Affinage

ATXN1

Ataxin-1 · UniProt P54253

Round 2 corrected
Length
815 aa
Mass
86.9 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATXN1 encodes the nuclear transcriptional regulator ataxin-1, which assembles into distinct native protein complexes—most prominently with the transcriptional repressor Capicua (CIC) and with RORα/Tip60—to control gene expression programs essential for cerebellar Purkinje cell maintenance and forebrain development (PMID:17190598, PMID:17110330, PMID:28288114). ATXN1 stability and function are governed by PKA-mediated phosphorylation at S776 (promoting 14-3-3 binding and protein stabilization), ubiquitin-dependent degradation via CHIP and UbcH6, and post-transcriptional dosage control by PUMILIO1 and multiple microRNAs targeting its extended 5′ UTR (PMID:19500214, PMID:16831871, PMID:25768905, PMID:32763910). CAG trinucleotide repeat expansion in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), in which polyglutamine-expanded ataxin-1 shifts the balance of endogenous complexes—favoring the pathogenic ATXN1–RBM17 interaction while impairing the ATXN1–CIC complex—with nuclear localization and S776 phosphorylation both required for neurodegeneration (PMID:8358429, PMID:18337722, PMID:12741986, PMID:36577403). Unbiased proteomics has further identified ATXN1 interactions with transcription factors RFX1, ZBTB5, and ZKSCAN1, whose dysregulation contributes to the broader transcriptional pathology of SCA1 (PMID:36577402).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    Identification of the causative mutation—an unstable CAG repeat expansion in ATXN1—established the molecular basis of SCA1 and linked polyglutamine tract length to disease severity.

    Evidence Positional cloning and linkage analysis in SCA1 families

    PMID:8358429

    Open questions at the time
    • Why Purkinje cells are selectively vulnerable was not explained
    • Function of the normal ataxin-1 protein was unknown
  2. 1995 High

    Demonstrating that ataxin-1 is a nuclear protein—with additional cytoplasmic localization in Purkinje cells—established that its primary site of action is the nucleus, redirecting the field away from cytoplasmic aggregation models.

    Evidence Immunoblot and immunofluorescence of patient and normal human brain tissues

    PMID:7647801

    Open questions at the time
    • Nuclear function remained undefined
    • Mechanism of nuclear targeting not mapped
  3. 1997 High

    Discovery that mutant ataxin-1 forms a single large nuclear inclusion that reorganizes the PML-containing nuclear matrix, and that LANP interacts with ataxin-1 in a glutamine-length-dependent manner in Purkinje cells, implicated nuclear matrix disruption and selective protein interactions in pathogenesis.

    Evidence Immunofluorescence and nuclear matrix fractionation in transgenic mice and patient tissue; yeast two-hybrid and co-IP for LANP

    PMID:9353120 PMID:9353121

    Open questions at the time
    • Whether nuclear inclusions are toxic or protective was unresolved
    • LANP's functional role in the ATXN1 pathway was unclear
  4. 1998 High

    Finding that proteasome subunits and chaperone HDJ-2 colocalize with nuclear inclusions, and that HDJ-2 overexpression reduces aggregation, established that protein quality control machinery engages misfolded ataxin-1.

    Evidence Immunostaining of patient and transgenic mouse brain, chaperone overexpression in HeLa cells

    PMID:9620770

    Open questions at the time
    • Whether chaperone-mediated clearance is sufficient to prevent disease in vivo was untested
    • Ubiquitination machinery for ataxin-1 was unidentified
  5. 2001 High

    In vivo demonstration that HSP70 overexpression suppresses SCA1 neuropathology in transgenic mice provided the first mammalian proof that enhancing proteostasis can rescue polyglutamine-mediated neurodegeneration.

    Evidence Crossbreeding SCA1 transgenic with iHSP70-overexpressing mice; rotarod and neuropathology

    PMID:11448943

    Open questions at the time
    • Specific substrates of HSP70 in this context were not defined
    • Whether clearance versus refolding underlies rescue was unclear
  6. 2003 High

    Identification of S776 phosphorylation as a disease-critical post-translational modification—required for 14-3-3 binding, protein stabilization, nuclear inclusion formation, and in vivo cerebellar pathology—established that polyglutamine expansion alone is insufficient for neurodegeneration.

