Tubulinopathies are a group of recently described diseases characterized by mutations in the tubulin genes. Mutations in TUBB4A produce diseases such as dystonia type 4 (DYT4) and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), which are clinically diagnosed by magnetic resonance imaging (MRI). We propose the taiep rat as the first animal model for tubulinopathies. The spontaneous mutant suffers from a syndrome related to a central leukodystrophy and characterized by tremor, ataxia, immobility, epilepsy, and paralysis. The pathological signs presented by these rats and the morphological changes we found by our longitudinal MRI study are similar to those of patients with mutations in TUBB4A. The diffuse atrophy we found in brain, cerebellum and spinal cord is related to the changes detectable in many human tubulinopathies and in particular in H-ABC patients, where myelin degeneration at the level of putamen and cerebellum is a clinical trademark of the disease. We performed Tubb4a exon analysis to corroborate the genetic defect and formulated hypotheses about the effect of amino acid 302 change on protein physiology. Optical microscopy of taiep rat cerebella and spinal cord confirmed the optical density loss in white matter associated with myelin loss, despite the persistence of neural fibers.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.

Hypomyelination with atrophy of the basal ganglia and cerebellum is a recently described tubulinopathy caused by a mutation in the tubulin beta 4a isoform, expressed in oligodendrocytes. The taiep rat is the only spontaneous tubulin beta 4a mutant available for the study of this pathology. We aimed to identify the effects of the tubulin mutation on freshly collected, unstained samples of the central white matter of taiep rats using second harmonic generation microscopy. Cytoskeletal differences between the central white matter of taiep rats and control animals were found. Nonlinear emissions from the processes and somata of oligodendrocytes in tubulin beta 4a mutant rats were consistently detected, in the shape of elongated structures and cell-like bodies, which were never detected in the controls. This signal represents the second harmonic trademark of the disease. The tissue was also fluorescently labeled and analyzed to corroborate the origin of the nonlinear signal. Besides enabling the description of structural and molecular aspects of H-ABC, our data open the door to the diagnostic use of nonlinear optics in the study of neurodegenerative diseases, with the additional advantage of a label-free approach that preserves tissue morphology and vitality.

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.

The cover image is based on the Research Article Auditory impairment in H‐ABC tubulinopathy by Alejandra Lopez‐Juarez et al., https://doi.org/10.1002/cne.24990.