML bodies.2019
Author(s)
Nagashima S, Takeda K, Shiiba I, Higashi M, Fukuda T, Tokuyama T, Matsushita N, Nagano S, Araki T, Kaneko M, Shioi G, Inatome R, Yanagi S.
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Journal Title
Sci Rep
Volume: 9
Issue: 1
Pages: 20107-20107
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A.2019
Author(s)
3. Numata-Uematsu Y, Wakatsuki S, Nagano S, Shibata M, Sakai K, Ichinohe N, Mikoshiba K, Ohshima T, Yamashita N, Goshima Y, Araki T.
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Journal Title
Neurosci Res
Volume: 139
Pages: 63-68
DOI
Related Report
Peer Reviewed
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[Journal Article] Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid.2019
Author(s)
2. Kakuda K, Ikenaka K, Araki K, So M, Aguirre C, Kajiyama Y, Konaka K, Noi K, Baba K, Tsuda H, Nagano S, Ohmichi T, Nagai Y, Tokuda T, El-Agnaf O, Ogi H, Goto Y, Mochizuki H.
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Journal Title
Sci Rep
Volume: 9
Issue: 1
Pages: 6001-6001
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Transgenic monkey model of the polyglutamine diseases recapitulating progressive neurological symptoms.2017
Author(s)
Tomioka I, Ishibashi H, Minakawa EN, Motohashi HH, Takayama O, Saito Y, Popiel HA, Puentes S, Owari K, Nakatani T, Nogami N, Yamamoto K, Noguchi S, Yonekawa T, Tanaka Y, Fujita N, Suzuki H, Kikuchi H, Aizawa S, Nagano S, Yamada D, Nishino I, Ichinohe N, Wada K, Kohsaka S, Nagai Y, Seki K.
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Journal Title
eNeuro
Volume: 4
Issue: 2
Pages: 0250-56
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Book] 今日の治療指針2020
Author(s)
長野清一,望月秀樹.
Total Pages
2192
Publisher
医学書院
ISBN
9784260039390
Related Report
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