| Project/Area Number |
17300121
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Tokai University |
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Principal Investigator |
HADANO Shinji Tokai University, School of Medicine, Associate Professor (60281375)
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| Co-Investigator(Kenkyū-buntansha) |
OSUGA Hitoshi Tokai University, Medical Research Institute, Associate Professor (60203775)
ONOE Kyuichiro Tokai University, Medical Research Institute, Assistant Professor (50276812)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,090,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2007: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2005: ¥6,200,000 (Direct Cost: ¥6,200,000)
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| Keywords | amyotrophic lateral sclerosis / the ALS2 gene / motor neuron / model animal / neurodegenerative disease / endosome / guanine nucleotide exchange factor / グアニンヌクレオチド交換因子 / エンドソ-ム / AIS2遺伝子 / ALS2タンパク質 |
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| Research Abstract |
Loss of function mutations in ALS2 account for a number of juvenile/infantile recessive motor neuron diseases, indicating that its gene product, ALS2, plays a crucial role in maintenance and survival for a subset of neurons. However, the normal physiological role of ALS2 in vivo and the molecular mechanisms underlying motor dysfunction are still unknown. To address these issues, we generated several lines of ALS2 transgenic mice and congenic lines of the Als2 knock-out (KO) mice in this study. Neither loss nor overexpression of ALS2 solely produced a severe disease phenotype in mice. However, when the Als2-KO mice was crossed with the SOD1R46R mouse line expressing familial ALS-linked SOD1H46R Als2-KO ; SOD1^<H46R>mice showed a much earlier motor dysfunction as well as a shorter life span than SODIH46R mice, suggesting that ALS2 plays a role in the onset and/or progression of motor neuron disease associated with mutant SOD1 in vivo. Next, to elucidate the neuronal ALS2 functions, we in
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vestigated cellular phenotypes of ALS2-deficient primary cultured neurons. ALS2 deficiency resulted not only in the delay of axon outgrowth in hippocampal neurons, but also in a decreased level of the macropinocytic activity in cortical neurons, suggesting that ALS2 acts as a modulator in neuronal differentiation and/or development through regulation of membrane dynamics. Finally, we investigated the molecular features of ALS2CL, a novel ALS2 homolog, and its functional relationship with ALS2. It was revealed that ALS2CL was a novel ALS2-interacting protein and was implicated in ALS2-mediated endosome dynamics. Collectively, our newly generated animals overexpressing and/or deleting ALS2 should provide invaluable research tools with which to understand the interplay between ALS2-mediated endosomal dynamics and the long-term viability of motor neurons in vivo. Further characterization of these mice will also clarify the implication of the ALS2-mediated neuronal functions in the pathogenesis for mutant SOD1-linkedALS. Less
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