Affinage

ATXN1

Ataxin-1 · UniProt P54253

Length
815 aa
Mass
86.9 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

ATXN1 is a chromatin-associated nuclear protein that functions as a transcriptional co-regulator, and whose polyglutamine-expanded form causes the cell-autonomous, gain-of-function neurodegeneration of spinocerebellar ataxia type 1 (SCA1) (PMID:7553854, PMID:15016912). In the nucleus ATXN1 binds DNA and represses transcription through the corepressor SMRT/HDAC3 (PMID:15016912), and assembles into complexes with the transcription factor RORα and the acetyltransferase Tip60 — the latter binding the ATXN1 AXH domain — to control Purkinje cell development and degeneration (PMID:17110330, PMID:21427130). ATXN1 (redundantly with ATXN1L) stabilizes the transcriptional repressor Capicua (CIC), restraining the ETV4→MMP9 axis and ECM remodeling (PMID:22014525); in disease, gain-of-function of the ATXN1–CIC complex is the primary driver of cerebellar Purkinje cell toxicity, since disrupting this interaction abolishes cerebellar pathology while loss of CIC alone does not cause ataxia (PMID:29526553). Additional ATXN1 partners identified by unbiased proteomics (RFX1, ZBTB5, ZKSCAN1) contribute to SCA1 phenotypes beyond CIC in different cell populations (PMID:36577402). Pathogenic ATXN1 toxicity requires nuclear localization (PMID:21900557, PMID:36577403) and phosphorylation at serine 776, which stabilizes the protein and is mediated by PKA in the cerebellum; reducing S776 phosphorylation or PKA activity lowers ATXN1 and rescues motor and survival phenotypes (PMID:19500214, PMID:29758256, PMID:33554954). ATXN1 protein dosage is tightly controlled — post-transcriptionally by the RNA-binding protein PUM1, by miRNAs including miR760 acting on its long 5' UTR, and by RAS-MAPK-MSK1 and PAK1 signaling, all of which modulate disease severity (PMID:25768905, PMID:32763910, PMID:23719381, PMID:29860311). Beyond the cerebellum, ATXN1 loss-of-function potentiates BACE1 β-secretase processing of APP to raise amyloid-β levels (PMID:20097758).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1995 High

    Established that polyglutamine-expanded ATXN1 acts cell-autonomously as a gain-of-function toxin sufficient to cause Purkinje cell degeneration, framing SCA1 as a toxic-protein disorder.

    Evidence Purkinje-cell-targeted expanded-CAG transgenic mice with ataxia and histopathology

    PMID:7553854

    Open questions at the time
    • Did not identify the molecular partners through which toxicity is exerted
    • Did not establish whether wild-type ATXN1 has an essential normal function
  2. 2001 High

    Showed that impaired clearance/misfolding of expanded ATXN1 contributes to pathology, since chaperone augmentation mitigates disease.

    Evidence Cross of SCA1 mice with iHSP70-overexpressing mice; behavioral and neuropathological rescue

    PMID:11448943

    Open questions at the time
    • Did not define the degradation machinery normally handling ATXN1
    • Mechanism of chaperone protection not resolved at the molecular level
  3. 2002 High

    Endogenous knock-in established a faithful disease model and linked neuronal vulnerability to the inability to sequester mutant protein into aggregates.

    Evidence 154Q CAG knock-in mice; solubility fractionation, behavioral, electrophysiological analysis

    PMID:12086639

    Open questions at the time
    • Did not establish whether soluble mutant protein is the toxic species mechanistically
    • Did not identify the downstream effectors of toxicity
  4. 2004 High

    Defined ATXN1 as a chromatin-binding transcriptional repressor acting through the SMRT/HDAC3 corepressor pathway, providing a molecular function for the protein.

    Evidence Co-IP, chromatin binding and reporter assays, Drosophila Smrter genetic epistasis

    PMID:15016912

    Open questions at the time
    • Direct DNA-binding specificity of ATXN1 not defined
    • Relationship of SMRT pathway to Purkinje-cell-specific toxicity unclear
  5. 2006 High

    Identified an ATXN1-RORα-Tip60 complex and connected RORα-dependent cerebellar development to SCA1, showing that developmental timing of mutant expression shapes disease severity.

    Evidence Conditional transgenic mice, Co-IP, RORα heterozygous crosses, behavioral readout

    PMID:17110330

    Open questions at the time
    • Whether RORα destabilization is direct or secondary not fully resolved
    • Quantitative contribution of RORα versus other pathways to toxicity unknown
  6. 2009 High

    Identified PKA, not Akt, as the cerebellar kinase phosphorylating ATXN1 at S776, the modification that stabilizes the protein.

