Affinage

ATXN3

Ataxin-3 · UniProt P54252

Length
361 aa
Mass
41.2 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATXN3 is a Josephin-family deubiquitinating enzyme that maintains protein homeostasis through the ubiquitin-proteasome system, with knockout animals accumulating ubiquitinated proteins in vivo (PMID:17764659). It removes ubiquitin from a broad range of substrates to control their stability, including HDAC3 during antiviral interferon-I signaling (PMID:29802126), the transcription factors KLF4 (PMID:31563563), YAP via Josephin-domain engagement of the YAP WW domain with K48-linkage specificity (PMID:37349820), and JunB/IRF1/STAT3/HIF-2α to drive PD-L1 expression in tumor cells (PMID:38038129). Beyond catalysis, ATXN3 operates in genome maintenance as a component of a transcription-coupled DNA repair complex with RNA polymerase II, PNKP and CBP, where its activity protects CBP from ubiquitin-mediated degradation and supports global transcription and error-free double-strand break repair (PMID:30994454, PMID:32205441). It also functions through a catalytic-independent activity to organize chromatin, controlling HDAC3 subcellular localization and chromatin recruitment, with loss producing abnormal nuclear morphology, altered replication timing and epigenetic marks (PMID:36971114, PMID:30231063). Nuclear entry of ATXN3 is gated by CK2/GSK3 phosphorylation of serine 29 within the Josephin domain (PMID:20347968), and the protein is processed by calpains and caspases to generate C-terminal fragments (PMID:23100324, PMID:19783548). ATXN3 also participates in ER-associated retrotranslocation, deubiquitinating type II iodothyronine deiodinase as it is extracted via the p97 ATPase (PMID:24196352). Polyglutamine expansion causes the SCA3/MJD spinocerebellar ataxia through multiple toxic mechanisms: nuclear inclusion formation that sequesters the proteasome (PMID:10072437), physical inactivation of PNKP leading to persistent DNA damage and ATM-mediated apoptotic signaling (PMID:25590633), cell-autonomous impairment of oligodendrocyte maturation (PMID:35042771), potassium channel dysfunction (PMID:16765348), and toxicity arising from -1 ribosomal frameshifting at the expanded CAG repeat rather than the polyQ tract alone (PMID:16087686, PMID:22337953).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1999 Medium

    Established that mutant ataxin-3 forms nuclear inclusions that sequester the 26S proteasome, linking the proteasome system to polyglutamine aggregation pathology in SCA3.

    Evidence Immunohistochemistry of SCA3 brain and proteasome-inhibitor perturbation in transfected cells

    PMID:10072437

    Open questions at the time
    • Does not establish whether proteasome sequestration is cause or consequence of toxicity
    • Mechanism of proteasome suppression of aggregation not resolved
  2. 2004 Medium

    Showed that misfolding and ubiquitination of ataxin-3 scale with polyQ length, defining the biochemical basis of the toxic gain-of-function.

    Evidence Cell-based ubiquitination assays across polyQ-length and truncation constructs

    PMID:15639784

    Open questions at the time
    • Ubiquitin ligase responsible not identified
    • Cellular consequence of expanded-form ubiquitination not addressed
  3. 2005 Medium

    Identified -1 ribosomal frameshifting at the expanded CAG repeat as a toxicity mechanism distinct from polyQ itself, reframing how repeat expansion causes disease.

    Evidence Cell-based frameshifting reporter, CAG vs CAA constructs, anisomycin pharmacology

    PMID:16087686

    Open questions at the time
    • Contribution of frameshift products to human disease not quantified
    • Identity and fate of polyalanine products in neurons not characterized
  4. 2006 Medium

    Demonstrated that expanded ataxin-3 disrupts potassium channel function before cell death, identifying an early electrophysiological deficit.

    Evidence Patch-clamp electrophysiology in inducible PC12 model

    PMID:16765348

    Open questions at the time
    • Molecular link between ATXN3 and the channel not defined
    • Not confirmed in neurons of patients or animal models
  5. 2007 High

    Provided the first in vivo evidence that ATXN3 is a functional deubiquitinase, since its loss elevates ubiquitinated proteins.

    Evidence Atxn3 knockout mice with western blot for ubiquitinated proteins and behavioral testing

    PMID:17764659

    Open questions at the time
    • Physiological substrates not identified in this study
    • Mild phenotype leaves functional redundancy unresolved
  6. 2009 Medium

    Established that proteolytic cleavage of ataxin-3 enhances neurotoxicity, since blocking caspase sites reduces neuronal loss.

    Evidence Drosophila transgenics with caspase-site mutants and cell-based cleavage assays

    PMID:19783548

    Open questions at the time
    • Specific protease in vivo not definitively assigned
    • Mechanism by which fragments confer toxicity not addressed here
  7. 2010 High

    Defined how ATXN3 nuclear entry is regulated, identifying CK2/GSK3 phosphorylation of S29 as the switch controlling nuclear localization.

