Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury.
Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury.
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DOI：
10.1523/jneurosci.3376-09.2009
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发表时间：
2009-10-21
期刊：
影响因子：
--
通讯作者：
Rasband MN
中科院分区：
文献类型：
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作者：
Schafer DP;Jha S;Liu F;Akella T;McCullough LD;Rasband MN
许多因素导致神经系统功能障碍和损伤或疾病后再生失败。在这里，我们描述了一个以前未被认识到的神经系统损伤的机制。我们发现，神经元损伤导致快速，不可逆的，和优先的轴突起始段（AIS）细胞骨架的蛋白水解独立于细胞死亡或轴突变性，导致离子通道簇和神经元极性的损失。此外，我们还发现这是由钙依赖性半胱氨酸蛋白酶钙蛋白酶对AIS细胞骨架蛋白anklectin G和βIV血影蛋白的蛋白水解引起的。重要的是，钙蛋白酶抑制足以在体外和体内保持AIS的分子组织。我们的结论是AIS离子通道簇和神经元极性的损失是损伤后神经元功能障碍的重要因素，促进恢复的策略必须保护或修复AIS细胞骨架。
Many factors contribute to nervous system dysfunction and failure to regenerate after injury or disease. Here, we describe a previously unrecognized mechanism for nervous system injury. We show that neuronal injury causes rapid, irreversible, and preferential proteolysis of the axon initial segment (AIS) cytoskeleton independently of cell death or axon degeneration, leading to loss of both ion channel clusters and neuronal polarity. Furthermore, we show this is caused by proteolysis of the AIS cytoskeletal proteins ankyrinG and βIV spectrin by the calcium-dependent cysteine protease calpain. Importantly, calpain inhibition is sufficient to preserve the molecular organization of the AIS both in vitro and in vivo. We conclude that loss of AIS ion channel clusters and neuronal polarity are important contributors to neuronal dysfunction after injury, and that strategies to facilitate recovery must preserve or repair the AIS cytoskeleton.