{"gene":"ATXN1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"Transgenic mouse generation; behavioral testing (rotarod/ataxia); histopathology of Purkinje cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean transgenic loss/gain-of-function model with specific cellular phenotype, replicated across multiple transgenic lines","pmids":["7553854"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Cross-breeding SCA1 transgenic mice with iHSP70 over-expressing mice; behavioral and neuropathological assessment","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue experiment in mammalian model with defined cellular phenotype and behavioral readout","pmids":["11448943"],"is_preprint":false},{"year":2002,"finding":"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.","method":"CAG knock-in mouse model; protein solubility fractionation; behavioral, electrophysiological, and neuropathological analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous knock-in model with multiple orthogonal biochemical and behavioral readouts","pmids":["12086639"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Co-immunoprecipitation; chromatin binding assays; transcriptional reporter assays; Drosophila genetic epistasis (Smrter loss/gain-of-function modifier screen)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis in Drosophila with specific phenotypic readout, multiple orthogonal methods","pmids":["15016912"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Conditional transgenic mouse model; Co-immunoprecipitation; gene expression analysis; genetic cross with RORα heterozygous mice; behavioral assessment","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional mouse model, reciprocal Co-IP identifying ATXN1-RORα-Tip60 complex, genetic modifier cross with specific behavioral readout","pmids":["17110330"],"is_preprint":false},{"year":2008,"finding":"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.","method":"miRNA inhibitor transfection in human cells; Western blot for ATXN1 levels; cell viability assays","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, cell-based assays showing miRNA regulation of ATXN1 levels with cytotoxicity readout, no in vivo validation reported","pmids":["18758459"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro cerebellar extract-based phosphorylation assay; immunodepletion; pharmacological kinase inhibition; Western blot","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with cerebellar extracts, immunodepletion and pharmacological inhibition, single lab but multiple orthogonal methods","pmids":["19500214"],"is_preprint":false},{"year":2010,"finding":"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.","method":"RNA interference knockdown; ATXN1 overexpression; Aβ ELISA; β-secretase activity assays in human neuronal cell line and mouse primary cortical neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with rescue by overexpression, specific enzymatic pathway (β-secretase) assay, single lab but multiple orthogonal methods","pmids":["20097758"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Knockout mouse generation (Atxn1L−/−, Atxn1−/−;Atxn1L−/−); Co-immunoprecipitation; gene expression analysis; CIC protein stability assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific developmental phenotype, Co-IP identifying ATXN1/ATXN1L-CIC complex, epistasis via double knockout","pmids":["22014525"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation; genetic cross (ATXN1[82Q] × Tip60+/− mice); behavioral and neuropathological assessment; gene expression analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction mapped to AXH domain, genetic rescue experiment with specific phenotypic readout, multiple methods","pmids":["21427130"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Flavoprotein autofluorescence optical imaging; extracellular field potential recordings; immunostaining for VGluT2; transgenic mouse models including nuclear localization mutants","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo circuit imaging with multiple transgenic lines including nuclear localization mutant controls, specific mechanistic requirement for nuclear ATXN1","pmids":["21900557"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Review/synthesis of prior experimental evidence including phosphomimetic and phosphonull mutant analyses in cell and animal models","journal":"Progress in neurobiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review article synthesizing prior mutagenesis and mouse model data; confidence limited as this paper itself is a review","pmids":["22531670"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Cell-based genetic screen; Drosophila genetic screen; pharmacological inhibition in mice; Western blot for ATXN1 levels; Drosophila neurodegeneration assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — parallel genetic screens in two organisms plus pharmacological validation in mice, replicated across multiple methods and model systems","pmids":["23719381"],"is_preprint":false},{"year":2015,"finding":"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.","method":"PUM1 knockout/haploinsufficiency mouse models; genetic epistasis crosses (Pum1+/−× Atxn1154Q/+ and Pum1+/− × Atxn1+/−); ATXN1 protein level measurement; behavioral assessment","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with three-way crosses, direct protein level measurement, specific behavioral and neuropathological readouts","pmids":["25768905"],"is_preprint":false},{"year":2018,"finding":"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.","method":"In vivo genetic disruption of ATXN1-CIC interaction; Purkinje cell-specific CIC knockout mice; expression profiling; iPSC-derived neurons from SCA1 patients; behavioral assessment","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo interaction disruption with specific genetic controls, human iPSC validation, multiple orthogonal approaches","pmids":["29526553"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and genetic approaches in both human iPSC-derived neurons and mouse model, specific protein level and behavioral