    Evidence Cerebellar extract phosphorylation assay with immunodepletion and pharmacological PKA inhibition

    PMID:19500214

    Open questions at the time
    • In vitro extract assay; cellular PKA-ATXN1 mechanism not directly demonstrated in vivo here
    • Phosphatase counter-regulating S776 not identified
  7. 2008 Medium

    Established miRNA-mediated dosage control of ATXN1 as a modulator of polyQ toxicity, introducing the theme that ATXN1 protein levels gate disease.

    Evidence miR-19/101/130 inhibition in human cells, ATXN1 Western blot, viability assays

    PMID:18758459

    Open questions at the time
    • No in vivo validation of these miRNAs
    • Direct binding to ATXN1 transcript not fully mapped in this study
  8. 2011 High

    Revealed the normal developmental function of ATXN1/ATXN1L: stabilizing CIC to repress the ETV4-MMP9 axis and regulate ECM remodeling, with functional redundancy between paralogs.

    Evidence Atxn1L and Atxn1;Atxn1L knockout mice, Co-IP, CIC stability and expression assays

    PMID:22014525

    Open questions at the time
    • Did not establish how the same CIC complex becomes toxic when ATXN1 is polyQ-expanded
    • Tissue scope of ATXN1/ATXN1L redundancy not fully mapped
  9. 2011 High

    Mapped the ATXN1-Tip60 interaction to the AXH domain and showed S776 phosphomimicry enhances it, linking phosphorylation to complex assembly and disease modification.

    Evidence Co-IP, ATXN1[82Q] x Tip60+/- crosses, gene expression and neuropathology

    PMID:21427130

    Open questions at the time
    • Rescue was partial and mid-stage-specific
    • Structural basis of S776-dependent affinity change not resolved
  10. 2011 High

    Demonstrated that nuclear pathogenic ATXN1 selectively disrupts climbing fiber-Purkinje cell synaptic transmission before cell death, establishing a circuit deficit upstream of degeneration.

    Evidence Optical imaging, field recordings, VGluT2 staining in nuclear-localization mutant transgenic mice

    PMID:21900557

    Open questions at the time
    • Molecular link between nuclear transcriptional dysregulation and the synaptic defect not defined
    • Reversibility of the circuit deficit not tested here
  11. 2013 High

    Identified RAS-MAPK-MSK1 signaling as a druggable regulator of ATXN1 protein levels, providing a pathway-level lever on disease.

    Evidence Parallel cell-based and Drosophila genetic screens plus pharmacological inhibition in mice

    PMID:23719381

    Open questions at the time
    • Mechanism by which the pathway sets ATXN1 stability/translation not fully defined
    • Whether the effect is S776-dependent not resolved here
  12. 2015 High

    Established PUM1 as a direct post-transcriptional regulator of ATXN1 mRNA whose loss causes SCA1-like disease through ATXN1 elevation, formalizing dosage as a disease determinant.

    Evidence Pum1 knockout/haploinsufficiency mice and three-way epistasis crosses with Atxn1 alleles

    PMID:25768905

    Open questions at the time
    • Whether PUM1 acts on ATXN1 stability versus translation not fully separated
    • Other PUM1 targets contributing to phenotype not excluded
  13. 2018 High

    Demonstrated that gain-of-function of the ATXN1-CIC complex, not loss of CIC, is the primary driver of cerebellar Purkinje cell toxicity in SCA1.

    Evidence In vivo ATXN1-CIC interaction disruption, Purkinje-cell CIC knockout, expression profiling, patient iPSC neurons

    PMID:29526553

    Open questions at the time
    • Did not account for extracerebellar phenotypes
    • How polyQ expansion alters CIC complex output mechanistically not fully defined
  14. 2018 High

    Confirmed PKA as the biologically relevant S776 kinase in vivo and showed that reducing PKA catalytic activity enhances ATXN1 degradation and improves motor function, validating PKA as a target.

    Evidence PKA Cα genetic reduction in ATXN1[82Q] mice and pharmacological inhibition in patient iPSC neurons

    PMID:29758256

    Open questions at the time
    • PKA also has essential physiological roles limiting therapeutic window
    • Did not map the degron exposed by S776 dephosphorylation
  15. 2018 High

    Identified PAK1 as an S776-independent regulator of ATXN1 levels, expanding the network of dosage-controlling pathways and showing additive benefit with MSK1 inhibition.

    Evidence Drosophila forward genetic screen, mammalian PAK1 knockdown, pharmacological PAK inhibition in SCA1 mice

    PMID:29860311

    Open questions at the time
    • Molecular mechanism by which PAK1 sets ATXN1 abundance not defined
    • Whether PAK1 acts on ATXN1 directly or via intermediates unknown
  16. 2020 High

    Demonstrated direct miR760-5'UTR regulation of ATXN1 and showed AAV-delivered miR760 lowers ATXN1 and rescues motor deficits in vivo, establishing a targeted dosage-reduction therapeutic strategy.