    Evidence In vitro kinase assay, MS, S29A/S29D mutagenesis and kinase inhibitors with cell localization

    PMID:20347968

    Open questions at the time
    • Consequence of regulated nuclear entry for substrate processing not shown
    • Whether polyQ expansion alters this regulation not tested
  8. 2012 High

    Showed that calpain cleavage generates fragments and that enhancing calpain activity worsens SCA3 pathology in vivo, establishing calpain as a disease modifier.

    Evidence In vitro calpain cleavage and SCA3 transgenic x calpastatin-KO epistasis with histology and behavior

    PMID:23100324

    Open questions at the time
    • Precise cleavage sites not mapped
    • Relative contribution of calpain vs caspase fragments unresolved
  9. 2013 Medium

    Connected ATXN3 to ER-associated degradation, showing it deubiquitinates D2 during p97-mediated retrotranslocation.

    Evidence Co-IP of D2 with p97 and Atx3, eeyarestatin-I inhibition, retrotranslocation assays

    PMID:24196352

    Open questions at the time
    • Pharmacological inhibitor may have off-target effects
    • Generality across other ERAD substrates not established
  10. 2013 Medium

    Used Drosophila genetic dissection to show ataxin-3's ubiquitin-binding capacity governs its behavior in disaggregation, revealing the UBA domains shape disease-relevant handling.

    Evidence Drosophila models with full-length, truncated and ubiquitin-binding-mutant constructs plus Hsp104 staging

    PMID:24039611

    Open questions at the time
    • Human relevance of Hsp104 interplay limited
    • Endogenous disaggregase partners not identified
  11. 2015 High

    Identified PNKP inactivation by mutant ATXN3 as a direct mechanism linking the protein to DNA damage accumulation and ATM-driven neuronal apoptosis.

    Evidence Reciprocal Co-IP, PNKP activity assays, DNA damage and ATM pathway readouts, PNKP-overexpression and ATM-inhibitor rescue

    PMID:25590633

    Open questions at the time
    • Whether wild-type ATXN3 normally activates PNKP not fully resolved here
    • Spatial/temporal sequence of damage vs aggregation in neurons unclear
  12. 2015 Medium

    Distinguished SCA3 from Huntington disease at the molecular level by showing ATXN3 does not engage UBQLN2 and UBQLN2 is not recruited to SCA3 inclusions.

    Evidence Co-IP comparing ATXN3 vs HTT with UBQLN2 and IHC of SCA3 and HD brain

    PMID:26141599

    Open questions at the time
    • Negative result; does not rule out weak or transient interactions
    • Functional consequence of absent UBQLN2 recruitment not explored
  13. 2017 Medium

    Demonstrated that the truncated C-terminal mutant fragment drives mitochondrial fission and oxidative stress more potently than full-length protein, linking fragmentation to mitochondrial toxicity.

    Evidence Neuroblastoma and transgenic mouse comparison of truncated vs full-length mutant ATXN3 with mitochondrial and ROS readouts

    PMID:28676741

    Open questions at the time
    • Direct molecular link to fusion machinery not defined
    • Single-lab observation
  14. 2018 Medium

    Established ATXN3 as a deubiquitinase for HDAC3 that stabilizes it to promote interferon-I-mediated antiviral signaling, defining a physiological substrate.

    Evidence Reciprocal Co-IP, HDAC3 ubiquitination assays, ATXN3 knockdown/KO and IFN-I signaling readouts in viral infection models

    PMID:29802126

    Open questions at the time
    • Single-lab finding
    • Linkage to ATXN3's neuronal roles not made
  15. 2018 Medium

    Linked ATXN3 to transcriptional and chromatin control, showing its loss alters signaling-pathway gene expression and histone acetylation at the Efna3 promoter alongside reduced HDAC3/NCoR.

    Evidence RNA-seq, ChIP for histone acetylation, HDAC3/NCoR westerns and ATXN3 rescue in MEFs and KO brainstem

    PMID:30231063

    Open questions at the time
    • Direct vs indirect transcriptional effects not separated
    • Mechanism connecting ATXN3 to HDAC3/NCoR levels not resolved here
  16. 2019 High

    Placed ATXN3 within a transcription-coupled DNA repair complex (RNAP II, PNKP, CBP) where its activity protects CBP from degradation, bridging transcription and repair functions.

    Evidence Co-IPs, PNKP/ATXN3 activity assays, CBP ubiquitination/stability assays, ChIP and HD mouse models

    PMID:30994454

    Open questions at the time
    • Stoichiometry and assembly order of the complex not defined
    • Whether expanded ATXN3 disrupts CBP protection not directly tested here
  17. 2019 Medium

    Identified KLF4 as an ATXN3 substrate stabilized via deubiquitination, implicating ATXN3 in breast cancer metastasis.

    Evidence DUB-library screen, Co-IP, ubiquitination assays, knockdown/rescue, migration and xenograft assays

    PMID:31563563

    Open questions at the time
    • Ubiquitin linkage type not specified
    • Single-lab cancer-context finding
  18. 2020 High

    Showed ATXN3 physiologically associates with RNAP II and C-NHEJ machinery to sustain transcription and error-free DSB repair, and that SCA3 patient brain shows impaired PNKP activity and RNAP II degradation.