    Evidence Phospho-site identification, co-IP with 14-3-3, Drosophila epistasis, S776A transgenic mice with rotarod and neuropathology

    PMID:12741986 PMID:12757707

    Open questions at the time
    • The kinase responsible for S776 phosphorylation in Purkinje cells was initially misassigned to Akt
    • Downstream consequences of 14-3-3 binding beyond stabilization were unexplored
  7. 2006 High

    Purification of native ATXN1-containing complexes revealed that ataxin-1 functions primarily as a component of large transcriptional regulatory complexes: a CIC-containing repressor complex, an RORα/Tip60 coactivator complex, and a SMRT/HDAC3 corepressor complex, redefining ataxin-1 as a transcriptional regulator rather than merely an aggregation-prone protein.

    Evidence Native complex purification from mouse cerebellum, co-IP, reporter assays, Drosophila genetic epistasis for SMRT and RORα pathways

    PMID:15016912 PMID:17110330 PMID:17190598

    Open questions at the time
    • How ATXN1 coordinates membership across distinct complexes was unknown
    • Genome-wide transcriptional targets of these complexes were not mapped
  8. 2006 High

    Demonstration that CHIP ubiquitin ligase and UbcH6 ubiquitin-conjugating enzyme mediate ataxin-1 ubiquitination and degradation defined the proteolytic pathway controlling ataxin-1 turnover.

    Evidence In vitro ubiquitination assays, co-IP, Drosophila CHIP overexpression rescue

    PMID:16831871 PMID:18439907

    Open questions at the time
    • Relative contributions of CHIP versus UbcH6-mediated ubiquitination in vivo were not resolved
    • Ubiquitin chain type specificity was not determined
  9. 2008 High

    The finding that polyglutamine expansion shifts the equilibrium between ATXN1 complexes—favoring the pathogenic ATXN1–RBM17 complex while attenuating the ATXN1–CIC complex—established a dual gain-of-function/partial loss-of-function model for SCA1 pathogenesis.

    Evidence Native complex purification, co-IP, Drosophila genetic epistasis

    PMID:18337722

    Open questions at the time
    • Structural basis for differential complex assembly was unknown
    • Whether therapeutic rebalancing of complexes is achievable was untested
  10. 2009 High

    Reassignment of the S776 kinase from Akt to PKA in cerebellar Purkinje cells corrected a key mechanistic detail and focused therapeutic kinase-targeting efforts on the cAMP-PKA signaling axis.

    Evidence Cerebellar extract kinase assay with immunodepletion and inhibition, in vivo kinase inhibition

    PMID:19500214

    Open questions at the time
    • Whether other kinases contribute in non-cerebellar cell types was unexplored
    • Upstream signals regulating PKA-dependent ATXN1 phosphorylation were not defined
  11. 2015 High

    Discovery that PUMILIO1 post-transcriptionally controls ATXN1 mRNA levels, and that Pum1 haploinsufficiency causes SCA1-like neurodegeneration rescuable by reducing Atxn1 gene dosage, established that ATXN1 protein levels are tightly regulated and that even modest elevation is pathogenic.

    Evidence Mouse genetic epistasis (Pum1+/− × Atxn1+/−), behavioral assays, protein quantification

    PMID:25768905

    Open questions at the time
    • Whether PUM1 acts on the 3′ UTR, 5′ UTR, or coding sequence was not fully resolved
    • Other RNA-binding proteins regulating ATXN1 mRNA were not systematically identified
  12. 2017 High

    Conditional knockout studies demonstrated that the ATXN1–CIC complex is essential for forebrain neuron maturation, learning, memory, and social behavior, extending ATXN1 function beyond the cerebellum and linking CIC mutations to intellectual disability and autism in humans.

    Evidence Conditional mouse knockouts, behavioral phenotyping, cortical neuron characterization, human de novo CIC mutation analysis

    PMID:28288114

    Open questions at the time
    • Direct genomic targets of ATXN1–CIC in forebrain were not comprehensively mapped
    • Whether ATXN1-independent CIC functions contribute to the human phenotype was unclear
  13. 2020 High

    Identification of miR-760 as a regulator acting through the ATXN1 5′ UTR, with AAV-delivered miR-760 reducing ATXN1 levels and rescuing motor deficits in SCA1 mice, established a therapeutic strategy exploiting post-transcriptional dosage control.