    Evidence Target-site mutagenesis, luciferase reporters, Western blot, AAV delivery and behavior in SCA1 mice

    PMID:32763910

    Open questions at the time
    • Durability and off-target effects of AAV-miR760 not fully addressed
    • Endogenous regulation of miR760 in disease not defined
  17. 2021 High

    Showed allele-specific protection: blocking S776 phosphorylation on the expanded allele rescues disease, while disrupting it on the WT allele attenuates rescue, revealing a protective function of WT ATXN1 phosphorylation.

    Evidence Allele-specific S776 phospho-null knock-in mice with behavioral, respiratory, and survival readouts

    PMID:33554954

    Open questions at the time
    • Molecular basis of WT-allele protection not resolved
    • Did not define how WT and mutant ATXN1 functionally interact
  18. 2021 Medium

    Extended ATXN1 loss-of-function biology beyond the nervous system, showing it regulates B-1a cell receptor signaling and immunoglobulin gene transcription.

    Evidence Atxn1-null mice, flow cytometry, B-1a transcriptomics, BCR stimulation assays

    PMID:33478569

    Open questions at the time
    • Limited mechanistic detail on the molecular BCR pathway
    • Whether ATXN1's nuclear transcriptional role mediates this is not established
  19. 2022 High

    Used precise NLS mutagenesis to prove nuclear localization of mutant ATXN1 is required across the full SCA1 phenotype spectrum, and showed transcriptomic pathology is region-specific.

    Evidence CRISPR K772T NLS knock-in in Atxn1175Q mice with behavioral, survival, and RNA-seq analysis

    PMID:36577403

    Open questions at the time
    • Did not identify the nuclear effectors responsible for each phenotype
    • Region-specific transcriptional drivers not individually validated
  20. 2022 High

    Identified ATXN1 nuclear partners beyond CIC (RFX1, ZBTB5, ZKSCAN1) and showed CIC-interaction disruption only partially corrects phenotypes, establishing multi-interactor, cell-population-specific pathogenesis.

    Evidence Unbiased proteomics, ATXN1-CIC disruption knock-in mice, RNA-seq, CIC ChIP-seq, patient iNeurons

    PMID:36577402

    Open questions at the time
    • Functional contributions of RFX1/ZBTB5/ZKSCAN1 not individually dissected
    • Which interactors drive which extracerebellar phenotypes unknown
  21. 2023 High

    Defined a circuit-level mechanism in which molecular layer interneuron hyperexcitability acts upstream of Purkinje cell death, and chemogenetic correction delays degeneration and motor deficits.

    Evidence In vivo two-photon calcium imaging, DREADD inhibition, synaptic density and proteomics in SCA1 mice

