Post-translational modifications as a regulatory code for tau function in health and disease

Tau is an intrinsically disordered microtubule-associated protein that performs diverse roles in neuronal physiology, including regulation of microtubule stability, intracellular transport, and synaptic signaling. These functions are dynamically regulated by an extensive array of post-translational modifications (PTMs) that collectively shape tau conformation, interactions, localization, and turnover. Under physiological conditions, PTMs act as a regulatory system that enables tau to transition between functional states in response to cellular cues. In neurodegenerative diseases collectively known as tauopathies, however, this finely balanced modification landscape becomes disrupted, leading to tau mislocalization, impaired clearance, and assembly into toxic oligomers and fibrillar aggregates. Although phosphorylation has historically dominated the tau field, growing evidence indicates that multiple PTMs, including acetylation, ubiquitination, truncation, oxidation, nitration, methylation, and glycosylation, cooperatively influence tau structure and pathogenic potential. Recent proteomic studies reveal that tau can harbor dozens of modifications simultaneously, highlighting the importance of understanding PTMs as an integrated regulatory network rather than independent events. Crosstalk between modifications can generate synergistic or antagonistic effects that influence tau aggregation, proteostasis, and propagation. In this review, we synthesize current knowledge of major tau PTMs and highlight emerging principles governing their interactions. We discuss how dysregulation of PTM networks contributes to tau state transitions during aging and neurodegeneration and consider how targeting PTM-regulating enzymes may provide therapeutic strategies for Alzheimer's disease and related tauopathies.