Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons
Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons
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DOI：
10.1038/s41598-019-56930-w
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发表时间：
2020-01-17
影响因子：
4.6
通讯作者：
Kao, Aimee W.
中科院分区：
文献类型：
--
作者：
Alquezar, Carolina;Felix, Jessica B.;Kao, Aimee W.
进行性核上性瘫痪(PSP)是一种神经退行性疾病，其特征是细胞内存在tau蛋白聚集体，神经元丢失导致认知和运动功能障碍。大多数是零星发生的，但罕见的家族聚集性已被描述。虽然PSP的发病机制尚不清楚，但MAPT/tau基因突变和暴露于环境毒素可增加PSP的风险。在这里，我们使用细胞模型来研究在法国一个高度工业化的地区富含重金属的潜在神经毒性效应，并对一系列散发性PSP病例进行了研究。我们发现，来自MAPT突变载体的iPSC来源的iNeurons对铬(Cr)和镍(Ni)暴露所致的细胞死亡倾向于比同基因对照系更敏感。我们推测，基因变异可能容易导致这些重金属引起的神经退行性变。此外，使用SH-SY5Y神经母细胞瘤细胞系，我们发现这两种重金属都通过一种凋亡机制诱导细胞死亡。有趣的是，铬和镍处理增加了两种细胞类型的总tau水平和磷酸化tau水平，暗示在tau病理中暴露于铬和镍。总体而言，这项研究表明，铬和镍可能通过促进tau积聚和神经细胞死亡而参与PSP等tau病的病理生理学。
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death.