TUBA8 promotes neuronal dendrite development through its 40th alanine.

The functional specificity of tubulin isotypes has been demonstrated by various neurological diseases caused by an increasing number of mutations in tubulin isotypes. TUBA8 is specifically localized in cerebellar Purkinje cells, which exhibit the most elaborate dendritic trees in the central nervous system. However, the role and related molecular mechanism of TUBA8 in regulating neuronal dendritic morphology remain poorly understood. Here, we report that TUBA8 is required for neuronal dendrite development. As the most divergent member in α-tubulin isotypes, the expression of TUBA8 in Purkinje cells starts at P0, plateaus at P10, and persists into adulthood. Loss of TUBA8 in Purkinje cells induces global dendritic height defects in multiple lobules during development and aging. Meanwhile, TUBA8 deficiency causes age-dependent decreased locomotor activity and anxiety-like behavior. In contrast to TUBA8, TUBA4A, another tubulin isotype highly expressed in Purkinje cells, is not required for dendrite development. Furthermore, the 40th alanine, which differs with any other α-tubulin isotype and cannot be modified by acetylation, methylation, or lactylation, mediates the promoting effect of TUBA8 in neuronal dendrite development. This study reveals a specific role of TUBA8 in regulating neuronal dendritic morphology and highlights the importance of the 40th amino acid in implementing functions of α-tubulin isotypes.