readouts","pmids":["29758256"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Drosophila forward genetic screen; PAK1 knockdown in mammalian cells; pharmacological PAK inhibition in SCA1 mice; Western blot for ATXN1 levels; Drosophila neurodegeneration assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen in Drosophila validated in mammalian cells and mouse model, with pharmacological and genetic approaches","pmids":["29860311"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Drosophila ALS phenotype assays; TDP-43 nuclear/cytoplasmic fractionation; population genetic association study","journal":"Brain communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — functional Drosophila assay and fractionation from single study; mechanistic detail limited in abstract","pmids":["32954321"],"is_preprint":false},{"year":2020,"finding":"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.","method":"miRNA-target site mutagenesis; luciferase reporter assays; Western blot; AAV delivery in vivo; behavioral assessment in SCA1 mice","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 5' UTR binding validated by mutagenesis and reporter assay, in vivo AAV validation with behavioral readout","pmids":["32763910"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — allele-specific knock-in mouse models with multiple physiological readouts, demonstrates mechanistic distinction between alleles","pmids":["33554954"],"is_preprint":false},{"year":2022,"finding":"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.","method":"CRISPR-Cas9 knock-in of K772T nuclear localization sequence mutation in Atxn1175Q mice; behavioral (motor, cognitive), survival, and RNA-seq analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise CRISPR knock-in targeting nuclear localization sequence with multiple behavioral and transcriptomic readouts","pmids":["36577403"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Global ATXN1-CIC interaction disruption in knock-in mice; unbiased proteomics; RNA-seq; ChIP-seq for CIC; human SCA1 patient-derived iNeurons; behavioral assessment","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteomics plus genetic interaction disruption in knock-in mice, validated in human patient-derived neurons","pmids":["36577402"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Atxn1 knockout mice; flow cytometry; transcriptomic profiling of B-1a cells; BCR stimulation assays","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, knockout mouse phenotype with transcriptomics, limited mechanistic detail on molecular pathway in abstract","pmids":["33478569"],"is_preprint":false},{"year":2023,"finding":"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.","method":"In vivo two-photon calcium imaging in behaving SCA1 mice; chemogenetic (DREADD) inhibition; synaptic density analysis; behavioral assessment; proteomics of SCA1 MLINs","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo two-photon imaging plus chemogenetic intervention with multiple mechanistic readouts in SCA1 mice","pmids":["37321222"],"is_preprint":false}],"current_model":"ATXN1 is a nuclear protein whose polyglutamine-expanded form causes SCA1 through gain-of-function mechanisms dependent on nuclear localization and S776 phosphorylation (stabilized by PKA and modulated by RAS-MAPK-MSK1 and PAK1 signaling); in the nucleus, mutant ATXN1 forms toxic complexes with the transcriptional repressor CIC (the primary driver of cerebellar Purkinje cell pathology), as well as with RORα, Tip60, SMRT/HDAC3, and other transcription factors (RFX1, ZBTB5, ZKSCAN1), dysregulating transcriptional programs; wild-type ATXN1 normally stabilizes CIC to repress ETV4/MMP genes and regulate ECM remodeling, modulates β-secretase processing of APP, and influences B cell receptor signaling, while its protein levels are post-transcriptionally regulated by PUM1 and multiple miRNAs (miR-19, miR-101, miR-130, miR760 via the 5' UTR)."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1995,"claim":"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","pmids":["7553854"],"confidence":"High","gaps":["Did not identify the molecular partners through which toxicity is exerted","Did not establish whether wild-type ATXN1 has an essential normal function"]},{"year":2001,"claim":"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","pmids":["11448943"],"confidence":"High","gaps":["Did not define the degradation machinery normally handling ATXN1","Mechanism of chaperone protection not resolved at the molecular level"]},{"year":2002,"claim":"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","pmids":["12086639"],"confidence":"High","gaps":["Did not establish whether soluble mutant protein is the toxic species mechanistically","Did not identify the downstream effectors of toxicity"]},{"year":2004,"claim":"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","pmids":["15016912"],"confidence":"High","gaps":["Direct DNA-binding specificity of ATXN1 not defined","Relationship of SMRT pathway to Purkinje-cell-specific toxicity unclear"]},{"year":2006,"claim":"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","pmids":["17110330"],"confidence":"High","gaps":["Whether RORα destabilization is direct or secondary not fully resolved","Quantitative contribution of RORα versus other pathways to toxicity unknown"]},{"year":2009,"claim":"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","pmids":["19500214"],"confidence":"High","gaps":["In vitro extract assay; cellular PKA-ATXN1 mechanism not directly demonstrated in vivo here","Phosphatase counter-regulating S776 not identified"]},{"year":2008,"claim":"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","pmids":["18758459"],"confidence":"Medium","gaps":["No in vivo validation of these miRNAs","Direct binding to ATXN1 transcript not fully mapped in this study"]},{"year":2011,"claim":"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","pmids":["22014525"],"confidence":"High","gaps":["Did not establish how the same CIC complex becomes toxic when ATXN1 is polyQ-expanded","Tissue scope of ATXN1/ATXN1L redundancy not fully mapped"]},{"year":2011,"claim":"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","pmids":["21427130"],"confidence":"High","gaps":["Rescue