Production of sporadic ALS model mice by targeting the ADAR2 gene in motor neurons
| Project/Area Number |
17390251
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | The University of Tokyo |
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Principal Investigator |
KWAK Shin The University of Tokyo, Faculty off Medicine, Department of Neurology, Associate Professor (40160981)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Ryosuke University of Kyoto, Department of Neurology, Professor (90216771)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2006: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2005: ¥8,100,000 (Direct Cost: ¥8,100,000)
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| Keywords | Degenerative neurological disease / Amyotrophic Lateral Sclerosis / glutamate receptor / AMPA receptor / RNA editing / GluR2 / ADAR2 / knockout mouse / G1uR2 / 核酸 |
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| Research Abstract |
We recently demonstrated that Q/R site-RNA editing of GluR2, a subunit of AMPA receptors, is markedly decreased in motor neurons of sporadic, but not familial, ALS patients in a disease-specific and neuronal class-selective manner. GluR2 Q/R. site-editing is specifically catalyzed by adenosine deaminase acting on RNA type 2 (ADAR2) and systemic ADAR2-null mice die young from status epilepticus due to a marked reduction in RNA editing at this site. Reduction of this enzyme activity is likely the cause of GluR2 Q/R site-underediting and neuronal death observed in sporadic ALS motor neurons.
To investigate whether deficient ADAR2 is a cause of slow death of motor neurons as seen in sporadic ALS, we developed genetically modified mice in that the ADAR2 gene is selectively knocked out in motor neurons using Cre-loxP system. We investigated the changes in motor function, survival length, neuronal loss of ADAR2-deficient neurons in these mice as compared to control mice.
These mutant mice displayed significantly shorter mean survival than control mice and progressive motor-selective behavioral deficit in a Cre expression-dependent manner. Motor neurons deficient for ADAR2 underwent slowly progressive death, whereas ADAR2-expressing motor neurons remains intact during the mouse life. RNA editing at the GluR2 Q/R site was completely lost in dying, ADAR2-deficient motor neurons.
Here we demonstrated that loss of ADAR2 induces GluR2 Q/R site-underediting with resultant slowly progressive death of motor neurons in the ADAR2 knockout mice. Present results likely indicate that ADAR2 under-activity may be a cause of neuronal death in sporadic ALS. This mutant mouse model would be useful in research into sporadic ALS.
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Report
(3 results)
Research Products
(104 results)
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[Journal Article] Quantitative evaluation of the pyramidal tract segmented by diffusion tensor tractography : feasibility study in patients with ainyotrophic lateral sclerosis.2005
Author(s)
Aoki S, Iwata NK, Masutani Y. Yoshida M, Abe 0, Ugawa Y, Masumoto T, Mori H, Hayashi N, Kabasawa H, Kwak S, Takahashi S, Tsuji S, Ohtomo K
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Journal Title
Radiat Med 23
Pages: 195-9
Description
「研究成果報告書概要(和文)」より
Related Report
Peer Reviewed
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[Journal Article] ALSの分子生物学2005
Author(s)
日出山拓人, 河原行郎, 郭 伸
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Journal Title
Current Insights in Neurological Science 13
Pages: 2-3
Description
「研究成果報告書概要(和文)」より
Related Report
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[Journal Article] Quantitative evaluation of the pyramidal tract segmented by diffusion tensor tractography: feasibility study in patients with amyotrophic lateral sclerosis.2005
Author(s)
Aoki S, Iwata NK, Masutani Y, Yoshida M, Abe 0, Ugawa Y, Masumoto T, Mori H, Hayashi N, Kabasawa H, Kwak S, Takahashi S, Tsuji S, Ohtomo K
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Journal Title
Radiat Med 23
Pages: 195-9
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Quantitative evaluation of the pyramidal tract segmented by diffusion tensor tractography : feasibility study in patients with amyotrophic lateral sclerosis2005
Author(s)
Aoki S, Iwata NK, Masutani Y, Yoshida M, Abe O, Ugawa Y, Masumoto T, Mori H, Hayashi N, Kabasawa H, Kwak S, Takahashi S, Tsuji S, Ohtomo K
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Journal Title
Radiat Med 23
Pages: 195-199
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[Presentation] 初代培養脊髄運動ニューロンにおける興奮性アミノ酸毒性の検討2005
Author(s)
深田 潤, 相澤仁志, 牧田圭弘, 鈴木康博, 油川陽子, 片山隆行, 榎本(中谷)雪, 菊池健次郎, 木村 隆, 箭原 修, 濤川一彦, 木山博資, 郭 伸
Organizer
第46回日本神経学会総会
Place of Presentation
鹿児島
Description
「研究成果報告書概要(和文)」より
Related Report
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