Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning 110001, People's Republic of China.
Toxicology. 2013 Mar 8;305:71-8. doi: 10.1016/j.tox.2013.01.006. Epub 2013 Jan 23.
Overexposure to manganese (Mn) has been known to induce neuronal damage. However, little is known of the role that reactive oxygen species (ROS) play in protein aggregation resulting from Mn exposure. The current study investigated whether oxidative stress is involved in manganese-induced alpha-synuclein oligomerization in organotypic brain slices. After application of Mn (0-400μM) for 24h, there was a dose-dependent increase in average percentage of propidium iodide positive (PI(+)) nuclei in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, the treatment with Mn resulted in a dose-dependent increase in neurocyte apoptosis, ROS level, and decrease in superoxide dismutase (SOD) activity. Mn also caused oxidative damage in cell lipid and protein. At the same time, the exposure of Mn leaded to significantly increase in the expression of alpha-synuclein mRNA and protein. Alpha-synuclein oligomerization occurred in Mn-treated slices, especially on membrane-bound form. It indicated that alpha-synuclein oligomers were more likely to combination cell membranes and resulting in membrane damage. Mn-induced neurocyte damage and alpha-synuclein oligomerization were also partially alleviated by the pretreatment with GSH and aggravated by H2O2 pretreatment. The findings revealed Mn might exert its neurotoxic effects by oxidative stress-mediated alpha-synuclein oligomerization in organotypic brain slices.
过量的锰（Mn）已被证实会导致神经元损伤。然而，对于活性氧（ROS）在锰暴露导致的蛋白质聚集中所起的作用，人们知之甚少。本研究探讨了氧化应激是否参与了锰诱导的脑片α-突触核蛋白寡聚化。在应用 Mn（0-400μM）24 小时后，切片中碘化丙啶阳性（PI(+))核的平均百分比和培养上清液中乳酸脱氢酶（LDH）的水平呈剂量依赖性增加。此外，Mn 处理导致神经细胞凋亡、ROS 水平呈剂量依赖性增加，超氧化物歧化酶（SOD）活性降低。Mn 还导致细胞脂质和蛋白质的氧化损伤。同时，Mn 的暴露导致α-突触核蛋白 mRNA 和蛋白的表达显著增加。Mn 处理的切片中出现α-突触核蛋白寡聚体，特别是膜结合形式。这表明α-突触核蛋白寡聚体更有可能与细胞膜结合，导致细胞膜损伤。用 GSH 预处理可以部分减轻 Mn 诱导的神经细胞损伤和α-突触核蛋白寡聚化，而过氧化氢预处理则加剧了这种损伤。这些发现表明，Mn 可能通过氧化应激介导的脑片α-突触核蛋白寡聚化发挥其神经毒性作用。
