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.

中文翻译：

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重金属污染进行性核上性麻痹簇的环境，会在培养的神经元中引起tau积累和细胞死亡。

进行性核上性麻痹（PSP）是一种神经退行性疾病，其特征在于存在tau蛋白的细胞内聚集体和导致认知和运动障碍的神经元丢失。发生大多是零星的，但已描述了罕见的家族簇。尽管PSP的病因病理尚不清楚，但MAPT / tau基因的突变和暴露于环境毒素会增加PSP的风险。在这里，我们使用细胞模型来调查在法国高度工业化地区富集的重金属对潜在的神经毒性作用，其中包括一堆散发的PSP病例。我们发现，来自MAPT突变载体的iPSC衍生的iNeurons倾向于比同基因对照品系对铬（Cr）和镍（Ni）暴露诱导的细胞死亡更为敏感。我们假设遗传变异可能导致这些重金属诱发神经变性。此外，使用SH-SY5Y神经母细胞瘤细胞系，我们显示两种重金属均通过凋亡机制诱导细胞死亡。有趣的是，Cr和Ni处理增加了两种细胞类型中总tau和磷酸化tau的水平，这暗示了tau病理学中Cr和Ni的暴露。总体而言，这项研究表明，铬和镍可通过促进tau积累和神经元细胞死亡来促进诸如PSP之类的疾病。在tau病理学中暗示了Cr和Ni的暴露。总体而言，这项研究表明，铬和镍可通过促进tau积累和神经元细胞死亡来促进诸如PSP之类的疾病。在tau病理学中暗示了Cr和Ni的暴露。总体而言，这项研究表明，铬和镍可通过促进tau积累和神经元细胞死亡来促进诸如PSP之类的疾病。