Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology
Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology
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DOI：
10.1093/toxsci/kfy267
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Wolozin, Benjamin
中科院分区：
文献类型：
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作者：
Ash, Peter E. A.;Dhawan, Uma;Wolozin, Benjamin
重金属，如铅、汞和硒，在流行病学上与ALS的风险有关，但证明这种联系的分子机制尚未显示。推定的发育神经毒素的屏幕表明，重金属（铅，汞和锡）触发TDP-43积累到核颗粒与弥散性核TDP-43的损失伴随。铅（Pb）和甲基汞（MeHg）破坏TDP-43在神经元中的稳态，导致TDP-43的转录水平增加和剪接活性增加。TDP-43稳态受到严格调节，并且积极或消极地改变其剪接抑制活性已被证明对神经元有害。这些变化与TDP-43进入核体的液-液相分离有关。我们发现，铅直接促进TDP-43在体外的剂量依赖性的方式相分离，可能解释的手段，铅治疗的结果在神经元核颗粒。金属毒物还引发了不溶性TDP-43在培养细胞和暴露小鼠皮质中的积累。这些结果提供了新的证据，表明重金属（常被引用的ALS环境风险）与TDP-43（ALS中积累的主要病理蛋白质）的分子变化之间存在直接的机械联系。
Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.