Affinage

TUBA4A

Tubulin alpha-4A chain · UniProt P68366

Round 2 corrected
Length
448 aa
Mass
49.9 kDa
Annotated
2026-04-28
52 papers in source corpus 10 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TUBA4A encodes an α-tubulin isotype that serves as an essential structural subunit of the microtubule cytoskeleton, with disease-linked mutations disrupting microtubule stability through position-dependent mechanisms. C-terminal mutations act as dominant-negative alleles that impair microtubule repolymerization, while N-terminal variants cause haploinsufficiency with reduced TUBA4A mRNA and protein (PMID:25374358, PMID:35327632). TUBA4A protein levels are negatively regulated by tubulin-folding cofactor B (TBCB), which is itself controlled by miR-1825; loss of TUBA4A function in zebrafish causes motor axonopathy with reduced tubulin acetylation, detyrosination, and polyglutamylation, and specific missense variants cause congenital myopathy characterized by ubiquitin-positive cytoplasmic aggregates in muscle (PMID:30030593, PMID:38463699, PMID:38413182). Mutations in TUBA4A are causative for familial ALS, FTD, spastic ataxia (SPAX11), and congenital myopathy (CMYO26) (PMID:25374358, PMID:34169147, PMID:38884572, PMID:41678358).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2014 High

    The identification of TUBA4A mutations in familial ALS families, combined with functional repolymerization assays showing these mutations destabilize microtubules, established TUBA4A as a disease gene and linked α-tubulin dysfunction to neurodegeneration.

    Evidence Exome-wide rare variant burden analysis in ALS cohorts plus microtubule repolymerization assay in patient-derived cells

    PMID:25374358

    Open questions at the time
    • Mechanism by which microtubule destabilization leads to motor neuron death not defined
    • Whether TUBA4A mutations act via dominant-negative or loss-of-function was not resolved
  2. 2018 High

    Defining the miR-1825/TBCB/TUBA4A regulatory axis revealed that upstream TUBA4A degradation—not just coding mutations—can deplete functional α-tubulin and cause motor axon defects, broadening the pathogenic landscape beyond missense variants.

    Evidence Transcriptomic/proteomic analysis in ALS cortex tissue, TBCB overexpression studies, and zebrafish orthologue knockdown with motor axon visualization

    PMID:30030593

    Open questions at the time
    • Whether miR-1825/TBCB axis is dysregulated in non-ALS neurodegenerative contexts is unknown
    • Direct evidence that TBCB-mediated degradation is the primary mechanism of TUBA4A loss in sporadic ALS is lacking
  3. 2021 Medium

    Extending TUBA4A to FTD and showing that FTD-linked variants cluster at the N-terminus with reduced protein abundance—contrasting with C-terminal ALS variants—suggested position-dependent pathogenic mechanisms for the same gene.

    Evidence Microtubule repolymerization assay and immunoblotting of FTD-associated TUBA4A variant

    PMID:34169147

    Open questions at the time
    • Small number of FTD families studied; genotype–phenotype correlations not yet robust
    • Structural basis for N-terminal versus C-terminal mechanistic distinction not resolved
  4. 2022 Medium

    Demonstrating that an N-terminal frameshift produces no truncated protein and reduces total TUBA4A levels formalized haploinsufficiency as the mechanism for N-terminal variants, contrasting with dominant-negative effects of C-terminal mutations.

    Evidence qPCR, immunohistochemistry, and Western blotting in post-mortem brain tissue from a patient with N-terminal frameshift

    PMID:35327632

    Open questions at the time
    • Single case study limits generalizability
    • Whether haploinsufficiency alone is sufficient for disease without modifier loci is unclear
  5. 2024 High

    Zebrafish loss-of-function studies with dose-dependent phenotypes rescued by human TUBA4A mRNA established a causal in vivo model and revealed that TUBA4A is required for normal tubulin post-translational modifications including acetylation, detyrosination, and polyglutamylation.

    Evidence Morpholino knockdown in zebrafish embryos with motor axon visualization, touch-evoked escape assay, and mRNA rescue

    PMID:38463699

    Open questions at the time
    • Whether PTM changes are a cause or consequence of axonopathy is not resolved
    • Mammalian in vivo confirmation of PTM changes was not provided in this study
  6. 2024 Medium

    Patient fibroblast studies and the discovery of myopathy-causing TUBA4A variants expanded the phenotypic spectrum beyond neurodegeneration, showing that specific mutations drive ubiquitin-positive protein aggregation in muscle cells and directly impair microtubule organization.

