Pathological inclusions composed of tau protein are hallmarks of neurodegenerative diseases collectively known as tauopathies, of which the most common is Alzheimer's Disease (AD). Tau is most well-known as a microtubule-associated protein involved in regulating microtubule dynamics, but accumulating evidence suggests tau is involved in many biological functions. Deciphering the tau protein interactome is critical for better understating the physiological and pathological roles of tau. This work aimed to identify tau interacting partners using the in situ protein labelling BioID2 method by creating fusion proteins between full-length human tau and either BioID2 on the N-terminus (BioID2-Tau) or C-terminus (Tau-BioID2). A total of 372 proteins were identified, of which 269 interacted with Tau-BioID2, 169 with BioID2-Tau, and 66 proteins overlapped between both tau proteins. Gene Ontology (GO) cellular component analysis mapped protein interactions in the mitochondria, cytoskeleton, dendrites, nucleus, synaptic vesicles, and the ribonucleoprotein complex. While GO molecular function pathways identified proteins involved in RNA binding, translation regulation, ubiquitin ligase activity, kinase binding, mitochondrial oxidoreductase, and peroxidase activity. KEGG pathway analysis identified proteins associated with neurodegenerative diseases, including AD, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Thus, this approach can identify members of the tau interactome via in situ labeling, that may help shed light on tau's functional roles and provide novel therapeutic strategies for neurodegenerative diseases.
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