Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou 510515, PR China.
Forensic Science Institute of Ganzhou Public Security Bureau, Ganzhou 341000, PR China.
Neurotoxicology. 2024 Jul;103:134-145. doi: 10.1016/j.neuro.2024.06.006. Epub 2024 Jun 18.
Methamphetamine (METH) is a widely abused amphetamine-type psychoactive drug that causes serious health problems. Previous studies have demonstrated that METH can induce neuron autophagy and apoptosis in vivo and in vitro. However, the molecular mechanisms underlying METH-induced neuron autophagy and apoptosis remain poorly understood. Stromal interacting molecule 1 (STIM1) was hypothesized to be involved in METH-induced neuron autophagy and apoptosis. Therefore, the expression of STIM1 protein was measured and the effect of blocking STIM1 expression with siRNA was investigated in cultured neuronal cells, and the hippocampus and striatum of mice exposed to METH. Furthermore, intracellular calcium concentration and endoplasmic reticulum (ER) stress-related proteins were determined in vitro and in vivo in cells treated with METH. The results suggested that STIM1 mediates METH-induced neuron autophagy by activating the p-Akt/p-mTOR pathway. METH exposure also resulted in increased expression of Orai1, which was reversed after STIM1 silencing. Moreover, the disruption of intracellular calcium homeostasis induced ER stress and up-regulated the expression of pro-apoptotic protein CCAAT/enhancer-binding protein homologous protein (CHOP), resulting in classic mitochondria apoptosis. METH exposure can cause neuronal autophagy and apoptosis by increasing the expression of STIM1 protein; thus, STIM1 may be a potential gene target for therapeutics in METH-caused neurotoxicity.
甲基苯丙胺（METH）是一种广泛滥用的苯丙胺类精神活性药物，会导致严重的健康问题。先前的研究表明，METH 可以在体内和体外诱导神经元自噬和细胞凋亡。然而，METH 诱导神经元自噬和凋亡的分子机制仍知之甚少。基质相互作用分子 1（STIM1）被假设参与了 METH 诱导的神经元自噬和凋亡。因此，在培养的神经元细胞中测量了 STIM1 蛋白的表达，并通过 siRNA 阻断 STIM1 表达来研究其对神经元的影响，同时还研究了 METH 暴露的小鼠海马体和纹状体中的情况。此外，还在体外和体内的细胞中测定了细胞内钙浓度和内质网（ER）应激相关蛋白。结果表明，STIM1 通过激活 p-Akt/p-mTOR 通路介导 METH 诱导的神经元自噬。METH 暴露还导致 Orai1 的表达增加，而在沉默 STIM1 后这种增加得到了逆转。此外，细胞内钙稳态的破坏诱导 ER 应激并上调促凋亡蛋白 CCAAT/增强子结合蛋白同源蛋白（CHOP）的表达，导致经典的线粒体凋亡。METH 暴露可通过增加 STIM1 蛋白的表达引起神经元自噬和凋亡；因此，STIM1 可能是治疗 METH 引起的神经毒性的潜在基因靶点。