    Evidence Patient fibroblast microtubule imaging (spastic ataxia), cellular overexpression with immunofluorescence co-localization (myopathy), and muscle biopsy immunohistochemistry

    PMID:38413182 PMID:38884572

    Open questions at the time
    • Whether aggregate toxicity versus microtubule loss is the primary pathogenic insult in myopathy remains undefined
    • Animal model confirmation of myopathy phenotype from specific variants was not yet available from peer-reviewed sources
  7. 2025 Medium

    Multicenter analysis of myopathy-associated TUBA4A variants demonstrated that domain location within the protein correlates with both pattern of muscle involvement and extent of microtubule disruption, establishing a genotype–phenotype framework for TUBA4A-related myopathy.

    Evidence Immunohistochemistry of muscle biopsies (p62/TDP-43 staining), in vitro microtubule assays, and in silico modeling across multiple patient cohorts

    PMID:41678358

    Open questions at the time
    • Precise structural mechanisms by which different domain mutations differentially affect microtubule dynamics are not resolved
    • Whether p62 and TDP-43 co-accumulation reflects a shared proteostatic failure or distinct pathways is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The cell-type selectivity of TUBA4A dysfunction—why certain mutations preferentially affect motor neurons, Purkinje neurons, or skeletal muscle—remains mechanistically unexplained, as does the contribution of tubulin isotype compensation and the therapeutic potential of modulating the TBCB/TUBA4A axis.
  • No structural model of disease-mutant TUBA4A within the αβ-tubulin heterodimer has been experimentally determined
  • Role of tubulin isotype compensation in modifying disease severity is unknown
  • Whether restoring TUBA4A levels (e.g., via miR-1825 modulation) can rescue neurodegeneration in mammalian models is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 4 GO:0005829 cytosol 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3
Partners
TBCBTUBB4B
Complex memberships
αβ-tubulin heterodimer

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 TUBA4A missense mutations found in familial ALS patients destabilize the microtubule network and diminish its repolymerization capability, as demonstrated by functional microtubule repolymerization assays in patient-derived cells. Exome-wide rare variant burden analysis plus microtubule repolymerization functional assay Neuron High 25374358
2018 Excess TBCB (tubulin-folding cofactor B), caused by downregulation of microRNA-1825, leads to depolymerization and degradation of TUBA4A protein. This miR-1825/TBCB/TUBA4A pathway was confirmed in ALS brain cortex tissue and knockdown of the TUBA4A orthologue in zebrafish caused motor axon defects, establishing TBCB as a negative regulator of TUBA4A stability. Combined transcriptomic and proteomic analysis, in vivo zebrafish knockdown, Western blotting of patient brain tissue Cellular and molecular life sciences : CMLS High 30030593
2021 A TUBA4A variant associated with familial FTD results in decreased TUBA4A protein abundance and disrupted α-tubulin function as shown by microtubule repolymerization assay; FTD-associated variants appear more localized to the N-terminus compared to ALS variants, suggesting distinct pathogenic mechanisms. Microtubule repolymerization assay, immunoblotting, immunohistochemistry Neurology. Genetics Medium 34169147
2022 An N-terminal frameshift mutation in TUBA4A (p.Arg64Glyfs*90) produces no detectable truncated protein and leads to reduced total TUBA4A mRNA and protein levels, supporting haploinsufficiency as a pathogenic mechanism for N-terminal TUBA4A mutations; in contrast, C-terminal TUBA4A mutations are proposed to act via dominant-negative disruption of the microtubule network. qPCR, immunohistochemistry, Western blotting of patient brain tissue Biomolecules Medium 35327632
2024 Knockdown of the zebrafish TUBA4A orthologue induced motor axonopathy and disturbed motor behavior in a dose-dependent manner; both phenotypes were rescued by human wild-type TUBA4A mRNA. TUBA4A loss-of-function also caused significant changes in tubulin post-translational modifications, including reduced acetylation, detyrosination, and polyglutamylation. Antisense morpholino knockdown in zebrafish embryos, motor axon visualization, touch-evoked escape response assay, mRNA rescue experiment Frontiers in cellular neuroscience High 38463699
2023 In silico molecular dynamics modeling of ALS-linked TUBA4A mutations predicts that specific mutations (e.g., K430N, R215C, W407X) impair GTP binding and tubulin polymerization, while others (R320C, K430N) significantly increase aggregation propensity of the TUBA4A α-chain, suggesting that failure to form a stable tubulin heterocomplex is a key pathogenic mechanism. Molecular dynamics simulation, molecular docking Scientific reports Low 36747013
2024 A de novo heterozygous TUBA4A variant (p.L227F) causes congenital myopathy; overexpression of the L227F mutant TUBA4A in a cellular model produced cytoplasmic protein aggregates that co-localized with ubiquitin, indicating that this mutation leads to protein misfolding and ubiquitin-positive aggregation rather than simple loss of function. Whole-exome sequencing, cellular overexpression model, immunofluorescence co-localization Journal of medical genetics Medium 38413182
2024 Cultured fibroblasts from patients harboring distinct TUBA4A missense variants associated with spastic ataxia showed significant alterations in microtubule organization and dynamics, establishing that TUBA4A variants directly impair the microtubule cytoskeleton in patient-derived cells. Patient fibroblast cultures, microtubule organization/dynamics imaging Brain : a journal of neurology Medium 38884572
2025 TUBA4A missense variants causing myopathy lead to TUBA4A protein accumulation detectable by immunohistochemistry in patient myofibres (positive for p62 and TDP-43 in some cases), and in vitro/in silico investigations indicate these variants cause protein abnormalities that differentially impact microtubule dynamics; domain location within TUBA4A correlates with both pattern of muscle involvement and extent of microtubule disruption. Immunohistochemical staining of muscle biopsies, in silico modeling, in vitro microtubule assays Brain : a journal of neurology Medium 41678358
2026 A mouse model carrying the Tuba4a p.Gln176Pro missense mutation (confirmed by CRISPR engineering) exhibits Purkinje neuron degeneration, skeletal muscle defects, and ataxia by 30 days of age with decreased lifespan, but without motor neuron degeneration; this demonstrates cell-type selective vulnerability to TUBA4A dysfunction and models human SPAX11 and CMYO26 phenotypes. ENU mutagenesis screen, CRISPR-engineered knock-in mouse, behavioral testing, neuropathology bioRxiv : the preprint server for biologypreprint Medium 41889878
2024 Overexpression of TUBA4A and TUBB4B in vascular smooth muscle cells (VSMCs) was shown by in vitro experiments to promote contractile-to-synthetic phenotypic switching, migration, and proliferation of VSMCs, implicating TUBA4A in cytoskeletal regulation of VSMC phenotype downstream of the GJA1-mediated PI3K/AKT/KLF4 pathway. Organoid modeling, single-cell sequencing, proteomics/RNA-seq, in vitro VSMC functional assays bioRxivpreprint Low