    Evidence miRNA target site mapping, reporter assays, AAV delivery in SCA1 mouse cerebellum, motor coordination assay

    PMID:32763910

    Open questions at the time
    • Long-term safety and off-target effects of miR-760 delivery were not assessed
    • Whether combining miR-760 with other miRNAs (miR-19, miR-101, miR-130) provides additive benefit was untested
  14. 2022 High

    CRISPR-based disruption of the ATXN1 nuclear localization signal rescued motor, cognitive, and transcriptomic phenotypes genome-wide, definitively proving that nuclear localization of mutant ATXN1 is required for the full spectrum of SCA1 pathology; meanwhile, disrupting the ATXN1–CIC interaction only partially corrected phenotypes, and proteomics identified RFX1, ZBTB5, and ZKSCAN1 as additional transcription factor partners whose target genes are dysregulated in SCA1.

    Evidence CRISPR-Cas9 NLS knock-in mouse, CIC-interaction mutant knock-in mouse, ChIP-seq, RNA-seq, affinity purification mass spectrometry, patient-derived iNeurons

    PMID:36577402 PMID:36577403

    Open questions at the time
    • Relative pathogenic contributions of RFX1, ZBTB5, and ZKSCAN1 complex disruption versus CIC complex disruption are unquantified
    • Structural basis for ATXN1 interaction with these new partners is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full transcription factor interaction landscape of ATXN1, the structural basis for polyglutamine-dependent complex switching, and the therapeutic potential of combined dosage-reduction and complex-rebalancing strategies remain to be determined.
  • No high-resolution structure of ATXN1 in complex with CIC or RBM17 exists
  • How ATXN1 intermediate-length repeats contribute to ALS via TDP-43 mislocalization requires mechanistic resolution
  • Whether pharmacological PKA inhibition or miRNA-based ATXN1 reduction translates to human SCA1 therapy is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 6 GO:0005654 nucleoplasm 3 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 2
Partners
CICKAT5NCOR2PUM1RBM17RORASTUB1YWHAZ
Complex memberships
ATXN1-CIC repressor complexATXN1-RBM17 complexATXN1-RORα-Tip60 complexATXN1-SMRT-HDAC3 complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 SCA1 is caused by expansion of an unstable CAG trinucleotide repeat within the coding region of the ATXN1 gene on chromosome 6p, encoding a polyglutamine tract in the protein ataxin-1; repeat size directly correlates with age of onset. Positional cloning, CAG repeat identification, linkage analysis, mRNA characterization Nature genetics High 8358429
1994 The SCA1 gene spans 450 kb, is organized in nine exons (first seven in the 5' UTR with alternative splicing), produces a 10,660-base transcript encoding ataxin-1, and is transcribed from both wild-type and expanded alleles. cDNA cloning, genomic organization, Northern blot, sequencing Nature genetics High 7951322
1995 Ataxin-1 protein localizes to the nucleus in all brain regions examined, with cytoplasmic localization also observed in cerebellar Purkinje cells; mutant protein migrates aberrantly by size proportional to CAG repeat length and shows normal stability and distribution. Immunoblot analysis of patient and normal tissues, immunofluorescence Nature genetics High 7647801
1997 Mutant ataxin-1 with expanded polyglutamine localizes to a single large nuclear inclusion (~2 µm) in Purkinje cells of transgenic mice and SCA1 patients, whereas wild-type ataxin-1 distributes to multiple smaller nuclear structures (~0.5 µm); both forms associate with the nuclear matrix, and mutant ataxin-1 causes redistribution of the PML-containing nuclear matrix-associated domain. Immunofluorescence in transgenic mice and SCA1 patient neurons, nuclear matrix fractionation, COS-1 cell transfection Nature High 9353120
1997 The leucine-rich acidic nuclear protein LANP interacts with ataxin-1 in a glutamine-length-dependent manner (stronger interaction with expanded polyglutamine); both proteins co-localize in nuclear matrix-associated subnuclear structures, and LANP is expressed predominantly in Purkinje cells — the primary site of SCA1 pathology. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, Western blot Nature High 9353121
