Untangling the complexity and impact of tau protein ubiquitination

The microtubule-associated protein tau is an intrinsically disordered protein highly expressed in neuronal axons. Inhealthy neurons, tau regulates microtubule dynamics and neurite outgrowth. However, pathological conditions cantrigger aberrant tau aggregation into insoluble filaments, a hallmark of neurodegenerative disorders known astauopathies. Tau undergoes diverse posttranslational modifications (PTMs), suggesting complex regulation andpotentially varied functions. Among PTMs, the role and mechanisms of ubiquitination in physiology and disease haveremained enigmatic. The past three decades have witnessed the emergence of key studies on tau protein ubiquitination.In this concept, we discuss how these investigations have begun to shed light on the ubiquitination patterns ofphysiological and pathological tau, the responsible enzymatic machinery, and the influence of ubiquitination on tauaggregation. We also provide an overview of the semi-synthetic methods that have enabled in vitro investigations ofconformational transitions of tau induced by ubiquitin modification. Finally, we discuss future perspectives in the fieldnecessary to elucidate the molecular mechanisms of tau ubiquitination and clearance.