Dynein motors transport activated Trks to promote survival of target-dependent neurons
Dynein motors transport activated Trks to promote survival of target-dependent neurons
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DOI：
10.1038/nn1242
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发表时间：
2004-06-01
影响因子：
25
通讯作者：
Segal, RA
中科院分区：
文献类型：
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作者：
Heerssen, HM;Pazyra, MF;Segal, RA
改变动力蛋白功能的突变与神经退行性疾病有关，但尚不清楚为什么动力蛋白依赖性转运的缺陷会损害神经元的存活。在这里，我们表明，轴突中的动力蛋白功能是选择性地需要依赖于靶源性神经营养因子的神经元的生存。用神经营养蛋白刺激轴突末梢引起神经营养蛋白受体（Trks）的内化。使用荧光标记的Trks的实时成像，我们表明，动力蛋白是必需的快速运输的内化，激活受体从轴突末梢远程细胞体。当基于动力蛋白的转运被抑制时，轴突终末的神经营养因子刺激不支持存活。这些研究表明，基于动力蛋白的转运缺陷减少了活化的Trks的运输，从而阻碍了靶源性营养因子的促生存作用，导致靶依赖性神经元的变性。
Mutations that alter dynein function are associated with neurodegenerative diseases, but it is not known why defects in dynein-dependent transport impair neuronal survival. Here we show that dynein function in axons is selectively required for the survival of neurons that depend on target-derived neurotrophins. Stimulation of axon terminals with neurotrophins causes internalization of neurotrophin receptors (Trks). Using real-time imaging of fluorescently tagged Trks, we show that dynein is required for rapid transport of internalized, activated receptors from axon terminals to remote cell bodies. When dynein-based transport is inhibited, neurotrophin stimulation of axon terminals does not support survival. These studies indicate that defects in dynein-based transport reduce trafficking of activated Trks and thereby obstruct the prosurvival effect of target-derived trophic factors, leading to degeneration of target-dependent neurons.