Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission.

Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease defined pathologically by the presence of insoluble phosphorylated-Tau (p-Tau) in neurons and glia. Identifying co-aggregating proteins within p-Tau inclusions may reveal important insights into processes affected by the aggregation of Tau. We used a proteomic approach, which combines antibody-mediated biotinylation and mass spectrometry (MS) to identify proteins proximal to p-Tau in PSP. Using this proof-of-concept workflow for identifying interacting proteins of interest, we characterized proteins proximal to p-Tau in PSP cases, identifying >84% of previously identified interaction partners of Tau and known modifiers of Tau aggregation, while 19 novel proteins not previously found associated with Tau were identified. Furthermore, our data also identified confidently assigned phosphorylation sites that have been previously reported on p-Tau. Additionally, using ingenuity pathway analysis (IPA) and human RNA-seq datasets, we identified proteins previously associated with neurological disorders and pathways involved in protein degradation, stress responses, cytoskeletal dynamics, metabolism, and neurotransmission. Together, our study demonstrates the utility of biotinylation by antibody recognition (BAR) approach to answer a fundamental question to rapidly identify proteins in proximity to p-Tau from post-mortem tissue. The application of this workflow opens up the opportunity to identify novel protein targets to give us insight into the biological process at the onset and progression of tauopathies.