The emerging role of the tubulin code: From the tubulin molecule to neuronal function and disease

Abstract

Across different cell types and tissues, microtubules are assembled from highly conserved dimers of a-and b-tubulin. Despite their highly similar structures, microtubules have functional heterogeneity, generated either by the expression of different tubulin genes, encoding distinct isotypes, or by posttranslational modifications of tubulin. This genetically encoded and posttranslational generated heterogeneity of tubulinthe "tubulin code"-has the potential to modulate microtubule structure, dynamics, and interactions with associated proteins. The tubulin code is therefore believed to regulate microtubule functions on a cellular and sub-cellular level. This review highlights the importance of the tubulin code for tubulin structure, as well as on microtubule dynamics and functions in neurons. It further summarizes recent developments in the understanding of mutations in tubulin genes, and how they are linked to neurodegenerative and neurodevelopmental disorders. The current advances in the knowledge of the tubulin code on the molecular and the functional level will certainly lead to a better understanding of how complex signaling events control microtubule functions, especially in cells of the nervous system. V C 2016 Wiley Periodicals, Inc.

Microtubules in 3D cell motility

“…The expression or function of other microtubule regulators, such as survivin Rosa et al, 2006), ATIP3 (Molina et al, 2013;Velot et al, 2015) and the +TIPs EB1 (Liu et al, 2009;Stypula-Cyrus et al, 2014) and APC (Etienne-Manneville, 2009), was found to be altered in certain cancers, but the exact role of these proteins in 3D cell migration is still unclear. Mutations in genes encoding tubulin isoforms and different microtubule regulators including +TIPs have also been associated with neurodevelopmental diseases, including disorders of neuronal migration (Breuss and Keays, 2014;Chakraborti et al, 2016;van de Willige et al, 2016), and it will be interesting to investigate which of their functions reflect general mechanisms of 3D cell motility and which are neuron specific.…”

Tubulin isotype substitution revealed that isotype combination modulates microtubule dynamics in C. elegans embryos

“…Consistent with this hypothesis, distinct roles of tubulin isotypes have been implicated. In humans, mutations of different tubulin isotypes cause distinct neurological disorders (for reviews, see Chakraborti et al, 2016;Romaniello et al, 2015). In Drosophila, a testis-specific isotype cannot be replaced by a somatic isotype (Fackenthal et al, 1993;Hoyle and Raff, 1990).…”

The tubulin code at a glance

“…One possibility is that these mutations introduce very subtle changes into the tubulin structure, which only marginally affect MT functions. These defects would only become apparent in cellular processes (such as neuronal migration) that essentially depend on fine-tuned MT dynamics (discussed in detail in Chakraborti et al, 2016). Even more intriguingly, mutations of different amino acid residues in the same tubulin isotype can have distinct pathological outcomes.…”

“…The phenotypes generated by these mutations could be explained in different ways. One possibility is that single amino-acid replacements slightly alter the properties of tubulin, which can be tolerated in most MT functions but result in aberrations in some particularly challenging functions, such as longrange neuronal migration (discussed in Chakraborti et al, 2016). Indeed, single mutations in different isotypes can affect GTP hydrolysis and catastrophe rate of MTs (Geyer et al, 2015), as well as MT dynamic instability .…”

“…Even more intriguingly, mutations of different amino acid residues in the same tubulin isotype can have distinct pathological outcomes. Mutations of TubB4A, for instance, can affect either neurons or oligodendrocytes depending on the amino acid residue mutated (discussed in detail in Chakraborti et al, 2016).…”