Abstract

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.

Highlights

  • Tubulin is present in all nucleated cells, and at least three prokaryotic homologs are known (Kim, 2019); in humans, the tubulin superfamily includes more than 20 genes (HUGO, 2020)

  • When analyzing equivalent coronal sections of the taiep rats (Figures 1h,j,l), we found that the corpus callosum (CC) gets thinner, the ic is not visible and basal ganglia are poorly defined at any age

  • With what was known from the literature, i.e., a tubulin-related leukodystrophy was causing the taiep motor phenotype, we formulated the hypothesis that this Sprague Dawley mutant could display the magnetic resonance imaging (MRI) features that are used for the clinical diagnosis of H-ABC

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Summary

Introduction

Tubulin is present in all nucleated cells, and at least three prokaryotic homologs are known (Kim, 2019); in humans, the tubulin superfamily includes more than 20 genes (HUGO, 2020). MRI in a Tubulinopathy Model mutations affect primarily the nervous system (Chakraborti et al, 2016) This is well in accordance with the prominent role played by tubulins in brain development through neuronal genesis and migration, cortical organization and in axon guidance (Breuss et al, 2017). It is worth specifying that tubulinopathies are, to this date, the pathological manifestation of mutations in the genes of a just a subset of tubulin genes: TUBB2A, TUBB2B, TUBB3, TUBG1, TUBA8, TUBB, TUBA3E, and TUBB4A. This list is expected to grow as more genetic diagnoses are run and new mutations are discovered

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