The role for tubulin isotype diversity

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Microtubules are long dynamic filaments present in the cytoplasm of cells that perform essential tasks. They separate chromosomes during cell division, act as tracks for motors to transport cargos across the cell and contribute to cell shape and architecture. Microtubules are assembled from alpha/beta-tubulin heterodimers. There are 9 alpha-tubulin and beta-tubulin genes in humans, that code for protein variants called isotypes. In this grant, we seek to understand whether tubulin heterodimer assembly is random (hypothesis: any of the 9 alpha-tubulin isotypes can assemble with any of the 9 beta-tubulin isotypes), or whether it is determined (hypothesis: only certain combinations of alpha-tubulin isotypes can assemble with specific beta-tubulin isotypes).Second we will determine how the tubulin variants affect the assembly of microtubules and the proteins that interact with microtubules to build tracks and cellular structures, and examine if tubulin variants can generate a variety of cellular structures. Third, a growing number of patients are reported to have diseases caused by point mutations to specific tubulin genes. Very recently for the first time worldwide, we have identified patients with Primary Ciliary Dyskinesia, which have mutations in their tubulin genes. This disease causes mucus build-up in the lungs and inflammation of airways, with infections in the lungs, ear and nose. In these patients, the microtubules in the cilia are absent. Our last aim is to understand how these tubulin mutations cause the PCD disease, so that we can one day help and relieve patients' symptoms.