Heerssen Heather M, Pazyra Maria F, Segal Rosalind A
Department of Neurobiology, Harvard Medical School and Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Nat Neurosci. 2004 Jun;7(6):596-604. doi: 10.1038/nn1242. Epub 2004 May 2.
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.
改变动力蛋白功能的突变与神经退行性疾病相关，但动力蛋白依赖性运输缺陷为何会损害神经元存活尚不清楚。在这里，我们表明轴突中的动力蛋白功能对于依赖靶源性神经营养因子的神经元存活是选择性必需的。用神经营养因子刺激轴突终末会导致神经营养因子受体（Trks）内化。通过对荧光标记的Trks进行实时成像，我们表明动力蛋白是内化的、活化的受体从轴突终末快速运输到远处细胞体所必需的。当基于动力蛋白的运输受到抑制时，轴突终末的神经营养因子刺激不能支持神经元存活。这些研究表明，基于动力蛋白的运输缺陷会减少活化的Trks的运输，从而阻碍靶源性营养因子的促存活作用，导致靶依赖性神经元变性。
Zotero 插件