帕金森病(PD)是一种主要影响老年人群的神经退行性疾病,它的病因是神秘的。环境风险和遗传都可能影响PD的发展。过量的铜引起神经毒性并加速神经退行性疾病的进展。然而,铜诱导的神经毒性的潜在机制仍存在争议.在这项研究中,A53T转基因α-突触核蛋白(A53T)小鼠及其匹配的野生型(WT)小鼠用低剂量的铜(0.13ppm铜氯化饮用水,相当于人类每日铜摄入量的铜暴露量)4个月,并对过表达α-突触核蛋白的人A53T突变体SHSY5Y细胞进行铜中毒(剂量为1/4IC50),测试铜暴露对身体的影响。旷场试验的结果表明,Cu处理的小鼠的运动功能受损。蛋白质组学揭示了神经发育的变化,运输功能,和铜处理的WT小鼠的线粒体膜相关功能,与线粒体复合物(NDUFA10,ATP5A)的表达降低有关,多巴胺神经元(TH),和多巴胺转运蛋白(DAT)。线粒体功能,神经系统发育,突触功能,在Cu处理的A53T小鼠中,免疫应答改变。这些变化与线粒体分裂蛋白(Drp1)增加有关,减少线粒体融合蛋白(OPA1,Mfn1),线粒体自噬蛋白异常(LC3BII/I,P62),多巴胺神经元(TH)表达减少,α-突触核蛋白表达增加,炎症因子(IL-6,IL-1β,和TNF-α)释放和小胶质细胞(Iba1)激活。此外,我们发现Cu2+(30μM)在人A53T突变体α-突触核蛋白过表达SHSY5Y细胞中诱导过量ROS产生并减少线粒体ATP产生。总之,低剂量铜处理改变了涉及线粒体的关键蛋白质,神经发育,和炎症反应,并影响线粒体的ROS和ATP产生水平。
Parkinson\'s disease (PD) is a
neurodegenerative disorder that mainly affects the elder population, and its etiology is enigmatic. Both environmental risks and genetics may influence the development of PD. Excess copper causes neurotoxicity and accelerates the progression of
neurodegenerative diseases. However, the underlying mechanisms of copper-induced neurotoxicity remain controversial. In this study, A53T transgenic α-synuclein (A53T) mice and their matching wild-type (WT) mice were treated with a low dose of copper (0.13 ppm copper chlorinated drinking water, equivalent to the copper exposure of human daily copper intake dose) for 4 months, and copper poisoning was performed on human A53T mutant SHSY5Y cells overexpressed with α-synuclein (dose of 1/4 IC50), to test the effects of copper exposure on the body. The results of the open field test showed that the moto function of Cu-treated mice was impaired. Proteomics revealed changes in neurodevelopment, transport function, and mitochondrial membrane-related function in Cu-treated WT mice, which were associated with reduced expression of mitochondrial complex (NDUFA10, ATP5A), dopamine neurons (TH), and dopamine transporter (DAT). Mitochondrial function, nervous system development, synaptic function, and immune response were altered in Cu-treated A53T mice. These changes were associated with increased mitochondrial splitting protein (Drp1), decreased mitochondrial fusion protein (OPA1, Mfn1), abnormalities in mitochondrial autophagy protein (LC3BII/I, P62), decreased dopamine neuron (TH) expression, increased α-synuclein expression, inflammatory factors (IL-6, IL-1β, and TNF-α) release and microglia (Iba1) activation. In addition, we found that Cu2+ (30 μM) induced excessive ROS production and reduced mitochondrial ATP production in human A53T mutant α-synuclein overexpressing SHSY5Y cells by in vitro experiments. In conclusion, low-dose copper treatment altered critical proteins involved in mitochondrial, neurodevelopmental, and inflammatory responses and affected mitochondria\'s ROS and ATP production levels.