    PMID:37321222

    Open questions at the time
    • How nuclear ATXN1 dysregulation produces MLIN hyperexcitability not defined
    • Whether the circuit mechanism generalizes to human SCA1 not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How polyglutamine expansion converts the normal ATXN1-CIC/transcriptional regulatory function into a toxic gain-of-function, and the molecular chain linking nuclear transcriptional dysregulation to circuit-level synaptic deficits, remain unresolved.
  • No structural model of how polyQ length alters partner-complex composition or output
  • Mechanistic bridge from transcriptional changes to MLIN/Purkinje circuit dysfunction undefined
  • Individual contributions of non-CIC interactors to specific phenotypes not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ATXN1LCICHDAC3KAT5NCOR2RFX1RORAZKSCAN1
Complex memberships
ATXN1-CIC complexATXN1-RORα-Tip60 complexATXN1-SMRT/HDAC3 corepressor complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 SCA1 transgenic mice expressing human ATXN1 with an expanded CAG repeat (polyglutamine tract) in Purkinje cells developed ataxia and Purkinje cell degeneration, establishing that expanded CAG repeats expressed in Purkinje cells are sufficient to produce neurodegeneration and that the transgene acts in a cell-autonomous gain-of-function manner. Transgenic mouse generation; behavioral testing (rotarod/ataxia); histopathology of Purkinje cells Cell High 7553854
2001 Over-expression of inducible HSP70 chaperone in SCA1 mice suppressed neurodegeneration and improved motor function, indicating that protein misfolding and impaired clearance of polyglutamine-expanded ATXN1 underlie SCA1 pathogenesis and that chaperone activity can mitigate disease. Cross-breeding SCA1 transgenic mice with iHSP70 over-expressing mice; behavioral and neuropathological assessment Human molecular genetics High 11448943
2002 Knock-in of 154 CAG repeats into the endogenous mouse Sca1 locus produced progressive neurological disorder resembling human SCA1. Mutant ataxin-1 solubility varied by brain region, being most soluble in neurons most vulnerable to degeneration (Purkinje cells), and Purkinje cells did not form aggregates until advanced disease stages, indicating that inability to sequester mutant protein into aggregates correlates with neuronal vulnerability. CAG knock-in mouse model; protein solubility fractionation; behavioral, electrophysiological, and neuropathological analysis Neuron High 12086639
2004 ATXN1 interacts with the transcriptional corepressor SMRT (and its Drosophila cognate SMRTER) and with histone deacetylase 3; ATXN1 binds chromosomes and mediates transcriptional repression when tethered to DNA. In Drosophila, mutant ATXN1 aggregates sequester SMRTER, and the neurodegenerative eye phenotype caused by mutant ATXN1 is enhanced by Smrter mutation and suppressed by Smrter duplication, placing ATXN1 in a corepressor-dependent transcriptional pathway. Co-immunoprecipitation; chromatin binding assays; transcriptional reporter assays; Drosophila genetic epistasis (Smrter loss/gain-of-function modifier screen) Proceedings of the National Academy of Sciences of the United States of America High 15016912
2006 RORα, a transcription factor critical for cerebellar development, is destabilized in SCA1 mice expressing mutant ATXN1. A complex containing ATXN1, RORα, and the acetyltransferase Tip60 was identified. Partial loss of RORα enhanced mutant ATXN1 pathogenicity. Delayed postnatal expression of mutant ATXN1 (after cerebellar development) substantially reduced disease severity, linking RORα-mediated Purkinje cell development to SCA1 pathogenesis. Conditional transgenic mouse model; Co-immunoprecipitation; gene expression analysis; genetic cross with RORα heterozygous mice; behavioral assessment Cell High 17110330
2008 miR-19, miR-101, and miR-130 co-regulate ATXN1 protein levels post-transcriptionally; inhibition of these miRNAs enhanced cytotoxicity of polyglutamine-expanded ATXN1 in human cells, establishing miRNA-mediated dosage control of ATXN1 as a modulator of SCA1 pathogenesis. miRNA inhibitor transfection in human cells; Western blot for ATXN1 levels; cell viability assays Nature neuroscience Medium 18758459
2009 Phosphorylation of ATXN1 at serine 776 (S776) stabilizes ATXN1 in Purkinje cells. Cyclic AMP-dependent protein kinase (PKA), not Akt, is the active kinase responsible for S776 phosphorylation in the cerebellum, as shown by immunodepletion and pharmacological inhibition of PKA decreasing S776 phosphorylation in cerebellar extracts, while Akt inhibition had no effect. In vitro cerebellar extract-based phosphorylation assay; immunodepletion; pharmacological kinase inhibition; Western blot Journal of neurochemistry High 19500214