    Evidence Co-IPs, nascent-RNA capture, DSB repair reporters, knockdown, patient/mouse brain extracts, Drosophila PNKP rescue

    PMID:32205441

    Open questions at the time
    • Causal order between transcription loss and repair loss not disentangled
    • Whether PNKP rescue translates to mammals not shown
  19. 2021 Low

    Extended ATXN3 substrate range to EIF5A2 in anaplastic thyroid carcinoma via reduced K48-linked ubiquitination and stabilization.

    Evidence Co-IP, ubiquitination and stability assays, gain/loss-of-function cellular assays

    PMID:34428509

    Open questions at the time
    • Limited mechanistic depth; single Co-IP and ubiquitination assay from one lab
    • No in vivo validation reported
  20. 2022 High

    Demonstrated a cell-autonomous toxic gain-of-function: mutant ATXN3 impairs oligodendrocyte maturation in vulnerable regions while loss of ATXN3 does not, identifying a non-neuronal disease mechanism.

    Evidence Longitudinal transcriptomics, reporter mouse crosses, electron microscopy and SCA3 OPC culture

    PMID:35042771

    Open questions at the time
    • Molecular target of mutant ATXN3 in oligodendrocytes not identified
    • Contribution to motor phenotype relative to neuronal loss unquantified
  21. 2023 High

    Defined a catalytic-independent chromatin-organizing role for ATXN3 acting through HDAC3 localization, and showed polyQ-expanded ATXN3 behaves as a null in these assays.

    Evidence ATXN3 KO cells, replication timing, FRAP, ChIP, MNase sensitivity, HDAC3 fractionation/imaging, catalytic-mutant comparison

    PMID:36971114

    Open questions at the time
    • How ATXN3 directs HDAC3 localization mechanistically unresolved
    • Relationship of chromatin role to disease progression not established
  22. 2023 Medium

    Showed ATXN3 deubiquitinates JunB and stabilizes IRF1/STAT3/HIF-2α to drive PD-L1 expression under IFN-γ and hypoxia, implicating it in tumor immune evasion.

    Evidence CRISPR screen, Co-IP, ubiquitination assays, knockdown/reconstitution and mouse tumor models

    PMID:38038129

    Open questions at the time
    • Direct vs indirect stabilization of the multiple factors not fully separated
    • Single-lab finding
  23. 2023 Medium

    Established ATXN3 as a YAP deubiquitinase in prostate cancer via Josephin-WW domain interaction and K48-specific deubiquitination, promoting YAP/TEAD target expression.

    Evidence Domain-mapping Co-IP, K48-specific ubiquitination assays, cycloheximide chase, depletion/rescue and xenograft

