Beyond microtubule regulation: the multifaceted roles of tau in neuronal function and dysfunction

The neuronal microtubule-associated protein tau is involved in several neurodegenerative diseases, collectively referred to as tauopathies. In these diseases, it aggregates and plays a central role in triggering cell death. Tau was originally identified as a factor that co-purifies with microtubules. Since then, it has been shown that, in addition to microtubules, it also interacts with many other molecules, is present in multiple cellular compartments, and influences various signaling pathways. Despite its diverse interactions and its potential function as a neuronal interaction hub, the exact role of tau in a neuron remains unclear even after decades of tau research. A better understanding of the physiological role of tau is therefore a prerequisite for the rational development of therapeutic strategies to manipulate its expression, modification, or interactions. Here, we discuss the current state of knowledge regarding the microtubule-related activities of tau, its propensity for self-assembly and aggregate formation, and its non-microtubule-related interactions. The aim is to develop a framework for understanding how tau acquires toxic properties during disease progression and how this knowledge can be used for the rational development of tau-targeted drugs.