2010 ATXN1 loss-of-function increases amyloid beta (Aβ40 and Aβ42) levels by potentiating β-secretase (BACE1) cleavage of APP in human neuronal cells and mouse primary cortical neurons; conversely, ATXN1 overexpression decreased Aβ levels. This was rescued by concurrent ATXN1 overexpression, establishing ATXN1 as a regulator of APP β-secretase processing. RNA interference knockdown; ATXN1 overexpression; Aβ ELISA; β-secretase activity assays in human neuronal cell line and mouse primary cortical neurons The Journal of biological chemistry High 20097758
2011 ATXN1 and ATXN1L form complexes with the transcriptional repressor Capicua (CIC). Loss of ATXN1L destabilizes CIC, leading to de-repression of ETV4, an activator of matrix metalloproteinase (MMP) genes, causing MMP9 overexpression. Atxn1L−/− mice have lung alveolarization defects and other developmental abnormalities, and Atxn1−/−;Atxn1L−/− double knockouts show more severe phenotypes, demonstrating functional redundancy and a role for ATXN1/ATXN1L-CIC complexes in ECM remodeling. Knockout mouse generation (Atxn1L−/−, Atxn1−/−;Atxn1L−/−); Co-immunoprecipitation; gene expression analysis; CIC protein stability assays Developmental cell High 22014525
2011 ATXN1 and Tip60 interact directly via the AXH domain of ATXN1. The phospho-mimicking S776D mutation increases ATXN1's interaction with Tip60. Partial loss of Tip60 (Tip60+/−) in SCA1 mice increased RORα and RORα-mediated gene expression and delayed cerebellar degeneration during mid-stage disease, demonstrating a functional role for the ATXN1-Tip60-RORα complex in SCA1 pathogenesis. Co-immunoprecipitation; genetic cross (ATXN1[82Q] × Tip60+/− mice); behavioral and neuropathological assessment; gene expression analysis Human molecular genetics High 21427130
2011 In SCA1 ATXN1[82Q] mice, there is a marked reduction in Purkinje cell responsiveness to climbing fiber (CF) activation and a decrement in CF extension on Purkinje cell dendrites. These CF-PC synaptic transmission deficits required nuclear localization of pathogenic ATXN1[82Q] and were absent with loss of endogenous Atxn1 alone, establishing that nuclear ATXN1[82Q] preferentially disrupts the CF-PC circuit before cell death. Flavoprotein autofluorescence optical imaging; extracellular field potential recordings; immunostaining for VGluT2; transgenic mouse models including nuclear localization mutants The Journal of neuroscience : the official journal of the Society for Neuroscience High 21900557
2012 Phosphorylation of ATXN1 at S776 regulates its interaction with cellular proteins and modulates its toxicity. The S776 phosphorylation site mediates interactions underlying SCA1 pathology, and polyglutamine expansion exaggerates ATXN1's native function through S776-dependent mechanisms. Review/synthesis of prior experimental evidence including phosphomimetic and phosphonull mutant analyses in cell and animal models Progress in neurobiology Medium 22531670
2013 Downregulation of components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice, as identified by parallel cell-based and Drosophila genetic screens. Pharmacological inhibition of pathway components also decreased ATXN1 levels in vivo, establishing RAS-MAPK-MSK1 signaling as a regulator of ATXN1 protein levels. Cell-based genetic screen; Drosophila genetic screen; pharmacological inhibition in mice; Western blot for ATXN1 levels; Drosophila neurodegeneration assays Nature High 23719381
2015 The RNA-binding protein PUMILIO1 (PUM1) directly regulates ATXN1 mRNA levels post-transcriptionally. Loss of Pum1 caused SCA1-like neurodegeneration primarily by increasing Ataxin-1 levels. Breeding Pum1+/− mice to SCA1 mice exacerbated disease, while breeding to Atxn1+/− mice (reducing Ataxin-1 levels) largely rescued the Pum1+/− phenotype, establishing PUM1 as a post-transcriptional regulator of ATXN1. PUM1 knockout/haploinsufficiency mouse models; genetic epistasis crosses (Pum1+/−× Atxn1154Q/+ and Pum1+/− × Atxn1+/−); ATXN1 protein level measurement; behavioral assessment Cell High 25768905
2018 The ATXN1-CIC complex is the primary driver of cerebellar toxicity in SCA1 through a gain-of-function mechanism. Disruption of the ATXN1-CIC interaction in vivo specifically abolishes cerebellar pathology, while loss of CIC alone in the cerebellum does not cause ataxia or Purkinje cell degeneration, demonstrating that gain-of-function of the ATXN1-CIC complex (not loss of CIC) drives cerebellar disease. In vivo genetic disruption of ATXN1-CIC interaction; Purkinje cell-specific CIC knockout mice; expression profiling; iPSC-derived neurons from SCA1 patients; behavioral assessment Neuron High 29526553