1998 Nuclear inclusions of mutant ataxin-1 in SCA1 patient neurons and transgenic mice stain positively for the 20S proteasome and the DnaJ chaperone HDJ-2/HSDJ; overexpression of wild-type HDJ-2/HSDJ in HeLa cells decreases frequency of ataxin-1 aggregation, implying that protein misfolding drives nuclear aggregate formation. Immunostaining of patient tissue and transgenic mouse brains, HeLa cell transfection, chaperone overexpression assay Nature genetics High 9620770
2001 Overexpression of inducible HSP70 in SCA1 transgenic mice suppresses neuropathology and improves motor function, indicating that enhancing chaperone activity mitigates polyglutamine-mediated neurodegeneration in a mammalian model. Crossbreeding of SCA1 transgenic mice with iHSP70-overexpressing mice, rotarod behavioral assay, neuropathological assessment Human molecular genetics High 11448943
2003 Phosphorylation of ataxin-1 at serine 776 (S776) by Akt is critical for SCA1 pathogenesis: S776 phosphorylation is required for binding to 14-3-3 protein, which stabilizes ataxin-1 and slows its degradation; both 14-3-3 and Akt modulate neurodegeneration in a Drosophila SCA1 model. Phosphorylation site identification, co-immunoprecipitation, Drosophila genetic epistasis, cell-based degradation assay Cell High 12757707
2003 Serine 776 (S776) phosphorylation of ataxin-1 is critical for polyglutamine-induced disease: ataxin-1[82Q]-A776 (S776A mutant) fails to form nuclear inclusions in cell culture and substantially fails to induce cerebellar disease in transgenic mice despite nuclear localization, demonstrating that polyglutamine expansion plus nuclear localization alone are insufficient without S776 phosphorylation. Mutagenesis, transgenic mouse generation, rotarod assay, neuropathological analysis Neuron High 12741986
2004 Ataxin-1 interacts with the transcriptional corepressor SMRT and with histone deacetylase 3; ataxin-1 binds chromosomes and mediates transcriptional repression when tethered to DNA; interaction with SMRT-related factors is conserved (ataxin-1 also binds Drosophila SMRTER); mutant ataxin-1 sequesters SMRTER into aggregates, and Smrter mutation enhances, while Smrter duplication suppresses, the neurodegenerative eye phenotype in flies. Co-immunoprecipitation, tethered transcriptional repression assay, Drosophila genetic epistasis, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 15016912
2006 The majority of both wild-type and expanded ATXN1 assembles into large stable protein complexes containing the transcriptional repressor Capicua (CIC) in mouse cerebellum; ATXN1 directly binds CIC, modulates CIC repressor activity, and loss of ATXN1 decreases CIC steady-state levels; the S776A mutation substantially reduces mutant ATXN1-CIC association in vivo, linking this interaction to neuropathogenesis. Native protein complex purification from mouse cerebellum, co-immunoprecipitation, Drosophila and mammalian cell reporter assays, Western blot Cell High 17190598
2006 ATXN1 forms a complex with RORalpha (a transcription factor critical for cerebellar development) and the RORalpha coactivator Tip60; mutant ATXN1 destabilizes RORalpha, reducing expression of RORalpha-controlled genes; partial loss of RORalpha enhances mutant ATXN1 pathogenicity, and delayed postnatal expression of mutant ATXN1 substantially reduces disease severity. Conditional transgenic mouse model, co-immunoprecipitation, gene expression analysis, behavioral assessment Cell High 17110330
2006 CHIP (E3 ubiquitin ligase) directly interacts with ataxin-1 (both expanded and unexpanded) and co-localizes in nuclear inclusions; CHIP promotes ubiquitination of ataxin-1 in vitro and in cell culture, augmented by Hsp70; CHIP overexpression in a Drosophila SCA1 model decreases ataxin-1 steady-state levels and suppresses toxicity for polyglutamine in the context of the ataxin-1 backbone. Co-immunoprecipitation, in vitro ubiquitination assay, Drosophila overexpression, protein level quantification The Journal of biological chemistry High 16831871
