Interactions between mercury-induced amyloid formation in the cell nucleus, gene expression and neural signalling.

汞(Hg)是一种生物积累的痕量金属，可以到达北极等偏远地区。一份关于大西洋和太平洋的全球汞浓度的开创性清单刚刚发布。前瞻性流行病学研究表明，无机汞(i-Hg)在美国人口中以年龄相关的方式积累。虽然汞代表着一种臭名昭著的神经毒物，但其潜在的细胞通路还不够清楚。我们可以证明，亚细胞毒性浓度的i-Hg加速了细胞培养和土壤线虫的核淀粉样蛋白的形成。在神经SH-SY5Y细胞中，核蛋白如层蛋白B1、核磷蛋白、核素和剪接体成分以及热休克蛋白和泛素原纤化形成耐十二烷基硫酸钠的聚集体网络。共聚焦成像发现在核斑点中心形成的淀粉样微环境在lamin B1的控制下富含RNA加工因子。依赖于Lamin B1的淀粉样蛋白的形成表明，类似于细胞骨架控制的蛋白质在细胞质中的聚集，核蛋白的淀粉样纤颤可能是由核骨架驱动的。基于广泛的知识表明核结构和功能之间的密切关系，我们建议调查I-Hg诱导的核内淀粉样蛋白形成对基因表达和神经功能的影响，例如信号通路。建议的工作计划旨在提高我们对核骨架、蛋白质稳态和基因表达之间的相互作用以及汞对神经损伤的理解。

Mercury (Hg) is a bioaccumulating trace metal that reaches remote regions such as the arctic. A seminal inventory of global Hg concentrations throughout the Atlantic and Pacific Oceans has just been published. Prospective epidemiologic studies indicate that inorganic mercury (I-Hg) accumulates in the US population in an age-dependent manner. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We could show that sub-cytotoxic concentrations of I-Hg accelerate nuclear amyloid formation in cell culture and the soil nematode C. elegans. In neural SH-SY5Y cells nuclear proteins such as lamin B1, nucleophosmin, nucleolin and spliceosomal components as well as heat shock proteins and ubiquitin fibrillate to an SDS-resistant aggregome network. Confocal imaging identified amyloid microenvironments that form in the center of nuclear speckles enriched with RNA processing factors under the control of lamin B1. Lamin B1-dependent amyloid formation suggests that similar to cytoskeleton-controlled protein aggregation in the cytoplasm, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton. Based on the extensive knowledge suggesting a close relationship between nuclear structure and function we propose to investigate the consequences of I-Hg-induced amyloid formation in the nucleus for gene expression and neural function, e.g. signalling pathways. The suggested work program is designed to improve our understanding of the interplay between the nucleoskeleton, protein homeostasis and gene expression as well as neural impairment by Hg.