Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function - Université Grenoble Alpes
Article Dans Une Revue FEBS Letters Année : 2020

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

Résumé

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 intra-dimer contacts may impair dimer stability and straightness. Other types of mutations are predicted to alter inter-dimer 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.

Dates et versions

hal-02987098 , version 1 (03-11-2020)

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Citer

Geneviève Fourel, Cécile Boscheron. Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function. FEBS Letters, 2020, ⟨10.1002/1873-3468.13958⟩. ⟨hal-02987098⟩
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