2006 Protein-protein interaction network screen (yeast two-hybrid) for ataxia-related proteins identified 770 novel interactions involving ATXN1 and other ataxia proteins; 83% of tested pairs verified in mammalian cells by co-IP, revealing shared interacting partners that modify neurodegeneration. Yeast two-hybrid screen, mammalian cell co-immunoprecipitation verification Cell Medium 16713569
2008 Polyglutamine expansion in ATXN1 has opposing effects on distinct endogenous protein complexes: it favors formation of an ATXN1-RBM17 complex (gain-of-function contributing to SCA1 neuropathology) while attenuating formation and function of the ATXN1-Capicua complex (partial loss-of-function); both mechanisms contribute to SCA1 pathogenesis. Native complex purification, co-immunoprecipitation, Drosophila genetic epistasis, cell-based functional assays Nature High 18337722
2008 miR-19, miR-101, and miR-130 co-regulate ataxin-1 levels; inhibition of these microRNAs enhanced cytotoxicity of polyglutamine-expanded ATXN1 in human cells, revealing post-transcriptional regulation of ATXN1 dosage. microRNA inhibitor experiments in human cells, ATXN1 protein level quantification, cytotoxicity assay Nature neuroscience Medium 18758459
2008 UbcH6, an E2 ubiquitin-conjugating enzyme, interacts with ataxin-1 via its AXH domain and ubiquitinates ataxin-1 in the absence of an E3 ligase; UbcH6 co-immunoprecipitates and co-localizes with ataxin-1 in the nucleus, and its expression level regulates the rate of ataxin-1 degradation. Yeast two-hybrid, co-immunoprecipitation, co-localization, in vitro ubiquitination assay, protein degradation assay Biochemical and biophysical research communications Medium 18439907
2009 Phosphorylation of ATXN1 at S776 in cerebellar Purkinje cells is mediated by cyclic AMP-dependent protein kinase (PKA), not Akt: immunodepletion and inhibition of PKA decreased S776 phosphorylation in a cerebellar extract-based assay and in vivo, while Akt inhibition did not; S776 phosphorylation is associated with ATXN1 stabilization in Purkinje cells. Cerebellar extract-based phosphorylation assay, kinase inhibition/immunodepletion, in vivo kinase inhibition, Western blot Journal of neurochemistry High 19500214
2010 Loss of function of ATXN1 increases amyloid beta-protein levels (Aβ40 and Aβ42) by potentiating β-secretase (BACE1) processing of APP; knockdown of ATXN1 by RNAi increased Aβ levels, and this was rescued by concurrent ATXN1 overexpression; overexpression of ATXN1 decreased Aβ levels. RNA interference in human neuronal cell model and mouse primary cortical neurons, ELISA for Aβ levels, ATXN1 overexpression rescue The Journal of biological chemistry Medium 20097758
2011 ATXN1 and ATAXIN1-Like (ATXN1L) form complexes with the transcriptional repressor Capicua (CIC) that are functionally redundant; loss of ATXN1L destabilizes CIC, leading to derepression of Etv4 (an activator of Mmp genes) and MMP9 overexpression, causing lung alveolarization defects and other developmental phenotypes. Knockout mouse generation (Atxn1L-/-, Atxn1-/-;Atxn1L-/-), Western blot, gene expression analysis, phenotypic characterization Developmental cell High 22014525
2013 HOTAIR lncRNA associates with the E3 ubiquitin ligase Dzip3 and its substrate ataxin-1, facilitating ubiquitination of ataxin-1 by Dzip3 in cells and in vitro, thereby accelerating ataxin-1 degradation; HOTAIR levels are elevated in senescent cells and drive rapid ataxin-1 decay. RNA immunoprecipitation, co-immunoprecipitation, in vitro ubiquitination assay, protein degradation assay Nature communications Medium 24326307
2015 The RNA-binding protein PUMILIO1 (PUM1) directly regulates ATXN1 mRNA levels post-transcriptionally; Pum1 haploinsufficiency causes SCA1-like neurodegeneration by increasing Ataxin-1 levels; breeding Pum1+/- mice with Atxn1+/- mice normalized ATAXIN1 levels and largely rescued the Pum1+/- phenotype. Mouse genetics (haploinsufficiency, crossbreeding, knockin), behavioral assays, protein level quantification, epistasis analysis Cell High 25768905
