Bcl-XL induces Drp1-dependent synapse formation in cultured hippocampal neurons
Bcl-XL induces Drp1-dependent synapse formation in cultured hippocampal neurons
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DOI：
10.1073/pnas.0711647105
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发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Jonas, Elizabeth A.
中科院分区：
文献类型：
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作者：
Li, Hongmei;Chen, Yingbei;Jonas, Elizabeth A.
神经元突触的成熟被认为涉及线粒体。Bcl-X-L蛋白抑制Bcl-X-L介导的细胞凋亡，但在Bcl-X-L丰富的健康成人神经元中可能具有其他功能。在这里，我们报告说，过度表达Bcl-X-L突触后增加的频率和幅度的自发微小突触电流在大鼠海马神经元的文化。Bcl-X-L在突触前或突触后过表达，增加突触数量、突触囊泡簇的数量和大小以及线粒体定位于囊泡簇和突触，可能解释了微型突触电流的变化。相反，Bcl-X-L的敲除或抑制。ABT-737可降低这些形态学参数。线粒体分裂蛋白，动力蛋白相关蛋白1（Drp1），是已知定位于突触并影响突触功能和结构的GTdR。Bcl-X-L的作用似乎是通过Drp1介导的，因为Drp1的过表达增加了突触标记物，而显性负性dnDrp1-K38A的过表达减少了它们。此外，Bcl-X-L与组织裂解物中的Drp1共免疫沉淀，并且在重组系统中，Bcl-X-L蛋白刺激Drp1的GT3活性。这些发现表明Bcl-X-L正向调节Drp 1，以刺激突触形成的方式改变线粒体功能。
Maturation of neuronal synapses is thought to involve mitochondria. Bcl-X-L protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-X-L is abundant. Here, we report that overexpression of Bcl-X-L postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-X-L, overexpressed either pre or postsynaptically, increases synapse number, the number and size of synaptic vesicle clusters, and mitochondrial localization to vesicle clusters and synapses, likely accounting for the changes in miniature synaptic currents. Conversely, knockdown of Bcl-X-L or inhibiting. it with ABT-737 decreases these morphological parameters. The mitochondrial fission protein, dynamin-related protein 1 (Drp1), is a GTPase known to localize to synapses and affect synaptic function and structure. The effects of Bcl-X-L appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-X-L coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-X-L protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-X-L positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation.