title: Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity.
abstract: Mercury (Hg) is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions. By mass spectrometry of purified protein aggregates, a subset of spliceosomal components and nucleoskeletal protein lamin B1 were detected as constituent parts of an Hg-induced nuclear aggregome network. The aggregome network was located by confocal imaging of amyloid-specific antibodies and dyes to amyloid cores within splicing-speckles that additionally recruit components of the ubiquitin-proteasome system. Hg significantly enhances global proteasomal activity in the nucleus, suggesting that formation of amyloid speckles plays a role in maintenance of protein homeostasis. RNAi knock down showed that lamin B1 for its part regulates amyloid speckle formation and thus likewise participates in nuclear protein homeostasis. As the Hg-induced cascade of interactions between the nucleoskeleton and protein homeostasis reduces neuronal signalling, amyloid fibrillation in the cell nucleus is introduced as a feature of Hg-neurotoxicity that opens new avenues of future research. Similar to protein aggregation events in the cytoplasm that are controlled by the cytoskeleton, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton.
authors.affiliation: IUF-Leibniz Research Institute for Environmental Medicine at Heinrich-Heine-University Duesseldorf , Duesseldorf , Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Arnhold
authors.affiliation: CF Proteomics, FLI-Leibniz-Institute for Age Research, Fritz-Lipman-Institute e.V. , Jena , Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Gührs
authors.affiliation: IUF-Leibniz Research Institute for Environmental Medicine at Heinrich-Heine-University Duesseldorf , Duesseldorf , Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: von Mikecz
keywords: Amyloid; Confocal microscopy; Lamin B; Mercury; Nucleoplasm; Nucleus; Protein fibrillation; Proteomics; RNA splicing; Ribonucleoproteins