2015 Soluble ATXN1 oligomers form in vivo and their levels correlate with disease progression in Atxn1(154Q/+) mice; oligomeric toxicity, stabilization, and seeding require interaction with Capicua, which is expressed at higher ratios relative to ATXN1 in the cerebellum than in less vulnerable brain regions, explaining regional vulnerability. Conformational antibody detection of oligomers, co-immunoprecipitation, disease progression correlation, regional expression analysis eLife Medium 25988806
2017 The ATXN1-CIC complex is essential for forebrain development: conditional loss of ATXN1-CIC causes hyperactivity, impaired learning and memory, and defective maturation of upper-layer cortical neurons; CIC in the hypothalamus and medial amygdala modulates social interactions; five individuals with de novo truncating CIC mutations share intellectual disability, ADHD, and autism features. Conditional mouse knockouts, behavioral phenotyping, cortical neuron characterization, human genetic analysis Nature genetics High 28288114
2002 PQBP-1 interacts with mutant ataxin-1 in a polyglutamine-length-dependent manner (both in vitro and in vivo); mutant ataxin-1 enhances PQBP-1 binding to the C-terminal domain of RNA Pol II large subunit, reducing Pol II phosphorylation and transcription; this interaction induces apoptotic cell death. In vitro and in vivo binding assays, co-immunoprecipitation, cell death assay, transcription assay Neuron Medium 12062018
2009 p62/SQSTM1 is essential for accumulation of polyubiquitinated proteins in PML nuclear bodies upon inhibition of nuclear protein export; p62 contributes to the assembly of proteasome-containing degradative compartments near nuclear aggregates containing polyglutamine-expanded Ataxin-1[Q84] and to degradation of Ataxin-1[Q84]. RNAi knockdown, immunofluorescence, nuclear fractionation, cell-based degradation assay The Journal of biological chemistry Medium 20018885
2020 miR760 binds a conserved site in ATXN1's unusually long 5' UTR to induce RNA degradation and translational inhibition; delivery of AAV-expressing miR760 in the cerebellum reduces ATXN1 levels in vivo and mitigates motor coordination deficits in a SCA1 mouse model. miRNA target site mapping, reporter assays, AAV delivery in vivo, motor coordination assay Genes & development High 32763910
2020 ATXN1 intermediate repeat expansions are significantly associated with ALS; ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances ALS phenotypes in Drosophila, implicating ATXN1 in TDP-43 mislocalization as a disease mechanism. Large-scale genetic association (11,700 individuals), Drosophila functional experiments, TDP-43 localization assay Brain communications Medium 32954321
2022 Nuclear localization of mutant ATXN1 is required broadly for SCA1-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality; CRISPR-Cas9 K772T mutation in the nuclear localization sequence of expanded ATXN1 corrected many disease-like phenotypes and normalized transcriptomic profiles in multiple brain regions. CRISPR-Cas9 knock-in mouse, behavioral testing, RNA sequencing across brain regions Neuron High 36577403
2022 Disrupting the ATXN1-CIC interaction globally normalizes genome-wide CIC binding but only partially corrects transcriptional and behavioral phenotypes; unbiased proteomics identified additional ATXN1-interacting transcription factors RFX1, ZBTB5, and ZKSCAN1 whose target genes show altered expression in SCA1 mice and patient-derived iNeurons. Knockin mouse with ATXN1-CIC interaction mutation, ChIP-seq, RNA-seq, affinity purification mass spectrometry proteomics, patient-derived neurons Neuron High 36577402
2016 Loss of ATXN1 induces early alterations in cerebellar bioenergetics proteins (glycolysis and ATP synthesis enzymes); ATXN1 regulates cerebellar bioenergetics via the GSK3β-mTOR pathway — GSK3β is decreased in Atxn1-KO and increased in SCA1 mice, while mTOR is decreased in SCA1 mice before ataxia onset; pharmacological inhibition of GSK3β and activation of mTOR ameliorated metabolic alterations in a SCA1 cell model. Proteomics of Atxn1-KO cerebellum, Western blot, pharmacological rescue in SCA1 cell model Human molecular genetics Medium 27466200

