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Roles of mitochondria and inhibitor of apoptosis proteins in the spatial and temporal regulation of caspase activation during axonal arborisation and degeneration

线粒体和凋亡蛋白抑制剂在轴突分枝和变性过程中 caspase 激活的空间和时间调节中的作用

基本信息

批准号：
20K06902
负责人：
Campbell Douglas
金额：
$ 1.75万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2020
资助国家：
日本
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-20K06902/
关键词：
Neuron Axon Branch Synapse Caspase Mitochondria IAP Imaging Arbor Menbrane Remodleing Trafficking Braanch Degeneration

项目摘要

The overall aim of our research is to understand the cellular and molecular mechanisms of axonal branching and synapse formation, key steps in the establishment of neuronal connectivity. We use the zebrafish visual system as a model for studying the cellular and molecular mechanisms of arborisation and synapse formation using the retinal ganglion cell axon arbors. We can perform in vivo imaging to follow their dynamics and manipulated the the function of potential genes playing roles. We have found that mitochondria are preferentially localised to stable presynaptic sites and branches rather than in the new / young highly dynamic branch tips and presynaptic sites. These data suggest that mitochondria may play roles at stable synapses that are more likely to be electrically active in neuronal circuits where higher amounts of ATP are necessary to maintain neural activity. We have also monitored a rapid switch in caspase activity in retinal axon arbors at the onset of neurodegeneration. There is a loss of spatially restricted caspase activation to a more widespread which may contribute to the neural degeneration observed. The mechanisms of which are currently unknown - to allow rapid and more spatially restricted caspase activation.

我们研究的总体目标是了解轴突分支和突触形成的细胞和分子机制，这是建立神经元连接的关键步骤。我们使用斑马鱼的视觉系统作为模型，研究利用视网膜神经节细胞轴突乔木形成树枝和突触的细胞和分子机制。我们可以进行体内成像来跟踪它们的动态，并操纵发挥作用的潜在基因的功能。我们发现，线粒体优先定位于稳定的突触前部位和分支，而不是新的/年轻的高度动态的分支末端和突触前部位。这些数据表明，线粒体可能在稳定的突触上发挥作用，这些突触在神经元回路中更有可能是电活跃的，在那里需要更高数量的ATP来维持神经活动。我们还监测到在神经变性开始时，视网膜轴突中caspase活性的快速转换。空间受限的半胱氨酸天冬氨酸氨基转移酶活性的丧失更广泛，这可能是导致观察到的神经变性的原因。其机制目前尚不清楚--允许快速和空间受限的caspase激活。