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

Neurodegenerative tauopathies, including Alzheimer's disease, are neuropathologically defined by pathological tau deposition. While tau drives neurotoxicity by disrupting cytoskeletal, nucleoskeletal, and genomic architecture, cellular mechanisms mediating tau-induced dysfunction of the cytoskeleton and nucleoskeleton are incompletely understood. Here, we identify proteins with differing abundance in a cellular tauopathy model, iTau. Building upon previous findings that pathogenic tau reduces nuclear tension, we find elevated levels of emerin, a central regulator of nuclear mechanotransduction, in iTau neurons and tau mutant iPSC-derived neurons. Neuronal emerin overexpression drives neurotoxicity, increases filamentous actin (F-actin), and induces nuclear invagination, mimicking cellular phenotypes of tauopathy. Alterations in emerin binding partners reflect its cytosolic relocalization in iTau neurons, suggesting that pathogenic tau may impact nuclear mechanotransduction by altering emerin levels and localization. Overall, we identify emerin as a potential mediator of cytoskeletal and nucleoskeletal remodeling in tauopathy and provide a foundation for future studies of emerin function in neurons.