Microtubule function and dysfunction in the nervous system

Abstract

Microtubules are core components of the neuronal cytoskeleton, providing structural support for the complex cytoarchitecture of neurons and serving as tracks for long-distance transport. The properties and functions of neuronal microtubules are controlled by tubulin isoforms and a variety of post-translational modifications, collectively known as the "tubulin code." The tubulin code exerts direct control over the intrinsic properties of neuronal microtubules and regulates the repertoire of proteins that read the code, which in turn, has a significant impact on microtubule stability and dynamics. Here, we review progress in the understanding of the tubulin code in the nervous system, with a particular focus on tubulin post-translational modifications that have been proposed as potential contributors to the development and maintenance of the mammalian nervous system. Furthermore, we also discuss the potential links between disruptions in the tubulin code and neurological disorders, including neurodevelopmental abnormalities and neurodegenerative diseases.

Keywords: Neural development; Neurodegeneration; Post-translational modification; Tubulin code; Tubulin isotype.

Fig. 1

Microtubule and post-translational modifications (PTMs) of tubulin. Schematic representation of a microtubule, tubulin PTMs, and the enzymes mediating the PTMs. Tubulin PTMs occur either at the luminal side of the microtubule (acetylation) or at the C-terminal tails of tubulin (glycylation, glutamylation, tyrosination, detyrosination, and generation of Δ2-tubulin).

Fig. 2

The role of tubulin PTMs in the developing nervous system. (a) Tubulin tyrosination and acetylation regulate radial migration of cortical plate neurons and tangential migration of inhibitory interneurons. Dysregulation of tyrosination and acetylation results in disrupted neocortical layer formation. (b) Tubulin tyrosination and acetylation regulate process outgrowth, neuronal polarization, and synapse formation. During development, one of the immature neurites accumulates tubulin acetylation and differentiates into an axon. During synapse formation, tyrosinated tubulin enters the dendritic spines. Dysregulation of PTMs results in abnormal axon growth and prevents synapse formation. o/e, overexpression; sh, short hairpin RNA.