    PMID:37349820

    Open questions at the time
    • Single-lab cancer-context finding
    • Connection to ATXN3's other substrate networks not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ATXN3's distinct activities — DUB catalysis, catalytic-independent chromatin organization, transcription-coupled repair, and regulated nuclear trafficking — are integrated, and which are mechanistically central to SCA3 neurodegeneration, remains unresolved.
  • No unifying model connecting catalytic and non-catalytic roles
  • Causal hierarchy among DNA damage, oligodendrocyte defects, fragment toxicity, and frameshifting in disease not established
  • Endogenous physiological substrate spectrum in neurons not comprehensively defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 4
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 3 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-4839726 Chromatin organization 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CBPHDAC3JUNBKLF4P97/VCPPNKPPOLR2AYAP
Complex memberships
transcription-coupled DNA repair complex (RNAP II / PNKP / CBP)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The 26S proteasome complex redistributes into polyglutamine aggregates in SCA3/MJD; in neurons from SCA3/MJD brain, the proteasome localizes to intranuclear inclusions containing mutant ataxin-3. Proteasome inhibitors caused a repeat length-dependent increase in aggregate formation, implying the proteasome directly suppresses polyglutamine aggregation. Inclusion formation by full-length mutant ataxin-3 required nuclear localization of the protein and occurred within PML oncogenic domains. Immunohistochemistry of human SCA3/MJD brain tissue, transfected cell models with proteasome inhibitors, subcellular fractionation/localization studies Human molecular genetics Medium 10072437
2007 Loss of Atxn3 in knockout mice increased levels of ubiquitinated proteins in vivo, providing direct evidence for ATXN3's deubiquitinating activity in a physiological context. Atxn3 ko mice showed no overt neurological abnormality on rotarod but displayed reduced exploratory behavior. Targeted gene knockout in mice; western blot for ubiquitinated proteins; behavioral testing (rotarod, open field) Biochemical and biophysical research communications High 17764659
2010 CK2 and GSK3 phosphorylate ATXN3 on serine 29 within the Josephin domain, and this phosphorylation promotes nuclear uptake of ATXN3. Site-directed mutagenesis of S29 to alanine strongly reduced nuclear localization, while phospho-mimic S29D restored wild-type nuclear localization. Treatment with CK2 and GSK3 inhibitors prevented S29 phosphorylation and inhibited nuclear uptake. In vitro kinase assay on purified ATXN3, MS analysis of phosphorylation sites, site-directed mutagenesis (S29A and S29D), CK2/GSK3 inhibitor treatment in COS-7 cells, subcellular localization by transfection Biochimica et biophysica acta High 20347968
2012 Calpain-2 cleaves ataxin-3 in vitro and in mouse brain homogenates, and polyglutamine-expanded ataxin-3 is more sensitive to calpain-mediated degradation than wild-type. In vivo, enhancing calpain activity (via calpastatin knockout in SCA3 transgenic mice) aggravated neurological phenotype, increased nuclear aggregate number, and accelerated cerebellar neurodegeneration. In vitro calpain cleavage assay, mouse brain homogenate cleavage experiments, double-mutant mouse model (SCA3 transgenic × calpastatin KO), immunohistochemistry for nuclear aggregates, behavioral assessment Human molecular genetics High 23100324
2009 Ataxin-3 protein cleavage (likely caspase-dependent) is conserved in Drosophila models of SCA3, and preventing cleavage by mutating caspase cleavage sites reduces neuronal loss in vivo, demonstrating that ataxin-3 cleavage enhances neurotoxicity. Drosophila transgenic models expressing wild-type vs. caspase-site mutant ataxin-3; quantification of neuronal loss in vivo; cell-based SL2 cleavage assay Human molecular genetics Medium 19783548
2015 Mutant ATXN3 (polyQ-expanded) physically interacts with and inactivates the DNA repair enzyme PNKP, resulting in inefficient DNA strand break repair, persistent DNA damage accumulation, and chronic ATM activation leading to p53 and PKC-δ pro-apoptotic signaling and neuronal death in SCA3. PNKP overexpression or ATM inhibition blocked mutant ATXN3-mediated cell death. Co-immunoprecipitation of ATXN3 with PNKP, PNKP enzyme activity assays, DNA damage assays (comet assay, γH2AX), ATM pathway activation assays, PNKP overexpression rescue, ATM inhibitor pharmacology in cell and mouse models PLoS genetics High 25590633
2019 Mutant HTT impairs a transcription-coupled DNA repair (TCR) complex that includes ATXN3, POLR2A, PNKP, and CBP. Within this complex, ATXN3 activity prevents CBP ubiquitination and degradation; loss of ATXN3 function in HD leads to CBP degradation, impairing transcription and DNA repair. Wild-type ATXN3 thus protects CBP from ubiquitin-mediated degradation as part of the TCR complex. Co-immunoprecipitation (ATXN3 with POLR2A, PNKP, CBP), PNKP and ATXN3 activity assays, CBP ubiquitination and stability assays, chromatin immunoprecipitation, HD transgenic mouse models eLife High 30994454