2018 PKA (protein kinase A) is a biologically important kinase for ATXN1-S776 phosphorylation in cerebellar Purkinje cells. Genetic reduction of the PKA catalytic subunit Cα in ATXN1[82Q] mice resulted in enhanced ATXN1 degradation and improved cerebellar-dependent motor performance. Pharmacological S776 phosphorylation inhibition in SCA1 patient iPSC-derived neurons decreased ATXN1 levels. Pharmacological PKA inhibition in transfected cells and SCA1 patient iPSC-derived neurons; genetic manipulation of PKA Cα in Pcp2-ATXN1[82Q] mice; Western blot; behavioral assessment Neurobiology of disease High 29758256
2018 PAK1 (p21-activated kinase 1) regulates ATXN1 protein levels through a pathway independent of S776 phosphorylation. Loss-of-function of PAK1/Pak3 in Drosophila and knockdown of PAK1 in mammalian cells reduced ATXN1 levels and improved disease pathology. Pharmacological PAK inhibition also decreased ATXN1 levels in a mouse model of SCA1. Combined inhibition of PAK and MSK1 produced additive reductions in ATXN1 levels. Drosophila forward genetic screen; PAK1 knockdown in mammalian cells; pharmacological PAK inhibition in SCA1 mice; Western blot for ATXN1 levels; Drosophila neurodegeneration assays Human molecular genetics High 29860311
2020 ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances ALS phenotypes in Drosophila, as demonstrated by functional experiments linking intermediate ATXN1 polyglutamine repeat expansions to ALS pathophysiology. Drosophila ALS phenotype assays; TDP-43 nuclear/cytoplasmic fractionation; population genetic association study Brain communications Medium 32954321
2020 miR760 binds a conserved site in ATXN1's unusually long 5' UTR to negatively regulate ATXN1 expression via RNA degradation and translational inhibition. AAV-mediated delivery of miR760 to the cerebellum reduced ATXN1 levels in vivo and mitigated motor coordination deficits in a mouse model of SCA1. miRNA-target site mutagenesis; luciferase reporter assays; Western blot; AAV delivery in vivo; behavioral assessment in SCA1 mice Genes & development High 32763910
2021 Abolishing S776 phosphorylation specifically on polyQ-expanded ATXN1 in SCA1 knock-in mice reduces ATXN1 throughout the brain and rescues cerebellar motor incoordination, respiratory function, and extends survival. Disrupting S776 phosphorylation on both WT and expanded ATXN1 alleles attenuated the rescue, demonstrating a protective role of WT allele phosphorylation and allele-specific toxicity. SCA1 knock-in mouse allele-specific S776 phospho-null mutation; allele-specific S776 disruption on both alleles; behavioral, respiratory, and survival analysis; Western blot for ATXN1 levels JCI insight High 33554954
2022 Nuclear localization of mutant ATXN1 is required for a broad spectrum of SCA1-like disease phenotypes including motor dysfunction, cognitive deficits, and premature lethality, as demonstrated by CRISPR-Cas9 introduction of a K772T amino acid change in the nuclear localization sequence of expanded ATXN1. RNA-seq revealed that transcriptomic aspects of SCA1 pathogenesis differ between brain regions. CRISPR-Cas9 knock-in of K772T nuclear localization sequence mutation in Atxn1175Q mice; behavioral (motor, cognitive), survival, and RNA-seq analysis Neuron High 36577403
2022 Beyond CIC, ATXN1 interacts with additional nuclear transcription factors RFX1, ZBTB5, and ZKSCAN1 (identified by unbiased proteomics). Disrupting the ATXN1-CIC interaction globally in Atxn1154Q/2Q knock-in mice normalized CIC binding genome-wide but only partially corrected transcriptional and behavioral phenotypes, demonstrating that multiple interactors contribute to SCA1 pathogenesis in different cell populations. Global ATXN1-CIC interaction disruption in knock-in mice; unbiased proteomics; RNA-seq; ChIP-seq for CIC; human SCA1 patient-derived iNeurons; behavioral assessment Neuron High 36577402
2021 ATXN1 loss-of-function regulates B cell receptor (BCR) signaling in B-1a cells. Atxn1-null mice exhibit increased B cell proliferation and expansion of B-1a cells. Transcriptomic profiling of Atxn1-null B-1a cells showed that ATXN1 regulates immunoglobulin gene transcription and signaling through the BCR in this B cell subpopulation. Atxn1 knockout mice; flow cytometry; transcriptomic profiling of B-1a cells; BCR stimulation assays Molecular brain Medium 33478569
2023 Molecular layer interneurons (MLINs) become prematurely hyperexcitable in SCA1 mice, displaying elevated parvalbumin, higher excitatory-to-inhibitory synaptic density, and more synaptic connections on Purkinje neurons (PNs). Chemogenetic inhibition of hyperexcitable MLINs normalized parvalbumin expression, restored calcium signaling in SCA1 PNs, delayed PN degeneration, and ameliorated motor deficits, establishing a circuit-level mechanism upstream of PN death in SCA1. In vivo two-photon calcium imaging in behaving SCA1 mice; chemogenetic (DREADD) inhibition; synaptic density analysis; behavioral assessment; proteomics of SCA1 MLINs Neuron High 37321222

