砷致海马神经元自噬激活及其对神经突触传递功能影响的机制研究

Chronic arsenic exposure is associated with cancer effects and non-cancer effects including central nervous system disorders such as cognitive impairment. Due to its severe health lesions, environmental arsenic exposure has been regarded as an urgent public issue worldwide. The mechanism of arsenic induced cognitive impairment is unclear. Autophagy is an essential process broadly existing in the euaryotic cells. Defective or excessive autophagy is related with many pathologic processes of the cell and the occurrence of diseases. Autophagy is reported to impair the synaptic transmission by reducing the neurotransmitter release, inducing degradation of the receptor of neurotransmitter, and decreasing protein expression of the synaptic plasticity. Excessive ROS is proposed to activate autophagy through a single signaling pathway or the crosslink of several signaling pathways. Convincing evidences suggested that arsenic could induce over production of ROS. Moreover, our previous findings indicated that perinatal arsenic exposure could induce cognitive impairment in the mice and the activation of autophagy in the hippocampal neurons. Whether arsenic can induce the activation of autophagy through the induced excessive ROS and its consequent effects on the synaptic transmission is unclear up to now. The aim of this study is to discuss the mechanisms of arsenic induced autophagy and its consequent effects on the synaptic transmission, which will add new insights to the arsenic related neurotoxicity.

长期环境砷暴露可引起癌性病变以及包括神经系统认知功能损伤在内的多种非癌性病变。环境砷暴露由于危害严重，现已成为世界范围内一个重要公共卫生问题。砷致认知功能损伤机制目前仍不清楚。自噬是广泛存在于真核细胞中的生命现象，自噬水平不足或过度自噬与细胞的很多病理过程及疾病发生有关。自噬可通过影响神经递质释放、降解神经递质受体，降低突触可塑性相关蛋白表达等途径引起神经突触传递功能异常。过量ROS可通过某一条或多条信号通路相互交叉激活自噬。而砷暴露已被确证可诱导过量ROS生成，且本研究组在前期研究中发现，经母体发生砷暴露的子代小鼠在出现认知功能损伤的同时，海马神经元中自噬水平增高。但关于砷暴露是否可通过其诱导产生的ROS激活自噬及其对神经突触传递功能的影响方面未见详细报道。本研究拟通过动物及细胞实验，探讨砷致海马神经元自噬发生的机制及其对神经突触传递功能的影响，为砷致认知功能损伤的机制研究提供基础数据。

砷位居危害人体健康的环境毒物首位，长期环境砷暴露可引起癌性病变以及包括神经系统认知功能损伤在内的多种非癌性病变，环境砷暴露及其健康危害一直是一个世界性公共卫生问题。砷致认知功能损伤机制目前仍不清楚。本研究发现，砷暴露诱导线粒体PGAM5水平表达上调，引起其参与调控的线粒体分裂融合功能障碍，造成线粒体损伤、膜电位下降、ATP水平下降，同时释放大量ROS。ROS通过JNK/CTSB信号通路引起神经细胞自噬通量改变，进而通过降低波形蛋白的表达引起神经生长异常，从而导致神经突触结构的异常；砷暴露致神经细胞自噬通量改变还可诱导α-syn寡聚化，从而抑制突触囊泡对接停靠、减少SNARE复合体形成，导致神经细胞多巴胺释放减少，从而引起神经突触的功能异常。此外，砷暴露致线粒体能量代谢障碍可活化AMPK通路，激活AMPK-mTOR自噬通路，通过小窝蛋白Cav-1介导自噬依赖性外源性细胞凋亡。抗氧化物NAC及虾青素可通过下调PGAM5水平，稳定线粒体功能，降低砷暴露诱导的自噬通量变化，从而改善其诱导的神经突触结构及功能损伤，降低自噬依赖性细胞凋亡水平。本研究结果可望对砷致神经系统损伤的机制提供基础数据，为神经系统损伤的防控提供潜在靶点。