神经元活性通过线粒体中CREB偶联线粒体基因转录的分子机制及其失调与亨廷顿舞蹈症的关系探讨

Communication between neuronal activity and nuclear transcription is thought to be crucial for long-term plasticity and learning. In addition to nucleus, mitochondrion also has its own transcription system and plays a critical role in neuronal homeostasis and plasticity. However, the relationship of mitochondrial transcription and neuronal activity, as well as its physiological significance still remains unclear. Our preliminary data showed that the transcription factor CREB was expressed in mitochondria and could be regulated by neuronal activity, indicating a potential coupling in between. In this proposal, the applicant will use in vitro and in vivo strategies to study mitochondrial CREB activation and its downstream targets. Because of the importance of axonal mitochondria in neuronal degeneration, the applicant will specifically manipulate the status of axonal mitochondria and investigate its role in regulating activity-dependent mitochondrial transcription. Moreover, the applicant will utilize the R6/2 transgenic mice and post-mortem brain samples of Huntington's disease patients to elucidate the in vivo role of such coupling. By doing this, the applicant aims to clarify the coupling mechanism between mitochondrial transcription and neuronal activity, and thus providing new insights into drug development targeting mitochondrial dysfunction-mediated impairments in Huntington's disease.

神经元活动通过信号转导可激活其细胞核内基因转录，这一过程对于神经元可塑性十分关键，被认为是长期记忆的分子基础之一。作为细胞核外唯一拥有自身转录系统的细胞器，线粒体在维持神经元稳态和功能可塑性中不可或缺，但其基因转录与神经元活性之间的关系及生理意义目前还不清楚。我们预实验结果发现和细胞核类似，神经元线粒体中也表达关键转录调控因子CREB，且其磷酸化可被神经元活性所调控，提示两者偶联的可能性。本项目将采用多元化手段，从研究线粒体CREB激活入手，通过操控神经元轴突中线粒体的运动分布状态，解析神经元活性依赖性线粒体基因转录对线粒体及神经元功能的影响，并利用亨廷顿舞蹈症转基因小鼠及临床样本进一步探讨其偶联的生理意义。通过体外体内实验有机结合，本项目的执行不仅可以阐明线粒体基因转录与神经元活性偶联机制这一重要的科学问题，更将为开发线粒体基因转录失调导致的神经退行性疾病的治疗提供新的思路与靶点。

神经元活动通过信号转导激活基因转录与翻译，这一过程中线粒体供能对于神经元应对整体或局部的刺激十分重要。已有研究表明，不同于突触前，突触后的能量供应仅来源于线粒体，线粒体基因转录缺陷可抑制神经元功能的执行。然而这种活性调控的线粒体内部的基因转录的机制尚不清楚，需要进一步探索研究。本项目本实验室的GOI为基础，发现在神经元活动中，定位于线粒体的钙调蛋白激酶CaMKII特异性调控线粒体钙离子流，其功能失调可损伤线粒体膜电位，降低静息状态神经元的表面GluA1，进而影响长时程增强。我们构建了特诱导的LoxP小鼠，发现调控线粒体基因转录可影响学习与记忆，其具体的在体效应正在研究中。此研究成果对于阐明神经活动-基因转录-线粒体功能耦连机制具有重要意义。在项目的支持下，本人分别作为并列第一作者，第二作者与第四作者在Autophagy、Cell Reports和Neuron上发表文章。