2020 ATXN3 associates with RNA polymerase II (RNAP II) and classical non-homologous end-joining (C-NHEJ) proteins including PNKP along with nascent RNAs under physiological conditions. ATXN3 depletion significantly decreases global transcription, repair of transcribed genes, and error-free double-strand break repair. Brain extracts from SCA3 patients show lower PNKP activity, elevated 53BP1, more DNA strand breaks in transcribed genes, and degradation of RNAP II. PNKP complementation completely rescues SCA3 phenotype in Drosophila. Co-immunoprecipitation of ATXN3 with RNAP II and C-NHEJ proteins, nascent RNA capture, transcription assays, DSB repair reporter assay, ATXN3 knockdown studies, brain extracts from SCA3 patients and mice, Drosophila genetic rescue with PNKP Proceedings of the National Academy of Sciences of the United States of America High 32205441
2018 ATXN3 physically interacts with HDAC3, deubiquitinates HDAC3, and thereby stabilizes HDAC3 protein. This ATXN3/HDAC3 interaction increases during viral infection and promotes IFN-I-mediated signaling pathway (not IFN-I production itself) to enhance antiviral response in murine primary lung cells and human cell lines. Co-immunoprecipitation of ATXN3 with HDAC3, ubiquitination assays of HDAC3 with and without ATXN3, ATXN3 knockdown/knockout studies, IFN-I signaling assays, viral infection models Journal of immunology Medium 29802126
2019 ATXN3 binds to KLF4 via immunoprecipitation and acts as a deubiquitinating enzyme for KLF4, mediating its deubiquitination and stabilization, thereby promoting breast cancer cell metastasis in vitro and in vivo. DUB library screen (65 enzymes), co-immunoprecipitation of ATXN3 with KLF4, ubiquitination assays, ATXN3 knockdown with KLF4 rescue, in vitro migration/invasion assays, mouse xenograft models Cancer letters Medium 31563563
2023 CRISPR screen identified ATXN3 as a positive regulator of PD-L1 transcription. ATXN3 deubiquitinates the AP-1 transcription factor JunB and also stabilizes IRF1, STAT3, and HIF-2α, transcription factors that drive PD-L1 expression in response to IFN-γ and hypoxia. ATXN3 deletion abolished IFN-γ- and hypoxia-induced PD-L1 expression. CRISPR-based screen, co-immunoprecipitation of ATXN3 with JunB, ubiquitination assays, ATXN3 knockdown with PD-L1 reconstitution, mouse tumor models, IFN-γ/hypoxia stimulation assays The Journal of clinical investigation Medium 38038129
2023 ATXN3 acts as a deubiquitinase for YAP in prostate cancer: the Josephin domain of ATXN3 interacts with the WW domain of YAP, deubiquitylates YAP (specifically inhibiting K48-linked polyubiquitination), and stabilizes YAP protein, thereby promoting YAP/TEAD target gene expression (CTGF, ANKRD1, CYR61) and prostate cancer cell proliferation and invasion. Co-immunoprecipitation (Josephin domain mapping), K48-specific ubiquitination assays, protein stability (cycloheximide chase), ATXN3 depletion with YAP overexpression rescue, xenograft mouse model, real-time PCR of YAP target genes Cell communication and signaling Medium 37349820
2021 ATXN3 promotes anaplastic thyroid carcinoma progression by directly binding to EIF5A2 and reducing its K48-linked ubiquitination and proteasomal degradation, thereby stabilizing EIF5A2 expression. Co-immunoprecipitation of ATXN3 with EIF5A2, ubiquitination assays, protein stability assays, ATXN3 gain/loss-of-function cellular assays Molecular and cellular endocrinology Low 34428509
2013 The type II iodothyronine deiodinase (D2) undergoes retrotranslocation from the ER to the cytoplasm via a p97-ATPase complex, and during this process, Ataxin-3 (Atx3) deubiquitinates ubiquitinated D2 (UbD2). Inhibiting Atx3 with eeyarestatin-I did not affect D2:p97 binding but decreased UbD2 retrotranslocation and caused ER accumulation of high-molecular-weight UbD2. Co-immunoprecipitation of D2 with p97 and Atx3, eeyarestatin-I pharmacological inhibition of Atx3, ubiquitination assays, subcellular fractionation, colocalization with 20S/19S proteasome subunits Molecular endocrinology Medium 24196352
2018 Loss of ATXN3 in null mouse embryonic fibroblasts altered transcription of multiple signal transduction pathways, including depressed Wnt and BMP4 and elevated Prolactin, TGF-β, and Ephrin pathways. The most upregulated gene was Efna3 (Ephrin receptor A3), associated with hyperacetylation of histones H3 and H4 at the Efna3 promoter and decreased HDAC3 and NCoR levels in ATXN3-null cells. Overexpression of normal or expanded ATXN3 suppressed Efna3 expression. RNA-seq transcriptomics in Atxn3 null vs. WT MEFs, chromatin immunoprecipitation for histone acetylation at Efna3 promoter, HDAC3/NCoR western blots, ATXN3 overexpression rescue in cells, qRT-PCR validation in knockout mouse brainstem PloS one Medium 30231063
2023 ATXN3 regulates chromatin organization in a catalytic-independent (deubiquitinase-independent) manner. Loss of ATXN3 leads to abnormal nuclear and nucleolar morphology, altered DNA replication timing, increased global transcription, increased histone H1 mobility, changes in epigenetic marks, and higher chromatin sensitivity to MNase digestion. ATXN3 controls the subcellular localization of HDAC3 (its interaction partner), and absence of ATXN3 decreases HDAC3 chromatin recruitment. PolyQ-expanded ATXN3 behaves as a null mutant in these assays, altering DNA replication parameters, epigenetic marks, and HDAC3 subcellular distribution. ATXN3 KO cell lines; DNA replication timing assays; FRAP for histone H1 mobility; ChIP for epigenetic marks; MNase sensitivity; HDAC3 localization by fractionation/imaging; comparison of catalytic mutant vs. null vs. PolyQ-expanded ATXN3 Nucleic acids research High 36971114
