Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway
Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway
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DOI：
10.1523/jneurosci.1017-05.2005
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发表时间：
2005-06-29
影响因子：
5.3
通讯作者：
Lee, FS
中科院分区：
文献类型：
--
作者：
Chen, ZY;Ieraci, A;Lee, FS
脑源性神经营养因子(BDNF)是由神经元分泌的一种活性依赖的神经营养因子，对神经系统的重要功能起调节作用。最近，人类脑源性神经营养因子基因的一个变异，导致原结构域中的缬氨酸替换为蛋氨酸，已被证明导致神经元调节分泌的缺陷和记忆障碍。在这里，我们报道了Vps10p结构域蛋白sortilin的一个新功能，它控制BDNF对调节的分泌途径进行分类。山梨素与脑源性神经营养因子在甲硫氨酸取代区域发生特异性相互作用，并与脑源性神经营养因子共同定位于神经元的分泌颗粒中。截短形式的山梨素导致BDNF错误地分选到构成分泌途径，而不影响神经营养素-4(NT-4)的分泌。此外，山梨素小干扰RNA进入原代神经元也导致BDNF从调节分泌途径到构成分泌途径的错误排序。综上所述，这些数据提示了一种机制来理解与变异型BDNF相关的缺陷，并提供了一个框架，基于不同的突触前对分泌途径的分类调节，来解释原肌球蛋白相关激酶B的两个配体BDNF和NT-4如何介导不同的生物反应。
Brain-derived neurotrophic factor ( BDNF), after activity-dependent secretion from neurons, modulates critical nervous system functions. Recently, a variant in the human bdnf gene, resulting in a valine to methionine substitution in the prodomain, has been shown to lead to defective regulated secretion from neurons and memory impairment. Here, we report a novel function for a Vps10p domain protein, sortilin, in controlling BDNF sorting to the regulated secretory pathway. Sortilin interacts specifically with BDNF in a region encompassing the methionine substitution and colocalizes with BDNF in secretory granules in neurons. A truncated form of sortilin causes BDNF missorting to the constitutive secretory pathway without affecting neurotrophin-4 (NT-4) secretion. In addition, sortilin small interfering RNA introduced into primary neurons also led to BDNF missorting from the regulated to the constitutive secretory pathway. Together, these data suggest a mechanism to understand the defect associated with variant BDNF and provide a framework, based on divergent presynaptic regulation of sorting to secretory pathways, to explain how two ligands for tropomyosin-related kinase B, BDNF and NT-4, can mediate diverse biological responses.