| First Author | Fertuzinhos S | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 7 | Pages | eabf7262 |
| PubMed ID | 35171680 | Mgi Jnum | J:321692 |
| Mgi Id | MGI:6887113 | Doi | 10.1126/sciadv.abf7262 |
| Citation | Fertuzinhos S, et al. (2022) A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy. Sci Adv 8(7):eabf7262 |
| abstractText | 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 Tubb4a 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 Tubb4a relative to the expression other beta-tubulin isotypes. Loss of Tubb4a 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. |
