Tubulin modifying enzymes as target for the treatment of tau-related diseases

In the brain of patients with Alzheimer's disease (AD), the number and length of microtubules (MTs) are significantly and selectively reduced. MTs are involved in a wide range of cellular functions, and defects of the microtubular system have emerged as a unifying hypothesis for the heterogeneous and variable clinical presentations of AD. MTs orchestrate their numerous functions through the spatiotemporal regulation of the binding of specialised microtubule-associated proteins (MAPs) and molecular motors. Covalent posttranslational modifications (PTMs) on the tubulin C-termini that protrude at the surface of MTs regulate the binding of these effectors. In neurons, MAP tau is highly abundant and its abnormal dissociation from MTs in the axon, cellular mislocalization and hyperphosphorylation, are primary events leading to neuronal death. Consequently, compounds targeting tau phosphorylation or aggregation are currently evaluated but their clinical significance has not been demonstrated yet. In this review, we discuss the emerging link between tubulin PTMs and tau dysfunction. In neurons, high levels of glutamylation and detyrosination profoundly impact the physicochemical properties at the surface of MTs. Moreover, in patients with early-onset progressive neurodegeneration, deleterious mutations in enzymes involved in modifying MTs at the surface have recently been identified, underscoring the importance of this enzymatic machinery in neurology. We postulate that pharmacologically targeting the tubulin-modifying enzymes holds promise as therapeutic approach for the treatment of neurodegenerative diseases.