Neuronal development via redox signaling and mitochondrial dynamics

通过氧化还原信号和线粒体动力学的神经元发育

基本信息

批准号：
20300133
负责人：
YANAGI Shigeru
金额：
$ 12.56万
依托单位：
Tokyo University of Pharmacy and Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

Neuronal network and axonal guidance are critical processes that are highly regulated through extracellular signaling. Neuronal outgrowth is directed by repelling signaling molecules such as semaphorins. Redox reaction via activation of oxidoreductase MICAL has been shown to be involved in semaphorin-mediated signaling, however, the molecular basis was unknown. We have previously identified a novel GTPase named CRAG which was activated by reactive oxygen species generated by semaphorin and translocated to the nucleus. In this study, we found that CRAG mediated neuronal cell survival pathway by transcriptional regulation of AP-1 and SRF in the nucleus. In addition, CRAG was found to activate anti-oxidant signaling which alsocontributes to the cell survival. Furthermore, we succeeded to generate CRAG conditionalknockout mice. These mice will provide an important information to understand the physiological role of CARG during neuronal development. On the other hand, MITOL is a novel mitochondrialubiquitin ligase which regulates mitochondrial dynamics by ubiquitination of mitochondrial fission factor Drp1. Subsequently, we suggested that MITOL is involved in mitochondrial quality control by ubiquitination of unfolded proteins such as mutant SOD1 and expanded polyQ accumulated in mitochondria. However, the exact role of MITOL is still obscure. Most recently we identified two physiological substrates of MITOL, MAP1B-LC1 and mitofusin2. Further analysis of MITOL will uncover the new role of mitochondria, thereby contributing to a greater understanding of the molecular basis of the neurodegenerative disorders.

神经元网络和轴突引导是通过细胞外信号传导高度调节的关键过程。神经元的生长是通过排斥信号分子（例如信号蛋白）来引导的。通过氧化还原酶 MICAL 激活的氧化还原反应已被证明参与信号蛋白介导的信号传导，但其分子基础尚不清楚。我们之前发现了一种名为 CRAG 的新型 GTP 酶，它被信号蛋白产生的活性氧激活并转移到细胞核。在本研究中，我们发现CRAG通过细胞核中AP-1和SRF的转录调节来介导神经元细胞存活途径。此外，CRAG 被发现可以激活抗氧化信号，这也有助于细胞存活。此外，我们成功地产生了 CRAG 条件敲除小鼠。这些小鼠将为了解 CARG 在神经元发育过程中的生理作用提供重要信息。另一方面，MITOL 是一种新型线粒体泛素连接酶，通过泛素化线粒体裂变因子 Drp1 来调节线粒体动力学。随后，我们提出 MITOL 通过泛素化未折叠蛋白（例如线粒体中积累的突变 SOD1 和扩展的 PolyQ）来参与线粒体质量控制。然而，MITOL 的确切作用仍然不清楚。最近，我们鉴定了 MITOL 的两种生理底物：MAP1B-LC1 和 mitofusin2。对 MITOL 的进一步分析将揭示线粒体的新作用，从而有助于更好地了解神经退行性疾病的分子基础。