Is the Regulation of Microtubule Stability at the Crossroad Between Aging and Disease of Dopaminergic neurons?

Abstract

Microtubules (MTs) are built up by αβ tubulin dimers, which assemble into non-covalent polymers with an intrinsic resistance to bending and compression and capable to alternate slow polymerizing phases to rapid shrinking ones, a behaviour called "dynamic instability" [1]. The proper regulation of MT stability (i.e., more stable MTs display a longer half-life) is fundamental for the development, the survival and the aging of neurons, since both hyper-stable and overly dynamic MTs affect neuronal functions eventually leading to cell death [2]. α and β tubulin Posttranslational Modifications (PTMs) mark dynamic or stable MTs, which are found in specific neuronal compartments and whose stability changes during neuronal differentiation and aging [3]. Indeed, tyrosinated α tubulin is associated to highly dynamic MTs, which are abundant in young neurons and at the presynaptic bouton of mature neurons. During neuronal maturation MT stability increases and MTs inside the axonal shaft accumulate PTMs which extend their half-life, either through a direct stabilization of the MT lattice [4] or by governing upstream events, such as the recruitment of MT-interacting protein [5] or by protecting MTs from depolymerizing kinesins and severing enzymes [6,7]. Nevertheless, the stability of MTs has to be maintained under a physiological threshold, since their excessive stabilization can eventually lead to MT bundling and block of axonal transport [8]. As many of the axonal MTs are long-lived polymers which persist for the entire life of the neuron, their aging is a critical event which potentially impacts on the neuron lifespan. Indeed, MTs are structures with an intrinsic self-repair capability [9] but, due to defects accumulated during growth [10] and to their ends which become more tapered during time [11], the older MTs are more susceptible to catastrophes than younger ones [12,13]. Interestingly, tubulin PTMs are potential regulators of this process as much as, for long time, acetylated MTs were referred almost synonymously to old and stable MTs. Indeed, among its several biological functions [14], it has been shown that acetylation accumulates during MT aging and it has been proposed that the MT-acetylase α Tubulin Acetyl Transferase1 (αTAT1) can act as a clock for MT lifetimes [15], due to its preference for MTs and its low catalytic rate. Nevertheless, other candidates may be responsible for minor tubulin acetylation in vivo, including Elongator Complex Protein Elp3, which acts as tubulin acetylase, controlling the development and the migration of cortical neurons [16]. Furthermore, the age-dependent decrease of the activity of sirtuin 1, a widespread deacetylase which also acts on MTs, could lead to increased acetylation of α tubulin in the cerebellum of aged mice [17]. These data suggest a functional link between MT acetylation patterns and brain aging, evidencing how the regulation of MT stability is critical during normal neuronal aging and supporting the concept that its failure may be a reliable candidate in causing n...