2004 The misfolding propensity and ubiquitination of ataxin-3 are directly proportional to the length of the polyglutamine repeat and inversely dependent on the size of the protein. Normal-repeat ataxin-3 (full-length and truncated) is not ubiquitinated, whereas expanded-polyQ ataxin-3 is ubiquitinated in proportion to its misfolding propensity. Cell-based ubiquitination assays with varying polyQ-length ataxin-3 constructs, immunoprecipitation, 1C2 antibody binding assays for misfolding assessment Neurotoxicity research Medium 15639784
2013 In Drosophila SCA3 models, Hsp104 suppressed toxicity of a C-terminal ataxin-3 fragment containing the expanded polyQ tract but unexpectedly enhanced aggregation and toxicity of full-length pathogenic ataxin-3. Hsp104 suppressed toxicity of MJD variants lacking part of the N-terminal deubiquitylase domain and variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 function. This demonstrates that the ubiquitin-binding capacity of ataxin-3 is functionally important for its behavior in protein disaggregation contexts. Drosophila transgenic models with various ataxin-3 constructs (full-length, truncated, ubiquitin-binding mutants), eye degeneration scoring, aggregation quantification, staging experiments with post-onset Hsp104 expression PLoS genetics Medium 24039611
2017 The truncated C-terminal fragment of mutant ATXN3 causes more mitochondrial fission, decreases expression of mitochondrial fusion markers Mfn-1 and Mfn-2, reduces mitochondrial membrane potential, increases reactive oxygen species, and leads to higher cell death than full-length mutant ATXN3 in neuroblastoma cells and transgenic mice. Neuroblastoma cell models and transgenic mouse models expressing truncated vs. full-length mutant ATXN3, mitochondrial morphology imaging, Mfn-1/Mfn-2 western blots, MMP assay, ROS measurement, cell death assays Frontiers in molecular neuroscience Medium 28676741
2006 Neuronally differentiated PC12 cells expressing expanded ataxin-3 showed significantly reduced resting membrane potential and a hyperpolarizing shift of the delayed rectifier potassium current activation curve, prior to neuronal cell death, indicating that mutant ataxin-3 causes potassium channel dysfunction. Stable inducible PC12 cell model with normal vs. expanded ataxin-3; patch-clamp electrophysiology; cell viability assay; ultrastructural analysis Experimental neurology Medium 16765348
2022 Oligodendrocyte maturation is impaired early in SCA3 disease in selectively vulnerable brain regions (cerebellum and brainstem) of SCA3 transgenic mice. This impairment is a cell-autonomous toxic gain-of-function of mutant ATXN3, as ATXN3 KO mice show no oligodendrocyte maturation defects. Ultrastructural microscopy confirmed abnormalities in axonal myelination in SCA3 mice. Weighted gene coexpression network analysis of longitudinal transcriptomics in SCA3 mouse brain, reporter mouse crosses to quantify mature oligodendrocytes, electron microscopy for axonal myelination, isolation and culture of oligodendrocyte precursor cells from SCA3 mice The Journal of neuroscience High 35042771
2005 Ribosomal frameshifting occurs at the expanded CAG repeat in ATXN3 mRNA, specifically by -1 slippage, generating polyalanine-containing proteins. This frameshifting is dependent on long CAG tract length. PolyQ-encoding CAA repeats (which cannot frameshift) were not toxic, while expanded CAG ATXN3 was toxic, indicating that frameshifting (not the polyQ per se) contributes to toxicity. Anisomycin reduced -1 frameshifting and also reduced toxicity. Cell-based ribosomal frameshifting reporter assay, comparison of CAG vs. CAA repeat ATXN3 constructs, anisomycin pharmacology, toxicity assays Human molecular genetics Medium 16087686
2012 Frameshifting events occurring at the expanded CAG repeat in ATXN3 are toxic in Drosophila and mammalian neurons. Transgenic expression of expanded CAG ATXN3 led to -1 frameshifting, whereas expression of polyglutamine-encoding expanded CAA ATXN3 (which cannot frameshift) was not toxic, demonstrating that expanded CAG-derived frameshifting (not polyQ per se) is necessary for toxicity in these models. Drosophila transgenic models and mouse neuron models expressing CAG vs. CAA repeat ATXN3 constructs, neurodegeneration scoring, frameshifting detection Human molecular genetics Medium 22337953
2015 ATXN3 does not interact with the ubiquitin-binding protein UBQLN2 (tested by Co-IP via UBA domain), in contrast to mutant HTT which does interact with UBQLN2. Consequently, UBQLN2 is not recruited to inclusions in SCA3 (neither in mouse models nor human SCA3 brain), distinguishing SCA3 inclusions from HD inclusions. Co-immunoprecipitation in cell-based system testing ATXN3 vs. HTT interaction with UBQLN2, immunohistochemistry of SCA3 and HD mouse and human brain for UBQLN2 localization Neurobiology of disease Medium 26141599

