Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function

Abstract

Malformations of cortical development (MCDs) are a group of severe brain malformations associated with intellectual disability and refractory childhood epilepsy. Human missense heterozygous mutations in the 9 α‐tubulin and 10 β‐tubulin isoforms forming the heterodimers that assemble into microtubules (MTs) were found to cause MCDs. However, how a single mutated residue in a given tubulin isoform can perturb the entire microtubule population in a neuronal cell remains a crucial question. Here, we examined 85 MCD‐associated tubulin mutations occurring in TUBA1A, TUBB2, and TUBB3 and their location in a three‐dimensional (3D) microtubule cylinder. Mutations hitting residues exposed on the outer microtubule surface are likely to alter microtubule association with partners, while alteration of intradimer contacts may impair dimer stability and straightness. Other types of mutations are predicted to alter interdimer and lateral contacts, which are responsible for microtubule cohesion, rigidity, and dynamics. MCD‐associated tubulin mutations surprisingly fall into all categories, thus providing unexpected insights into how a single mutation may impair microtubule function and elicit dominant effects in neurons.

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

“…We present three individuals harboring the known and recently reported substitutions p.(Pro173Leu) and p.(Ala174Val) at residues likely involved in GTP binding [ 29 ]. To date, only few substitutions of this functional class have been reported [ 13 ]. i03 and i04, both carrying p.(Ala174Val), are severely affected and i03 shares high phenotypic overlap with the published case [ 17 ].…”

“…Establishment of genotype-phenotype correlations is challenging and underlying pathomechanisms of variant-specific effects are not completely understood [ 11 ]. Depending on their localization in the quaternary structure, variants are predicted to alter longitudinal, lateral, or microtubule surface interactions, thereby disturbing interaction with different motor and microtubule-associated proteins (MAPs) potentiating phenotypic diversity [ 13 ].…”

Modeling a disease-correlated tubulin mutation in budding yeast reveals insight into MAP-mediated dynein function

“…Most prominent among them are neurological diseases, such as the malformations of cortical development (MCD) family of developmental brain disorders (Bahi-Buisson and Cavallin, 1993;Breuss et al, 2012;Cushion et al, 2014;Di Donato et al, 2018;Fourel and Boscheron, 2020;Jaglin et al, 2009;Poirier et al, 2013;Poirier et al, 2010). MCD diseases (e.g., lissencephaly, pachygyria, and polymicrogyria), which are characterized by severe brain malformations, are largely a consequence of defective neuronal migration in the developing brain.…”

“…Although the molecular basis for disease etiology in most patients remains unknown, a recent study predicted that the majority of mutations compromise protein folding and interaction with effectors (Hebebrand et al, 2019). In addition to providing insight into disease pathology, studying such mutations can reveal molecular insight into the cellular role of microtubules and their effectors (Fourel and Boscheron, 2020).…”

“…One residue that is mutated in at least two patients (both of whom are heterozygous for the mutation) is glycine 436 (to an arginine or aspartate), which maps to a region that is directly adjacent to the unstructured C-terminal domain of tubulin, a region that is important for interactions with a wide range of MAPs that are critical for various microtubule processes (Bahi-Buisson et al, 2008;Fourel and Boscheron, 2020;Hebebrand et al, 2019). The unstructured C-termini of -and tubulin are enriched in negatively-charged amino acids, most commonly glutamate (see Fig.…”