线粒体轴突转运和锚定在稀土元素镧中枢神经毒性中的作用及其机制

Lanthanum, a rare-earth element, can damage the abilities of learning and memory and has central neurotoxicity. However, the mechanism underlying the toxic effects is not clear completely. Moter Kinesin-1-drived axonal transport and Kinesin-1-SNPH-induced anchoring of mitochondria are very critical for the maintenance of funtions in synapses and neurons. Our previous studies showed that lanthanum exerted harmful effects on mitochondria and synaptic function in the hippocampus, and decreased the expression of KHC, which was the heavy chain of Kinesin-1. Thefefore, we assume that lanthanum may induce the aberrant axonal transport and anchoring of mitochondria by affecting the expression and interactions of Kinesin-1 and its adaptor, track and anchoring proteins, cause the abnormal distribution, molity and funtion of mitochondria, damage the functions of synapses and neurons, and thus lead to low intelligence and abilities of learning and memory. In this study, the assumption above will be confirmed by experiments in viov and in vitro, making use of many techniques such as neuroelectrophysiology and molecular biology. This study will confirm that the aberrant Kinesin-1-drived axonal transport and Kinesin-1-SNPH-induced anchoring of mitochondria are critical mechanism underlying the central neurotoxicity induced by lanthanum, and provide important foundation for effective intervention of harmful effects on the central nervous system caused by lanthanum and even rare-earth elements.

稀土元素镧损害学习记忆能力，具有中枢神经毒性作用，但其机制尚未完全明确。马达蛋白Kinesin-1驱动的线粒体轴突转运和Kinesin-1-SNPH介导的线粒体锚定在维持神经突触和神经元功能中发挥至关重要作用。我们前期研究发现，镧对海马神经元线粒体和神经突触功能产生损害效应，降低Kinesin-1重链KHC表达，因而提出假设：镧通过影响Kinesin-1及其衔接蛋白、轨道蛋白、锚定蛋白表达和/或相互作用，造成线粒体轴突转运和锚定障碍，引起线粒体分布、动力学特征和功能异常，损害神经突触和神经元功能，进而导致学习记忆能力低下。本研究拟采用体内外试验、利用神经电生理学和分子生物学等多种技术手段验证上述研究假设，阐明Kinesin-1驱动的线粒体轴突转运和Kinesin-1-SNPH介导的线粒体锚定障碍是镧所致中枢神经毒性作用的关键机制，为有效干预镧乃至稀土元素的中枢神经损害效应提供重要依据。

稀土元素镧（La）损害学习记忆能力，具有中枢神经毒性作用，但其机制尚未完全明确。突触是神经元间信息传递的关键部位，将线粒体准确转运并锚定到突触部位对维持突触功能是极为重要的。线粒体轴突转运和锚定障碍，导致线粒体分布异常，轴突末端突触部位线粒体数量减少，造成ATP供应不足，损害突触功能，引起学习记忆等认知能力下降。马达蛋白Kinesin-1驱动的线粒体轴突转运和Kinesin-1-SNPH介导的线粒体锚定在维持神经突触和神经元功能中发挥至关重要作用。本项目采用体内外试验、利用神经电生理学和分子生物学等多种技术手段，主要观察了La对学习记忆能力、神经元和神经突触结构与功能、线粒体结构、分布、动力学特征以及功能的影响，研究了La对海马线粒体轴突转运马达蛋白Kinesin-1及其衔接蛋白、轨道蛋白、锚定蛋白、相关调节激酶/因子表达和相互作用的影响，探讨了调控线粒体轴突转运和锚定的干预剂是否能够拮抗La的中枢神经毒性效应，明确了La所致学习记忆能力下降、神经元和神经突触结构与功能、线粒体结构、分布、动力学特征以及功能的异常变化，La的中枢神经毒性作用与海马线粒体轴突转运马达蛋白Kinesin-1及其衔接蛋白、轨道蛋白、锚定蛋白以及相关调节激酶/因子表达和相互作用异常有关，调控线粒体轴突转运和锚定的干预剂1-Azakenpaullone对La所致神经元和神经突触、线粒体结构、动力学特征和功能的异常具有拮抗作用，对La所致线粒体轴突转运速率下降、马达蛋白Kinesin-1、锚定蛋白SNPH及相关调节因子表达异常亦具有拮抗作用，从而确定了La通过影响Kinesin-1及其衔接蛋白、轨道蛋白、锚定蛋白表达和相互作用，造成线粒体轴突转运和锚定障碍，引起线粒体分布、动力学特征和功能异常，损害神经突触和神经元功能，进而导致学习记忆能力低下，进而确定了Kinesin-1驱动的线粒体轴突转运和Kinesin-1-SNPH介导的线粒体锚定障碍是La致中枢神经毒性作用的关键机制，为深入阐述La中枢神经毒性作用机制提供了新的资料，并为有效干预La乃至稀土元素的中枢神经损害效应提供重要线索和依据。