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Human molecular genetics 324 10072437
1996 Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain : a journal of neurology 197 8931575
2008 SCA3: neurological features, pathogenesis and animal models. Cerebellum (London, England) 181 18418689
2019 Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiology of disease 145 31669734
2000 Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Archives of neurology 141 10768629
2007 Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination. Biochemical and biophysical research communications 133 17764659
2019 Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. eLife 107 30994454
1997 Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3. Brain : a journal of neurology 104 9448569
2017 Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. Molecular therapy. Nucleic acids 103 28624196
2013 Silencing mutant ATXN3 expression resolves molecular phenotypes in SCA3 transgenic mice. Molecular therapy : the journal of the American Society of Gene Therapy 94 23820820
2017 ATX3, ATX4, and ATX5 Encode Putative H3K4 Methyltransferases and Are Critical for Plant Development. Plant physiology 89 28550207
2012 Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Cerebellum (London, England) 88 22198871
2015 Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3. PLoS genetics 72 25590633
2015 Toward therapeutic targets for SCA3: Insight into the role of Machado-Joseph disease protein ataxin-3 in misfolded proteins clearance. Progress in neurobiology 68 26123252
2013 Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model. PLoS genetics 68 24039611
2012 Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Human molecular genetics 67 23100324
2019 ATXN3 promotes breast cancer metastasis by deubiquitinating KLF4. Cancer letters 64 31563563
1999 Age related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). Journal of neurology, neurosurgery, and psychiatry 62 10071104
2001 The genomic structure and expression of MJD, the Machado-Joseph disease gene. Journal of human genetics 61 11450850
2013 Sodium valproate alleviates neurodegeneration in SCA3/MJD via suppressing apoptosis and rescuing the hypoacetylation levels of histone H3 and H4. PloS one 59 23382971
2013 White matter damage is related to ataxia severity in SCA3. Journal of neurology 59 24272589
2019 Taxonomy and Broad-Spectrum Antifungal Activity of Streptomyces sp. SCA3-4 Isolated From Rhizosphere Soil of Opuntia stricta. Frontiers in microbiology 58 31316480
2016 Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism & related disorders 58 26997655
2015 No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra. Brain : a journal of neurology 57 26362908
2000 CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Human molecular genetics 56 10942424
2014 A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD. Neurobiology of disease 53 25301414
1998 Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families. American journal of medical genetics 53 9613852
2005 Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts. Human molecular genetics 50 16087686
2005 Clinicopathological features and molecular markers of breast cancer in Jos, Nigeria. West African journal of medicine 49 16276696
2011 Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs. Biological chemistry 47 21294677
2009 Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Human molecular genetics 45 19783548
1995 Spinocerebellar ataxia, type 3 (SCA3) is genetically identical to Machado-Joseph disease (MJD). Journal of the neurological sciences 42 8523034
2022 Impaired Oligodendrocyte Maturation Is an Early Feature in SCA3 Disease Pathogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 35042771
2012 Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3). Neuropathology and applied neurobiology 41 21916928
2012 Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models. Human molecular genetics 41 22337953
1995 The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2. American journal of human genetics 41 7825578
2013 MicroRNA profiling in the serums of SCA3/MJD patients. The International journal of neuroscience 40 23879331
2017 The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models. Frontiers in molecular neuroscience 38 28676741
2009 Analysis of SCA2 and SCA3/MJD repeats in Parkinson's disease in mainland China: genetic, clinical, and positron emission tomography findings. Movement disorders : official journal of the Movement Disorder Society 38 19672991
2012 Body mass index is inversely correlated with the expanded CAG repeat length in SCA3/MJD patients. Cerebellum (London, England) 37 22090366
2021 A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes. Molecular neurobiology 36 34716557
2020 Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 36 32205441
2020 MR Imaging of SCA3/MJD. Frontiers in neuroscience 35 32848545
2018 ATXN3 Positively Regulates Type I IFN Antiviral Response by Deubiquitinating and Stabilizing HDAC3. Journal of immunology (Baltimore, Md. : 1950) 35 29802126
2016 Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells. BioMed research international 34 27847820
2014 miR-25 alleviates polyQ-mediated cytotoxicity by silencing ATXN3. FEBS letters 34 25451224
2009 Increased transcript diversity: novel splicing variants of Machado-Joseph disease gene (ATXN3). Neurogenetics 33 19714377
2014 Modifiers of (CAG)(n) instability in Machado-Joseph disease (MJD/SCA3) transmissions: an association study with DNA replication, repair and recombination genes. Human genetics 31 25026993
2013 Lithium chloride alleviates neurodegeneration partly by inhibiting activity of GSK3β in a SCA3 Drosophila model. Cerebellum (London, England) 31 23812869
1997 Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients. Arquivos de neuro-psiquiatria 31 9629399
2013 H1152 promotes the degradation of polyglutamine-expanded ataxin-3 or ataxin-7 independently of its ROCK-inhibiting effect and ameliorates mutant ataxin-3-induced neurodegeneration in the SCA3 transgenic mouse. Neuropharmacology 30 23347954
2023 CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1-positive regulator for tumor immune evasion. The Journal of clinical investigation 28 38038129
2020 Effectiveness and Safety of Hydroxyurea in the Treatment of Sickle Cell Anaemia Children in Jos, North Central Nigeria. Journal of tropical pediatrics 27 31608959
2018 Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways. PloS one 27 30231063
