Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology

Schoor, Evelien Van; Vandenbulcke, Mathieu; Bercier, Valérie; Vandenberghe, Rik; Zee, Julie van der; Broeckhoven, Christine Van; Otto, Markus; Hanseeuw, Bernard; Damme, Philip Van; Bosch, Ludo Van Den; Thal, Dietmar Rudolf

doi:10.3390/biom12030440

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…On the other hand, N-terminal TUBA4A mutations were identified in patients presenting with FTD, possibly with extrapyramidal symptoms (Perrone et al, 2017;Mol et al, 2021). We and others have shown that these mutations led to reduced TUBA4A levels in central nervous system tissues, suggesting a loss-of-function mechanism (Mol et al, 2021;Okada et al, 2021;Van Schoor et al, 2022). Interestingly, a downregulation of TUBA4A protein expression was also reported in the brain of sporadic ALS patients (Helferich et al, 2018), which we confirmed in this study via western blotting of motor cortex tissue.…”

Section: Discussionsupporting

confidence: 86%

“…Indeed, it was demonstrated that miR-1825 downregulation in ALS patient tissue led to increased tubulin-folding cofactor B (TBCB) levels, which led to the sequestration of TUBA4A and induced a decrease in its expression (Helferich et al, 2018). This gives an indication of the possible upstream events leading to decreased TUBA4A levels in ALS, aside from N-terminal TUBA4A mutations (Van Schoor et al, 2022). Importantly, we here demonstrate the causality of TUBA4A downregulation by showing that knockdown of the TUBA4A orthologue tuba8l2 in zebrafish embryos led to ALS-associated abnormalities, namely spinal axonopathy and behavioral deficits.…”

Section: Discussionmentioning

confidence: 99%

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TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish

Van Schoor,

Strubbe,

Braems

et al. 2024

Front. Cell. Neurosci.

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Disease-associated variants of TUBA4A (alpha-tubulin 4A) have recently been identified in familial ALS. Interestingly, a downregulation of TUBA4A protein expression was observed in familial as well as sporadic ALS brain tissue. To investigate whether a decreased TUBA4A expression could be a driving factor in ALS pathogenesis, we assessed whether TUBA4A knockdown in zebrafish could recapitulate an ALS-like phenotype. For this, we injected an antisense oligonucleotide morpholino in zebrafish embryos targeting the zebrafish TUBA4A orthologue. An antibody against synaptic vesicle 2 was used to visualize motor axons in the spinal cord, allowing the analysis of embryonic ventral root projections. Motor behavior was assessed using the touch-evoked escape response. In post-mortem ALS motor cortex, we observed reduced TUBA4A levels. The knockdown of the zebrafish TUBA4A orthologue induced a motor axonopathy and a significantly disturbed motor behavior. Both phenotypes were dose-dependent and could be rescued by the addition of human wild-type TUBA4A mRNA. Thus, TUBA4A downregulation as observed in ALS post-mortem motor cortex could be modeled in zebrafish and induced a motor axonopathy and motor behavior defects reflecting a motor neuron disease phenotype, as previously described in embryonic zebrafish models of ALS. The rescue with human wild-type TUBA4A mRNA suggests functional conservation and strengthens the causal relation between TUBA4A protein levels and phenotype severity. Furthermore, the loss of TUBA4A induces significant changes in post-translational modifications of tubulin, such as acetylation, detyrosination and polyglutamylation. Our data unveil an important role for TUBA4A in ALS pathogenesis, and extend the relevance of TUBA4A to the majority of ALS patients, in addition to cases bearing TUBA4A mutations.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish

Van Schoor,

Strubbe,

Braems

et al. 2024

Front. Cell. Neurosci.

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“…Besides, it had been proven that mutation in certain genes could facilitate immune escape to promote tumor development. [35–37] Although extensive research has been conducted on the mutation of TUBA4A in various diseases, [38,39] our findings indicate that most genes, including TUBA4A, exhibit low mutation rates in PTC. Furthermore, the CNV of FAM107B and TUBA4A was not related to the OS in PTC.…”

Section: Discussionmentioning

confidence: 79%

Establishment and validation of a novel risk model based on CD8T cell marker genes to predict prognosis in thyroid cancer by integrated analysis of single-cell and bulk RNA-sequencing

Du,

Song,

Wang

et al. 2023

Medicine

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Papillary thyroid cancer (PTC) is a histological type of thyroid cancer, and CD8T is important for the immune response. The single-cell RNA data were acquired from Gene Expression Omnibus. SingleR package was used for cluster identification, and CellChat was exploited to evaluate the interaction among several cell types. Bulk RNA data obtained from the cancer genome atlas were used for determination of prognosis using Kaplan–Meier and Receiver Operating Characteristic curve. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were applied for assessment of function enrichment. The drug sensitivity was calculated in Gene Set Cancer Analysis. The regulatory network was constructed by STRING and Cytoscape. We identified 23 cell clusters and 10 cell types. Cell communication results showed CD8T cell was vital among all immune cell types. Enrichment analysis found the marker genes of CD8T cell was enriched in some signal pathways related to tumor development. Overall, FAM107B and TUBA4A were considered as hub genes and used to construct a risk model. Most immune checkpoint expressions were upregulated in tumor group. Tumor mutation burden results indicated that prognosis of PTC was not related to the mutation of hub genes. Drug sensitivity analysis showed some drugs could be effectively used for the treatment of PTC, and regulatory network identified some targets for the immunotherapy. A 2-gene model of PTC was developed based on the single-cell RNA and bulk RNA data. Besides, we found CD8T was essential for the immune response in PTC.

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A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A

et al. 2023

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Tubulinopathies encompass neurodevelopmental disorders caused by mutations in genes encoding for different isotypes of α- and β-tubulins, the structural components of microtubules. Less frequently, mutations in tubulins may underlie neurodegenerative disorders. In the present study, we report two families, one with 11 affected individuals and the other with a single patient, carrying a novel, likely pathogenic, variant (p. Glu415Lys) in the TUBA4A gene (NM_006000). The phenotype, not previously described, is that of spastic ataxia. Our findings widen the phenotypic and genetic manifestations of TUBA4A variants and add a new type of spastic ataxia to be taken into consideration in the differential diagnosis.

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Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology

Cited by 6 publications

References 35 publications

TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish

TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish

Establishment and validation of a novel risk model based on CD8T cell marker genes to predict prognosis in thyroid cancer by integrated analysis of single-cell and bulk RNA-sequencing

A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A

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