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

• Applicant: Professorin Dr. Anna von Mikecz
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280527128

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.

• DFG Programme: Research Grants