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature genetics 1518 8358429
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
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
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
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1998 Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature genetics 696 9620770
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
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 527 11672547
1997 Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 470 9353120
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2001 Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Human molecular genetics 378 11448943
2013 Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination. Nature communications 370 24326307
2005 The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 343 15860580
2003 Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 338 12757707
2005 Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. American journal of human genetics 327 16380905
1997 A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. The Journal of biological chemistry 315 9083054
1994 Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nature genetics 298 7951322
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
1995 Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature genetics 265 7647801
2006 ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 259 17190598
2008 Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 246 18337722
2003 The DNA sequence and analysis of human chromosome 6. Nature 242 14574404
2003 Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 240 12741986
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 231 7731983
1997 The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 213 9353121
2009 Nucleocytoplasmic shuttling of p62/SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies. The Journal of biological chemistry 210 20018885
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 207 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 192 17110330
2013 Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies. The American journal of psychiatry 186 23377640
2006 The role of the sca-1+/CD31- cardiac progenitor cell population in postinfarction left ventricular remodeling. Stem cells (Dayton, Ohio) 183 16614004
2006 The Atx1-Ccc2 complex is a metal-mediated protein-protein interaction. Nature chemical biology 181 16732294
2011 Protein interactome reveals converging molecular pathways among autism disorders. Science translational medicine 180 21653829
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
2010 A human MAP kinase interactome. Nature methods 165 20936779
2006 CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. The Journal of biological chemistry 161 16831871
2008 The highly similar Arabidopsis homologs of trithorax ATX1 and ATX2 encode proteins with divergent biochemical functions. The Plant cell 159 18375658
2002 Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 159 12062018
2011 The Arabidopsis trithorax-like factor ATX1 functions in dehydration stress responses via ABA-dependent and ABA-independent pathways. The Plant journal : for cell and molecular biology 148 21309869
1998 Identification of a functional homolog of the yeast copper homeostasis gene ATX1 from Arabidopsis. Plant physiology 148 9701579
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 131 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 119 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 117 31883835
2017 Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nature genetics 109 28288114
2006 Stem cell-derived Sca-1+ progenitors differentiate into smooth muscle cells, which is mediated by collagen IV-integrin alpha1/beta1/alphav and PDGF receptor pathways. American journal of physiology. Cell physiology 108 16914533
2018 Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI insight 104 30385727
2007 The Arabidopsis homologs of trithorax (ATX1) and enhancer of zeste (CLF) establish 'bivalent chromatin marks' at the silent AGAMOUS locus. Nucleic acids research 95 17881378
2011 ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. Developmental cell 89 22014525
2006 Combinatorial Gata2 and Sca1 expression defines hematopoietic stem cells in the bone marrow niche. Proceedings of the National Academy of Sciences of the United States of America 88 16461905
2012 ATX1-generated H3K4me3 is required for efficient elongation of transcription, not initiation, at ATX1-regulated genes. PLoS genetics 86 23284292
2005 Sca-1 negatively regulates proliferation and differentiation of muscle cells. Developmental biology 86 15901485
2016 Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. Neuron 85 26948890
2001 Altered trafficking of membrane proteins in purkinje cells of SCA1 transgenic mice. The American journal of pathology 78 11549583
1993 Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias. Human molecular genetics 77 8111382
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
2008 The lineage-c-Kit+Sca-1+ cell response to Escherichia coli bacteremia in Balb/c mice. Stem cells (Dayton, Ohio) 74 18483422
2013 The role of interruptions in polyQ in the pathology of SCA1. PLoS genetics 69 23935513
2011 Two distinct roles of ARABIDOPSIS HOMOLOG OF TRITHORAX1 (ATX1) at promoters and within transcribed regions of ATX1-regulated genes. The Plant cell 68 21266657
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 67 21900557