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science (New York, N.Y.) 564 9346482
2001 Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 528 11672547
1995 SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 498 7553854
2001 Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Human molecular genetics 378 11448943
1997 A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. The Journal of biological chemistry 315 9083054
2002 A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 278 12086639
1995 The ATX1 gene of Saccharomyces cerevisiae encodes a small metal homeostasis factor that protects cells against reactive oxygen toxicity. Proceedings of the National Academy of Sciences of the United States of America 232 7731983
2011 Unification of the copper(I) binding affinities of the metallo-chaperones Atx1, Atox1, and related proteins: detection probes and affinity standards. The Journal of biological chemistry 208 21258123
1999 Crystal structure of the Atx1 metallochaperone protein at 1.02 A resolution. Structure (London, England : 1993) 196 10404590
2006 RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 194 17110330
2006 The Atx1-Ccc2 complex is a metal-mediated protein-protein interaction. Nature chemical biology 181 16732294
2008 miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis. Nature neuroscience 179 18758459
2000 Energetics of copper trafficking between the Atx1 metallochaperone and the intracellular copper transporter, Ccc2. The Journal of biological chemistry 173 10764731
2001 Solution structure of the Cu(I) and apo forms of the yeast metallochaperone, Atx1. Biochemistry 146 11327811
2004 Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Human molecular genetics 142 15317756
2015 Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. Cell 134 25768905
1991 The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. American journal of human genetics 126 2063871
2015 PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium. Nature communications 120 25980517
2004 Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proceedings of the National Academy of Sciences of the United States of America 119 15016912
2019 Arterial Sca1+ Vascular Stem Cells Generate De Novo Smooth Muscle for Artery Repair and Regeneration. Cell stem cell 118 31883835
2013 RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 118 23719381
2018 Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI insight 105 30385727
2018 ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism. Neuron 96 29526553
2011 ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. Developmental cell 90 22014525
2012 ATX1-generated H3K4me3 is required for efficient elongation of transcription, not initiation, at ATX1-regulated genes. PLoS genetics 87 23284292
2016 Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. Neuron 85 26948890
1988 The stem cell antigens Sca-1 and Sca-2 subdivide thymic and peripheral T lymphocytes into unique subsets. Journal of immunology (Baltimore, Md. : 1950) 76 2460547
2011 Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 70 21900557
2013 The role of interruptions in polyQ in the pathology of SCA1. PLoS genetics 69 23935513
2018 Cytokine- and TCR-Mediated Regulation of T Cell Expression of Ly6C and Sca-1. Journal of immunology (Baltimore, Md. : 1950) 64 29358280
2010 The Rickettsia conorii autotransporter protein Sca1 promotes adherence to nonphagocytic mammalian cells. Infection and immunity 63 20176791
2020 SRSF10 inhibits biogenesis of circ-ATXN1 to regulate glioma angiogenesis via miR-526b-3p/MMP2 pathway. Journal of experimental & clinical cancer research : CR 58 32600379
1998 Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families. American journal of medical genetics 53 9613852
2007 Interplay between glutathione, Atx1 and copper. 1. Copper(I) glutathionate induced dimerization of Atx1. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 52 17957393
2001 SCA1 molecular genetics: a history of a 13 year collaboration against glutamines. Human molecular genetics 51 11673415
2011 Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model. Human molecular genetics 50 21427130
2010 Loss of function of ATXN1 increases amyloid beta-protein levels by potentiating beta-secretase processing of beta-amyloid precursor protein. The Journal of biological chemistry 49 20097758
2009 Phosphorylation of ATXN1 at Ser776 in the cerebellum. Journal of neurochemistry 45 19500214
2012 Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders. Molecular cytogenetics 43 22480366
2014 Sca-1+ cardiac progenitor cells and heart-making: a critical synopsis. Stem cells and development 40 24926741
2007 Atx1-like chaperones and their cognate P-type ATPases: copper-binding and transfer. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 40 17225061
2020 ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain communications 39 32954321
2016 Impaired mTORC1-Dependent Expression of Homer-3 Influences SCA1 Pathophysiology. Neuron 39 26748090
1993 The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps centromeric to D6S89 and shows no recombination, in nine large kindreds, with a dinucleotide repeat at the AM10 locus. American journal of human genetics 38 8101039
2019 Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease. Neurobiology of aging 37 31810584
2017 ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis. Neurobiology of aging 37 29274668
2013 Altered Purkinje cell miRNA expression and SCA1 pathogenesis. Neurobiology of disease 35 23376683
2006 Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice. Brain research bulletin 35 16647585
2017 Adventitial SCA-1+ Progenitor Cell Gene Sequencing Reveals the Mechanisms of Cell Migration in Response to Hyperlipidemia. Stem cell reports 32 28757161
2011 Stem cell antigen-1 (sca-1) regulates mammary tumor development and cell migration. PloS one 32 22140470
2023 Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1. Neuron 31 38016472
2021 SCA-1 micro-heterogeneity in the fate decision of dystrophic fibro/adipogenic progenitors. Cell death & disease 31 33495447
