Tubulinopathies are a recently characterized group of neurological disorders caused by mutations in tubulin-encoding genes. Among them, mutations in TUBB4A have been linked to hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). In individuals affected by this condition — as well as in the taiep rat, a well-established spontaneous model of the disease — oligodendrocytes display an unusual pattern in both the amount and organization of their microtubules. These anomalies, likely reflecting disrupted microtubule dynamics, are closely tied to cellular dysfunction. However, the precise molecular events driving these changes are still not fully understood. In this study, we investigated whether specific post-translational modifications (PTMs) of tubulin are altered in H-ABC by performing immunostaining on the cerebellum and corpus callosum of control and taiep rats. Compared to controls, taiep rats displayed significantly elevated levels of tubulin acetylation and detyrosination within white matter regions. Moreover, tubulin phosphorylation—typically associated with polymerized tubulin—was also altered and elevated in the taiep model. Notably, increased tubulin acetylation was observed in cells positive for oligodendrocyte markers. Molecular models of this tubulin isotype, both wild type and the A302T mutation, with and without PTMs, suggest new interactions between T302 and the phosphorylated S172 that could account for increased stability. These findings suggest a link between H-ABC and greater microtubule stability in oligodendrocytes, a change that may limit their ability to properly myelinate axons and, in turn, contribute to the disease's characteristic pathology. • TUBB4A mutations drive microtubule changes in oligodendrocytes, underlying H-ABC. • The white matter of taiep rats showed increased PTM levels related to stabilization. • Elevated acetylated tubulin was detected in oligodendrocyte marker–positive cells. • Molecular modeling suggests T302–pS172 interactions boost microtubule stability. • Enhanced microtubule stability in oligodendrocytes may impair myelination in H-ABC.
Jaramillo-Restrepo et al. (Wed,) studied this question.