GRP78/SOD-1途径参与铅暴露致肌萎缩侧索硬化发病的机制研究

肌萎缩侧索硬化（ALS）是累及运动神经元的退行性疾病，铅是ALS重要环境危险因素，阐明铅暴露促进ALS发病的关键机制，对于ALS防治意义重大。SOD-1异常聚集是ALS发病的重要途径，铅是否通过SOD-1引起ALS发病目前尚不清楚。文献与我们前期研究显示：①ALS患者的血铅水平显著高于其他神经疾病；②铅能够引起SOD-1表达增多、酶活性降低；③铅暴露可引起SOD-1的上游分子GRP78表达增多、伴侣功能抑制；④异常聚集的SOD-1与GRP78相互作用形成包涵体，影响运动神经元蛋白降解。由此推测，铅通过干扰GRP78的表达或功能导致SOD-1异常聚集，从而引起运动神经元损伤，最终促进ALS发病。本课题拟构建ALS铅暴露模型，从整体、细胞、分子水平揭示GRP78/SOD-1途径在铅促进ALS发病中的关键作用。这些研究可加深对铅暴露致ALS发病分子机制的理解，为防治ALS提供新的角度和研究基础。

Amyotrophic lateral sclerosis (ALS) is a degenerative disease that motor neurons are damaged. Lead is an important environmental risk factor for ALS. Elucidating the key mechanisms that lead exposure promotes ALS is of great significance for the prevention and treatment of ALS. The abnormal aggregation of SOD-1 was an important pathogenesis of ALS, however, it was unclear whether lead causes ALS through SOD-1. Literature and our previous studies have shown that: ① The blood lead level of ALS patients was significantly higher than other neurological diseases; ② Lead caused abnormal aggregation of SOD-1 and decrease its enzyme activity; ③ Lead exposure increased expression of GRP78, an upstream molecule of SOD-1. Molecular chaperone activity of GRP78 was inhibited by lead exposure; ④ The abnormally aggregated SOD-1 interacted with GRP78 to form inclusion bodies, which affected degradation of motor neuron proteins. It was speculated that lead may cause abnormal aggregation of SOD-1 by interfering with the expression or function of GRP78, thereby damaging motor neuron and eventually promoting the pathogenesis of ALS. This project intended to construct a lead exposure model for ALS, and reveal the key role of GRP78/SOD-1 pathway in the pathogenesis of lead in ALS from overall, cellular and molecular levels. These studies will deepen the understanding of the molecular mechanism of ALS caused by lead exposure, and provide a new perspective and research basis for the prevention and treatment of ALS.