TAU ASSOCIATION WITH NUCLEAR ENVELOPE PROTEINS

The neuronal microtubule-associated protein Tau is best known for its axonal localization and role in microtubule stabilization. However, upon stress-induced somatodendritic missorting, Tau has a broader subcellular distribution with functions beyond the axon. For example, Tau in neuronal somata can dynamically associate with the nucleus, which is gaining interest because of Tau-nucleus interactions observed in Tau related neurodegenerative diseases, i.e., Alzheimer’s disease and frontotemporal dementia. To investigate how physiologically Tau levels influence nuclear function, we started by determining potential endogenous neuronal nuclear interactions partners of Tau using different proximity biotinylation approaches. Antibody-mediated proximity biotinylation in naïve, mature primary hippocampal mouse neurons revealed a significant association of Tau with nuclear-related proteins. To further define Tau-associated nuclear interaction networks, we used TurboID-Tau expression combined with nuclear fractionation, which identified interactions between Tau and proteins involved in chromatin organization at the nuclear membrane, e.g., lamin B receptor (LBR) and SUN1. Increased nuclear-associated Tau was accompanied by alterations in nuclear envelope architecture, characterized by invaginations and other structural perturbations, and chromatin re-arrangement. Together, these findings provide insight into how Tau redistribution may influence nuclear function and chromatin organization in neurons.