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 HDAC6 is a microtubule-associated deacetylase. Nature 2000 12024216
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Molecular cell 1280 12620231
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nature cell biology 636 12134159
2003 Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 616 14630798
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2008 Many sequence variants affecting diversity of adult human height. Nature genetics 520 18391951
2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 507 21565611
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1995 Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. The Journal of cell biology 427 7790358
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2004 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Current biology : CB 386 15324660
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2007 Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proceedings of the National Academy of Sciences of the United States of America 360 17620599
2001 Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Current biology : CB 350 11166179
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2014 Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 292 25374358
2016 Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients. Neurobiology of aging 59 28069311
2018 Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS. Cellular and molecular life sciences : CMLS 38 30030593
2021 Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia. Neurology. Genetics 21 34169147
2014 Excess of rare damaging TUBA4A variants suggests cytoskeletal defects in ALS. Neuron 20 25374348
1999 Expression of the pea (Pisum sativum L.) alpha-tubulin gene TubA1 is correlated with cell division activity. Plant molecular biology 17 10645720
2023 In silico analysis of TUBA4A mutations in Amyotrophic Lateral Sclerosis to define mechanisms of microtubule disintegration. Scientific reports 13 36747013
2021 An autopsy case of pure nigropathy with TUBA4A nonsense mutation. Neuropathology and applied neurobiology 12 33760283
2011 Behavioral and neuromorphological characterization of a novel Tuba1 mutant mouse. Behavioural brain research 12 22101068
2023 A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A. Journal of neurology 11 37418012
2022 Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology. Biomolecules 11 35327632
2015 Assessing the role of TUBA4A gene in frontotemporal degeneration. Neurobiology of aging 11 26675813
2024 De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity. Brain : a journal of neurology 7 38884572
2015 TUBA4A may not be a significant genetic factor in Chinese ALS patients. Amyotrophic lateral sclerosis & frontotemporal degeneration 7 26465396
1995 The Pisum sativum TubA1 gene, a member of a small family of alpha-tubulin sequences. Plant molecular biology 7 7727749
2024 Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation. Journal of medical genetics 6 38413182
2024 TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish. Frontiers in cellular neuroscience 4 38463699
2025 TUBA4A: The Tale of an Unconventional Tubulin. Cytoskeleton (Hoboken, N.J.) 2 40964866
2025 Missense variants in TUBA4A cause myo-tubulinopathies. medRxiv : the preprint server for health sciences 1 40666348
1991 Dinucleotide repeat polymorphism in the human tubulin alpha 1 (testis specific) gene (TUBA1). Nucleic acids research 1 1852622
2026 Missense variants in TUBA4A cause myo-tubulinopathies. Brain : a journal of neurology 0 41678358
2026 A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a. bioRxiv : the preprint server for biology 0 41889878