A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy.

Abstract

Mutations in tubulins cause distinct neurodevelopmental and degenerative diseases termed "tubulinopathies"; however, little is known about the functional requirements of tubulins or how mutations cause cell-specific pathologies. Here, we identify a mutation in the gene <i>Tubb4a</i> that causes degeneration of cerebellar granule neurons and myelination defects. We show that the neural phenotypes result from a cell type-specific enrichment of a dominant mutant form of <i>Tubb4a</i> relative to the expression other β-tubulin isotypes. Loss of <i>Tubb4a</i> function does not underlie cellular pathology but is compensated by the transcriptional up-regulation of related tubulin genes in a cell type-specific manner. This work establishes that the expression of a primary tubulin mutation in mature neurons is sufficient to promote cell-autonomous cell death, consistent with a causative association of microtubule dysfunction with neurodegenerative diseases. These studies provide evidence that mutations in tubulins cause specific phenotypes based on expression ratios of tubulin isotype genes.