Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants

Vulinović, Franca; Krajka, Victor; Hausrat, Torben J.; Seibler, Philip; Alvarez‐Fischer, Daniel; Madoev, Harutyun; Park, Jin-Sung; Kumar, Kishore R.; Sue, Carolyn M.; Lohmann, Katja; Kneussel, Matthias; Klein, Christine; Raković, Aleksandar

doi:10.1002/humu.23602

Cited by 21 publications

(12 citation statements)

References 51 publications

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“…Sanger sequencing showed that our patient carries a mutation in TUBB4A (D249N) which was previously identified in other patients (Curiel et al, 2017; Vulinovic et al, 2018) (Figure 1a, left square). We also found a GTT to GTC change in the nucleotide sequence, with no effects on the amino acid (Val) in position 258 (Figure 1a, right square).…”

Section: Resultssupporting

confidence: 76%

Auditory impairment in H‐ABC tubulinopathy

López-Juárez

Vega

Kleinert‐Altamirano³

et al. 2020

J of Comparative Neurology

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Hypomyelination with atrophy of the basal ganglia and cerebellum (H‐ABC) is a neurodegenerative disease due to mutations in TUBB4A. Patients suffer from extrapyramidal movements, spasticity, ataxia, and cognitive deficits. Magnetic resonance imaging features are hypomyelination and atrophy of the striatum and cerebellum. A correlation between the mutations and their cellular, tissue and organic effects is largely missing. The effects of these mutations on sensory functions have not been described so far. We have previously reported a rat carrying a TUBB4A (A302T) mutation and sharing most of the clinical and radiological signs with H‐ABC patients. Here, for the first time, we did a comparative study of the hearing function in an H‐ABC patient and in this mutant model. By analyzing hearing function, we found that there are no significant differences in the auditory brainstem response (ABR) thresholds between mutant rats and WT controls. Nevertheless, ABRs show longer latencies in central waves (II–IV) that in some cases disappear when compared to WT. The patient also shows abnormal AEPs presenting only Waves I and II. Distortion product of otoacoustic emissions and immunohistochemistry in the rat show that the peripheral hearing function and morphology of the organ of Corti are normal. We conclude that the tubulin mutation severely impairs the central hearing pathway most probably by progressive central white matter degeneration. Hearing function might be affected in a significant fraction of patients with H‐ABC; therefore, screening for auditory function should be done on patients with tubulinopathies to evaluate hearing support therapies.

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Section: Resultssupporting

confidence: 76%

Auditory impairment in H‐ABC tubulinopathy

López-Juárez

Vega

Kleinert‐Altamirano³

et al. 2020

J of Comparative Neurology

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“…Here, we observed no differences in overexpressed TUBB4A levels between WT and either p.R2G or p.R2W mutations, suggesting that the impaired autoregulation of TUBB4A mRNA does not play a major role in our cell model. This is consistent with the results of previous publications addressing mRNA and protein stability of TUBB4A ( 19 , 20 ). Notably, compared to other tubulin isoforms, TUBB4A does not appear to be susceptible to pharmacologically induced tubulin mRNA autoregulation ( 39 ).…”

Section: Discussionsupporting

confidence: 93%

“…Plasmids (pER4) expressing GFP-tagged TUBB4A variants and EB3-GFP were previously described ( 20 ). For our recent study, we have modified the plasmids to either tag TUBB4A variants C-terminally with GFP or coexpress with EB3-GFP.…”

Section: Methodsmentioning

confidence: 99%

H-ABC– and dystonia-causing TUBB4A mutations show distinct pathogenic effects

et al. 2022

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Mutations in the brain-specific β-tubulin 4A (TUBB4A) gene cause a broad spectrum of diseases, ranging from dystonia (DYT-TUBB4A) to hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Currently, the mechanisms of how TUBB4A variants lead to this pleiotropic manifestation remain elusive. Here, we investigated whether TUBB4A mutations causing either DYT-TUBB4A (p.R2G and p.Q424H) or H-ABC (p.R2W and p.D249N) exhibit differential effects at the molecular and cellular levels. Using live-cell imaging of disease-relevant oligodendrocytes and total internal reflection fluorescence microscopy of whole-cell lysates, we observed divergent impact on microtubule polymerization and microtubule integration, partially reflecting the observed pleiotropy. Moreover, in silico simulations demonstrated that the mutants rarely adopted a straight heterodimer conformation in contrast to wild type. In conclusion, for most of the examined variants, we deciphered potential molecular disease mechanisms that may lead to the diverse clinical manifestations and phenotype severity across and within each TUBB4A-related disease.

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“…Other minor β-tubulin isotypes (βII-tubulin and βIVα-tubulin) have also been associated with regulating mitochondrial localization specifically in cardiomyocytes [ 66 , 67 , 68 , 69 ], although the mechanisms by which they operate remain unknown. With increasing recognition for the combinatorial manner in which β-tubulin isotypes collectively regulate microtubule functions and microtubule-dependent processes in cells [ 18 , 21 , 70 ], it is likely that the tubulin code regulating mitochondrial dynamics is a complex spatiotemporal network that depends on the local β-tubulin composition.…”

Section: Discussionmentioning

confidence: 99%

βIII-Tubulin Structural Domains Regulate Mitochondrial Network Architecture in an Isotype-Specific Manner

Parker

Teo

Brayford

et al. 2022

Cells

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βIII-tubulin is a neuronal microtubule protein that is aberrantly expressed in epithelial cancers. The microtubule network is implicated in regulating the architecture and dynamics of the mitochondrial network, although the isotype-specific role for β-tubulin proteins that constitute this microtubule network remains unclear. High-resolution electron microscopy revealed that manipulation of βIII-tubulin expression levels impacts the volume and shape of mitochondria. Analysis of the structural domains of the protein identifies that the C-terminal tail of βIII-tubulin, which distinguishes this protein from other β-tubulin isotypes, significantly contributes to the isotype-specific effects of βIII-tubulin on mitochondrial architecture. Mass spectrometry analysis of protein–protein interactions with β-tubulin isotypes identifies that βIII-tubulin specifically interacts with regulators of mitochondrial dynamics that may mediate these functional effects. Advanced quantitative dynamic lattice light sheet imaging of the mitochondrial network reveals that βIII-tubulin promotes a more dynamic and extended reticular mitochondrial network, and regulates mitochondrial volume. A regulatory role for the βIII-tubulin C-terminal tail in mitochondrial network dynamics and architecture has widespread implications for the maintenance of mitochondrial homeostasis in health and disease.

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Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants

Cited by 21 publications

References 51 publications

Auditory impairment in H‐ABC tubulinopathy

Auditory impairment in H‐ABC tubulinopathy

H-ABC– and dystonia-causing TUBB4A mutations show distinct pathogenic effects

βIII-Tubulin Structural Domains Regulate Mitochondrial Network Architecture in an Isotype-Specific Manner

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