BioID2-Based Tau Interactome Reveals Novel and Known Protein Interactions Associated with Multiple Cellular Pathways

Pathological inclusions composed of tau are hallmarks of neurodegenerative diseases termed tauopathies, the most common of which is Alzheimer's disease. Accumulating evidence suggests that tau is involved in a multitude of physiological functions that are regulated, in part, by direct and/or transient protein interactions. Deciphering the tau interactome is critical for understanding the physiological and pathological roles of tau. This work aimed to identify potential tau interactors using the <i>in situ</i> protein labeling biotin identification (BioID2) method. Advantages of this approach include in-cell interactor labeling and an enhanced likelihood of detecting transient and/or weak interactions. We identified 324 potential tau interactors spanning multiple cellular compartments and pathways. We validated tau interactions with selected candidates using two independent approaches: proximity ligation assay and co-immunoprecipitation (co-IP) which included cytoskeletal proteins (MAP2 and MAP6), nucleus-associated proteins (FUS and prune1), and synaptic proteins (synapsin-1 and neurabin-2). Importantly, this approach revealed potential novel interactors that were not clearly identified by other interaction approaches such as co-IP. Thus, this approach is a powerful tool to identify potential members of the tau interactome via <i>in situ</i> labeling. This work helps expand our understanding of tau's physiological roles, which may also advance our understanding of its role in neurodegenerative diseases.