2009 Differentiation and migration of Sca1+/CD31- cardiac side population cells in a murine myocardial ischemic model. International journal of cardiology 64 19254813
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
2014 Arabidopsis homolog of trithorax1 (ATX1) is required for cell production, patterning, and morphogenesis in root development. Journal of experimental botany 58 25205583
2014 ATX1/AtCOMPASS and the H3K4me3 marks: how do they activate Arabidopsis genes? Current opinion in plant biology 57 25047977
2012 Sca-1 knockout impairs myocardial and cardiac progenitor cell function. Circulation research 57 22800687
2017 Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice. Journal of neuroinflammation 55 28545543
2010 Phosphatidylinositol 5-phosphate links dehydration stress to the activity of ARABIDOPSIS TRITHORAX-LIKE factor ATX1. PloS one 53 20967218
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
2018 Arabidopsis O-GlcNAc transferase SEC activates histone methyltransferase ATX1 to regulate flowering. The EMBO journal 50 30150325
1995 Analysis of spinocerebellar ataxia type 1 (SCA1)-related CAG trinucleotide expansion in Japan. Neurology 49 7543989
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 48 20097758
2009 Phosphorylation of ATXN1 at Ser776 in the cerebellum. Journal of neurochemistry 45 19500214
2018 Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL. Cancer research 44 29490943
2012 Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders. Molecular cytogenetics 43 22480366
1996 Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCA1 and SCA2 patients. Journal of the neurological sciences 43 8902719
2016 Ataxin-1 regulates the cerebellar bioenergetics proteome through the GSK3β-mTOR pathway which is altered in Spinocerebellar ataxia type 1 (SCA1). Human molecular genetics 40 27466200
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
2006 Sca1, a previously undescribed paralog from autotransporter protein-encoding genes in Rickettsia species. BMC microbiology 39 16504018
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 36 31810584
2009 The Arabidopsis chromatin modifier ATX1, the myotubularin-like AtMTM and the response to drought. Plant signaling & behavior 36 19901554
2006 Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice. Brain research bulletin 35 16647585
2015 A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1. eLife 33 25988806
2018 Cardiac Sca-1+ Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair. Circulation 32 30566018
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
2017 Triplin, a small molecule, reveals copper ion transport in ethylene signaling from ATX1 to RAN1. PLoS genetics 31 28388654
2020 Cerebellar contribution to the cognitive alterations in SCA1: evidence from mouse models. Human molecular genetics 30 31696233
2020 miR760 regulates ATXN1 levels via interaction with its 5' untranslated region. Genes & development 30 32763910
2015 CD201 and CD27 identify hematopoietic stem and progenitor cells across multiple murine strains independently of Kit and Sca-1. Experimental hematology 30 25892186
2012 SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis. Progress in neurobiology 30 22531670
2017 Leptin Induces Sca-1+ Progenitor Cell Migration Enhancing Neointimal Lesions in Vessel-Injury Mouse Models. Arteriosclerosis, thrombosis, and vascular biology 29 28935755
1999 D3: a gene induced during myeloid cell differentiation of Linlo c-Kit+ Sca-1(+) progenitor cells. Blood 29 9885214
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
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
2022 Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles. Neuron 25 36577403
2001 Calcium homeostasis and spinocerebellar ataxia-1 (SCA-1). Brain research bulletin 25 11719254
2021 Histone methyltransferase ATX1 dynamically regulates fiber secondary cell wall biosynthesis in Arabidopsis inflorescence stem. Nucleic acids research 24 33332564
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
2011 In vitro and in vivo proliferation, differentiation and migration of cardiac endothelial progenitor cells (SCA1+/CD31+ side-population cells). Journal of thrombosis and haemostasis : JTH 22 21615679
2023 Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization. Journal of nanobiotechnology 21 37322478
2018 PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption. Frontiers in cellular neuroscience 21 30108484
2017 Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1. Cerebellum (London, England) 20 27306906
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
2009 Wall-modifying genes regulated by the Arabidopsis homolog of trithorax, ATX1: repression of the XTH33 gene as a test case. The Plant journal : for cell and molecular biology 20 19154201
1996 The Ly-6E.1 (Sca-1) gene requires a 3' chromatin-dependent region for high-level gamma-interferon-induced hematopoietic cell expression. Blood 20 8639891
2008 UbcH6 interacts with and ubiquitinates the SCA1 gene product ataxin-1. Biochemical and biophysical research communications 19 18439907
2008 Copper distributed by Atx1 is available to copper amine oxidase 1 in Schizosaccharomyces pombe. Eukaryotic cell 19 18723604
2022 Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma. Genes, chromosomes & cancer 18 35715887
2014 The design and delivery of a PKA inhibitory polypeptide to treat SCA1. Journal of neurochemistry 18 24903464
2013 Adipogenic and osteogenic differentiation of Lin(-)CD271(+)Sca-1(+) adipose-derived stem cells. Molecular and cellular biochemistry 18 23430356