2020 Cerebellar contribution to the cognitive alterations in SCA1: evidence from mouse models. Human molecular genetics 31 31696233
2017 Triplin, a small molecule, reveals copper ion transport in ethylene signaling from ATX1 to RAN1. PLoS genetics 31 28388654
2020 miR760 regulates ATXN1 levels via interaction with its 5' untranslated region. Genes & development 30 32763910
2012 SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis. Progress in neurobiology 30 22531670
2021 SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 33888607
2018 Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. Neurobiology of disease 29 29758256
2017 Leptin Induces Sca-1+ Progenitor Cell Migration Enhancing Neointimal Lesions in Vessel-Injury Mouse Models. Arteriosclerosis, thrombosis, and vascular biology 29 28935755
2011 Cellular fusion for gene delivery to SCA1 affected Purkinje neurons. Molecular and cellular neurosciences 28 21420496
2009 Commentary: Sca-1 and Cells of the Lung: A matter of Different Sorts. Stem cells (Dayton, Ohio) 27 19259938
2022 Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles. Neuron 26 36577403
2017 Sca-1 identifies a trophoblast population with multipotent potential in the mid-gestation mouse placenta. Scientific reports 26 28717241
2014 Fat depot-specific gene signature and ECM remodeling of Sca1(high) adipose-derived stem cells. Matrix biology : journal of the International Society for Matrix Biology 26 24726953
2009 Interaction between cyanobacterial copper chaperone Atx1 and zinc homeostasis. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 26 19543924
2001 Calcium homeostasis and spinocerebellar ataxia-1 (SCA-1). Brain research bulletin 25 11719254
2016 c-Myb Regulates Proliferation and Differentiation of Adventitial Sca1+ Vascular Smooth Muscle Cell Progenitors by Transactivation of Myocardin. Arteriosclerosis, thrombosis, and vascular biology 24 27174098
2022 Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1. Neuron 23 36577402
2012 Suppression of calbindin-D28k expression exacerbates SCA1 phenotype in a disease mouse model. Cerebellum (London, England) 22 22076800
2013 PECAM1(+)/Sca1(+)/CD38(+) vascular cells transform into myofibroblast-like cells in skin wound repair. PloS one 21 23308177
2022 Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma. Genes, chromosomes & cancer 20 35715887
2017 Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1. Cerebellum (London, England) 20 27306906
2010 Sca-1 is negatively regulated by TGF-beta1 in myogenic cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 21156809
2010 The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: evidence from a large collaborative study totaling 4,963 subjects. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20 21302343
2018 Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition. Theranostics 19 29556355
2008 Copper distributed by Atx1 is available to copper amine oxidase 1 in Schizosaccharomyces pombe. Eukaryotic cell 19 18723604
2014 Sca1⁺ murine pituitary adenoma cells show tumor-growth advantage. Endocrine-related cancer 18 24481638
2014 The design and delivery of a PKA inhibitory polypeptide to treat SCA1. Journal of neurochemistry 18 24903464
2017 Mouse Bone Marrow Sca-1+ CD44+ Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway. Infection and immunity 17 28739828
2008 Cell surface expression of stem cell antigen-1 (Sca-1) distinguishes osteo-, chondro-, and adipoprogenitors in fetal mouse calvaria. Calcified tissue international 17 18175035
2008 Characterization of the zebrafish atxn1/axh gene family. Journal of neurogenetics 17 19085187
2000 The ins and outs of a polyglutamine neurodegenerative disease: spinocerebellar ataxia type 1 (SCA1). Neurobiology of disease 17 10860780
2018 PAK1 regulates ATXN1 levels providing an opportunity to modify its toxicity in spinocerebellar ataxia type 1. Human molecular genetics 16 29860311
2021 Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1. JCI insight 15 33554954
2021 Region-specific preservation of Purkinje cell morphology and motor behavior in the ATXN1[82Q] mouse model of spinocerebellar ataxia 1. Brain pathology (Zurich, Switzerland) 15 33724582
2017 Stance instability in preclinical SCA1 mutation carriers: A 4-year prospective posturography study. Gait & posture 15 28551466
2016 High relative frequency of SCA1 in Poland reflecting a potential founder effect. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 15 27193757
2023 Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1. Neuron 14 37321222
2023 Adiponectin stimulates Sca1+CD34--adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue. Metabolism: clinical and experimental 14 37918793
2022 Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice. Molecular therapy. Methods & clinical development 14 35573049
2021 Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis. Cerebellum (London, England) 14 33394333
2023 HD and SCA1: Tales from two 30-year journeys since gene discovery. Neuron 13 37863037
2020 The Sca-1+ and Sca-1- mouse prostatic luminal cell lineages are independently sustained. Stem cells (Dayton, Ohio) 13 32627901
2000 Physical mapping of the human ATX1 homologue (HAH1) to the critical region of the 5q- syndrome within 5q32, and immediately adjacent to the SPARC gene. Human genetics 13 10982193
2016 Transcriptomic response of yeast cells to ATX1 deletion under different copper levels. BMC genomics 12 27401861
2011 A cytoplasm-specific activity encoded by the Trithorax-like ATX1 gene. Nucleic acids research 12 21245040
2002 Toward cell specificity in SCA1. Neuron 12 12062012
2022 Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1+CD31- Cells. International journal of molecular sciences 11 36293311
2022 Suppressing gain-of-function proteins via CRISPR/Cas9 system in SCA1 cells. Scientific reports 11 36434031
2021 The novel multiple sclerosis susceptibility gene ATXN1 regulates B cell receptor signaling in B-1a cells. Molecular brain 11 33478569

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