2013 Knowledge and attitude of secondary school students in Jos, Nigeria on sickle cell disease. The Pan African medical journal 27 24255733
2011 Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report. BMC neurology 27 22023810
2019 Gene-Related Cerebellar Neurodegeneration in SCA3/MJD: A Case-Controlled Imaging-Genetic Study. Frontiers in neurology 26 31616370
2003 Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype. Acta neurologica Scandinavica 26 12614315
2020 RAN Translation of the Expanded CAG Repeats in the SCA3 Disease Context. Journal of molecular biology 25 33157084
2001 Molecular analysis of Spinocerebellar ataxias in Koreans: frequencies and reference ranges of SCA1, SCA2, SCA3, SCA6, and SCA7. Molecules and cells 25 11804332
2021 Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons. Molecular therapy. Nucleic acids 23 34938609
2017 Rescue of ATXN3 neuronal toxicity in Caenorhabditiselegans by chemical modification of endoplasmic reticulum stress. Disease models & mechanisms 23 29061563
2014 Nystagmus as an early ocular alteration in Machado-Joseph disease (MJD/SCA3). BMC neurology 23 24450306
2007 SCA 1, SCA 2 & SCA 3/MJD mutations in ataxia syndromes in southern India. The Indian journal of medical research 23 18160752
2006 A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus. European journal of human genetics : EJHG 23 16724006
2004 Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado-Joseph disease (MJD) gene. Genomics 23 15233999
2021 Level of utilization and provider-related barriers to the use of hydroxyurea in the treatment of sickle cell disease patients in Jos, North-Central Nigeria. African health sciences 22 34795734
2015 T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. Neuropharmacology 22 26254860
2013 The type II deiodinase is retrotranslocated to the cytoplasm and proteasomes via p97/Atx3 complex. Molecular endocrinology (Baltimore, Md.) 22 24196352
2009 Six cases of SCA3/MJD patients that mimic hereditary spastic paraplegia in clinic. Journal of the neurological sciences 22 19608203
2021 Antisense Oligonucleotide Therapy Targeted Against ATXN3 Improves Potassium Channel-Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3. Cerebellum (London, England) 21 32789747
2015 Two novel SNPs in ATXN3 3' UTR may decrease age at onset of SCA3/MJD in Chinese patients. PloS one 21 25689313
2015 Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3. Neurobiology of disease 21 26141599
1998 Somatic mosaicism of the expanded CAG trinucleotide repeat in mRNAs for the responsible gene of Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). Neurochemical research 21 9482263
2019 MicroRNA‑25/ATXN3 interaction regulates human colon cancer cell growth and migration. Molecular medicine reports 20 30942397
2019 Druggable genome screen identifies new regulators of the abundance and toxicity of ATXN3, the Spinocerebellar Ataxia type 3 disease protein. Neurobiology of disease 20 31783119
2018 Citalopram Reduces Aggregation of ATXN3 in a YAC Transgenic Mouse Model of Machado-Joseph Disease. Molecular neurobiology 20 30187384
2016 Alteration of methylation status in the ATXN3 gene promoter region is linked to the SCA3/MJD. Neurobiology of aging 20 28094059
2009 The (CAG)n tract of Machado-Joseph Disease gene (ATXN3): a comparison between DNA and mRNA in patients and controls. European journal of human genetics : EJHG 20 19935829
2022 The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors. Journal of neurology 19 36324033
2021 Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma. International journal of biological sciences 19 33613103
2012 Normal ATXN3 Allele but Not CHIP Polymorphisms Modulates Age at Onset in Machado-Joseph Disease. Frontiers in neurology 19 23181052
2010 CK2 and GSK3 phosphorylation on S29 controls wild-type ATXN3 nuclear uptake. Biochimica et biophysica acta 19 20347968
2006 Potassium channel dysfunction and depolarized resting membrane potential in a cell model of SCA3. Experimental neurology 19 16765348
2021 Broad Influence of Mutant Ataxin-3 on the Proteome of the Adult Brain, Young Neurons, and Axons Reveals Central Molecular Processes and Biomarkers in SCA3/MJD Using Knock-In Mouse Model. Frontiers in molecular neuroscience 18 34220448
2020 Pathomechanism characterization and potential therapeutics identification for SCA3 targeting neuroinflammation. Aging 18 33196459
2014 Differential mtDNA damage patterns in a transgenic mouse model of Machado-Joseph disease (MJD/SCA3). Journal of molecular neuroscience : MN 18 25001003
2024 ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice. Molecular therapy : the journal of the American Society of Gene Therapy 17 38429929
2019 Altered Levels of Proteins and Phosphoproteins, in the Absence of Early Causative Transcriptional Changes, Shape the Molecular Pathogenesis in the Brain of Young Presymptomatic Ki91 SCA3/MJD Mouse. Molecular neurobiology 17 31201651
2023 ATXN3 promotes prostate cancer progression by stabilizing YAP. Cell communication and signaling : CCS 16 37349820
2022 Inhibition of HDAC3 and ATXN3 by miR-25 prevents neuronal loss and ameliorates neurological recovery in cerebral stroke experimental rats. Journal of physiology and biochemistry 16 35025075
2021 The deubiquitinating enzyme ATXN3 promotes the progression of anaplastic thyroid carcinoma by stabilizing EIF5A2. Molecular and cellular endocrinology 16 34428509
2011 Relative contribution of SCA2, SCA3 and SCA17 in Korean patients with parkinsonism and ataxia. Parkinsonism & related disorders 16 21334959
2010 Polyglutamine-induced neurodegeneration in SCA3 is not mitigated by non-expanded ataxin-3: conclusions from double-transgenic mouse models. Neurobiology of disease 16 20079840
2024 ATXN3: a multifunctional protein involved in the polyglutamine disease spinocerebellar ataxia type 3. Expert reviews in molecular medicine 15 39320846
2023 ATXN3 controls DNA replication and transcription by regulating chromatin structure. Nucleic acids research 15 36971114
2021 miRNA-Mediated Knockdown of ATXN3 Alleviates Molecular Disease Hallmarks in a Mouse Model for Spinocerebellar Ataxia Type 3. Nucleic acid therapeutics 15 34878314
2004 Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJD. Neurotoxicity research 15 15639784
2003 The human MJD gene: genomic structure and functional characterization of the promoter region. Gene 15 14527720
2020 PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study. Journal of neurology 14 33106888

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