Elevation of the mechanically-sensitive protein emerin links nuclear mechanotransduction to tau-induced cytoskeletal remodeling in neurons.

Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease, that are neuropathologically defined by deposition of pathological forms of tau in the brain. While tau is reported to drive neurotoxicity by negatively affecting cytoskeletal, nucleoskeletal, and genomic architecture, the mechanisms mediating tau-induced dysfunction of the cytoskeleton and nucleoskeleton are incompletely understood. Based on proteomic profiling, we identify a suite of cytoskeletal and nucleoskeletal proteins with differing abundance in a cellular model of tauopathy, iTau. Building upon previous findings that pathogenic forms of tau reduce nuclear tension, we find that protein levels of emerin, a central regulator of nuclear mechanotransduction, are significantly elevated in iTau cells and in induced pluripotent stem cell (iPSC)-derived neurons carrying a mutation in the microtubule-associated protein tau (MAPT) gene that causes autosomal dominant frontotemporal dementia. We find that neuronal emerin overexpression is sufficient to drive neurotoxicity, increase overall levels of filamentous actin (F-actin), and induce nuclear invagination, cellular phenotypes that also occur in settings of tauopathy. Mass spectrometry-based identification of emerin-interacting proteins in iTau-derived neurons reveals increased interactions with cytoskeletal proteins and reduced interactions with nuclear proteins. Indeed, we find that emerin relocalizes from the nucleus to the cytosol in the setting of tauopathy, suggesting that pathogenic tau impacts nuclear mechanotransduction pathways. Overall, we identify emerin as a mediator of cytoskeletal remodeling in tauopathy and provide a foundation for future studies into the mechanosensitive function of emerin in neurons.