BDNF调控线粒体动态变化机制及功能研究

发布时间：2018-05-04 04:02

本文选题：脑源性神经营养因子(BDNF) + 线粒体　；参考：《山东大学》2017年硕士论文

【摘要】：神经元的生长、分化及突触传递等生命活动的正常进行,离不开线粒体为其提供能量和调节胞质内钙离子的内流。线粒体形态的改变可影响其功能的发挥。而线粒体形态和功能受到线粒体分裂和融合动态变化所调控。线粒体在神经元中的形态和分布均处于动态变化的状态中。此过程由多种蛋白质精确调控完成的。参与调控分裂的主要有Drp1、Mff和Fis1;Mfn1、Mfn2等蛋白调控线粒体外膜的融合,而Opa1等则参与线粒体内膜的融合。线粒体可通过分裂增加数目,有利于更多的线粒体被输送到需能的部位;而受损的线粒体可通过融合被清除掉,也在一定程度上保证了线粒体基因组的完整性。正常情况下,线粒体的分裂和融合维持在一个动态平衡的状态。若失衡则会导致诱发神经退行性疾病,线粒体的形态和功能也将发生变化。近年来,脑源性神经营养因子(BDNF)受到了科研者的广泛关注,因其在中枢神经系统中表达范围广,它不仅能调控神经元的生长、发育,并且在突触的可塑性中发挥着重要作用,研究显示它跟学习记忆有着密切的联系。而线粒体的动态变化与神经元的活性及突触可塑性密切相关。但BDNF与线粒体的动态变化的关系研究的不多。因此,我们在体外培养的神经元中,利用免疫荧光等方法探究了 BDNF与线粒体动态变化之间的联系,发现BDNF可通过调控线粒体的动态变化对神经元突触的可塑性发挥一定的作用。得到的结果具体有:1、BDNF刺激导致神经元树突中线粒体长度变短,提示BDNF诱导线粒体分裂增多;并且进一步研究发现BDNF刺激线粒体形态变化过程依赖于TrkB受体及其下游PLCγ-IP3、PI3K信号通路,从而实现对线粒体形态的调控。2、我们还发现BDNF处理下线粒体形态的变化与Drp1在线粒体上的分布有关。在BDNF刺激下,分布于线粒体上的Drp1蛋白含量升高,很可能是通过激活Myosin II从而进而调控更多的胞浆中的DRP1向线粒体外膜分布。3.BDNF促进线粒体分裂很可能在调控线粒体向神经元突触后的分布发挥重要的作用,跟神经元突触可塑性有密切的联系。
[Abstract]:The normal activities of neuronal growth, differentiation and synaptic transmission can not be achieved without mitochondria providing energy and regulating the influx of calcium ions in the cytoplasm. The changes of mitochondria morphology can affect the function of mitochondria. The morphology and function of mitochondria are regulated by the dynamic changes of mitochondrial division and fusion. The morphology and distribution of mitochondria in neurons are in a dynamic state. This process is accomplished by the precise regulation of a variety of proteins. Proteins such as Drp1mff and Fis1Mfn1Mfn2 regulate the fusion of mitochondria outer membrane, while Opa1 participate in the fusion of mitochondrial intima. Mitochondria can divide and increase the number of mitochondria, which is favorable for more mitochondria to be transported to the needed energy, while damaged mitochondria can be eliminated by fusion, which also ensures the integrity of mitochondrial genome to a certain extent. Normally, the mitosis and fusion of mitochondria remain in a dynamic equilibrium state. If imbalance leads to neurodegenerative diseases, the morphology and function of mitochondria will also change. In recent years, brain-derived neurotrophic factor (BDNF) has attracted wide attention from researchers. Because of its wide expression in the central nervous system, BDNFs can not only regulate the growth and development of neurons, but also play an important role in synaptic plasticity. Studies have shown that it is closely related to learning and memory. The dynamic changes of mitochondria are closely related to neuronal activity and synaptic plasticity. However, the relationship between BDNF and the dynamic changes of mitochondria is not studied much. Therefore, we explored the relationship between BDNF and mitochondrial dynamic changes in cultured neurons using immunofluorescence and other methods. It was found that BDNF could play a role in synaptic plasticity by regulating the dynamic changes of mitochondria. The results showed that the mitochondrial length in the dendrites of neurons was shortened by the stimulation of 1: 1 BDNF, which suggested that BDNF induced the increase of mitochondrial division, and further studies showed that the process of mitochondrial morphological changes induced by BDNF was dependent on the TrkB receptor and its downstream PLC 纬 -IP3 PI3K signaling pathway. We also found that the changes of mitochondrial morphology under BDNF treatment were related to the distribution of Drp1 in mitochondria. Under the stimulation of BDNF, the content of Drp1 protein distributed in mitochondria increased. It is possible that Myosin II activates the distribution of DRP1 in more cytoplasm to mitochondria outer membrane. 3. BDNF may play an important role in regulating mitochondrial postsynaptic distribution to neurons by promoting mitochondrial division. It is closely related to synaptic plasticity of neurons.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：Q42

【相似文献】