was partial and mid-stage-specific","Structural basis of S776-dependent affinity change not resolved"]},{"year":2011,"claim":"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","pmids":["21900557"],"confidence":"High","gaps":["Molecular link between nuclear transcriptional dysregulation and the synaptic defect not defined","Reversibility of the circuit deficit not tested here"]},{"year":2013,"claim":"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","pmids":["23719381"],"confidence":"High","gaps":["Mechanism by which the pathway sets ATXN1 stability/translation not fully defined","Whether the effect is S776-dependent not resolved here"]},{"year":2015,"claim":"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","pmids":["25768905"],"confidence":"High","gaps":["Whether PUM1 acts on ATXN1 stability versus translation not fully separated","Other PUM1 targets contributing to phenotype not excluded"]},{"year":2018,"claim":"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","pmids":["29526553"],"confidence":"High","gaps":["Did not account for extracerebellar phenotypes","How polyQ expansion alters CIC complex output mechanistically not fully defined"]},{"year":2018,"claim":"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","pmids":["29758256"],"confidence":"High","gaps":["PKA also has essential physiological roles limiting therapeutic window","Did not map the degron exposed by S776 dephosphorylation"]},{"year":2018,"claim":"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","pmids":["29860311"],"confidence":"High","gaps":["Molecular mechanism by which PAK1 sets ATXN1 abundance not defined","Whether PAK1 acts on ATXN1 directly or via intermediates unknown"]},{"year":2020,"claim":"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","pmids":["32763910"],"confidence":"High","gaps":["Durability and off-target effects of AAV-miR760 not fully addressed","Endogenous regulation of miR760 in disease not defined"]},{"year":2021,"claim":"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","pmids":["33554954"],"confidence":"High","gaps":["Molecular basis of WT-allele protection not resolved","Did not define how WT and mutant ATXN1 functionally interact"]},{"year":2021,"claim":"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","pmids":["33478569"],"confidence":"Medium","gaps":["Limited mechanistic detail on the molecular BCR pathway","Whether ATXN1's nuclear transcriptional role mediates this is not established"]},{"year":2022,"claim":"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","pmids":["36577403"],"confidence":"High","gaps":["Did not identify the nuclear effectors responsible for each phenotype","Region-specific transcriptional drivers not individually validated"]},{"year":2022,"claim":"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","pmids":["36577402"],"confidence":"High","gaps":["Functional contributions of RFX1/ZBTB5/ZKSCAN1 not individually dissected","Which interactors drive which extracerebellar phenotypes unknown"]},{"year":2023,"claim":"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","pmids":["37321222"],"confidence":"High","gaps":["How nuclear ATXN1 dysregulation produces MLIN hyperexcitability not defined","Whether the circuit mechanism generalizes to human SCA1 not established"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,4,8,14,21]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,20]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,8,14,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,14,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13,18]}],"complexes":["ATXN1-CIC complex","ATXN1-RORα-Tip60 complex","ATXN1-SMRT/HDAC3 corepressor complex"],"partners":["CIC","ATXN1L","RORA","KAT5","NCOR2","HDAC3","RFX1","ZKSCAN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P54253","full_name":"Ataxin-1","aliases":["Spinocerebellar ataxia type 1 protein"],"length_aa":815,"mass_kda":86.9,"function":"Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism (PubMed:21475249). In concert with CIC and ATXN1L, involved in brain development (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P54253/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATXN1","total_profiled":1310},"omim":[{"mim_id":"620719","title":"NEURODEVELOPMENTAL DISORDER WITH MOTOR ABNORMALITIES, SEIZURES, AND FACIAL DYSMORPHISM; NEDMSF","url":"https://www.omim.org/entry/620719"},{"mim_id":"620098","title":"DEVELOPMENTAL DELAY WITH VARIABLE INTELLECTUAL DISABILITY AND DYSMORPHIC FACIES; DIDDF","url":"https://www.omim.org/entry/620098"},{"mim_id":"617600","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 45; MRD45","url":"https://www.omim.org/entry/617600"},{"mim_id":"614301","title":"ATAXIN 1-LIKE; ATXN1L","url":"https://www.omim.org/entry/614301"},{"mim_id":"612876","title":"SPINOCEREBELLAR ATAXIA 9; SCA9","url":"https://www.omim.org/entry/612876"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATXN1"},"hgnc":{"alias_symbol":["D6S504E","ATX1"],"prev_symbol":["SCA1"]},"alphafold":{"accession":"P54253","domains":[{"cath_id":"-","chopping":"573-688","consensus_level":"medium","plddt":95.2844,"start":573,"end":688}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P54253","model_url":"https://alphafold.ebi.ac.uk/files/AF-P54253-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P54253-F1-predicted_aligned_error_v6.png","plddt_mean":50.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATXN1","jax_strain_url":"https://www.jax.org/strain/search?query=ATXN1"},"sequence":{"accession":"P54253","fasta_url":"https://rest.uniprot.org/uniprotkb/P54253.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P54253/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P54253"}},"corpus_meta":[{"pmid":"9346482","id":"PMC_9346482","title":"Metal ion chaperone function of the soluble Cu(I) receptor Atx1.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9346482","citation_count":564,"is_preprint":false},{"pmid":"11672547","id":"PMC_11672547","title":"Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity.","date":"2001","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11672547","citation_count":528,"is_preprint":false},{"pmid":"7553854","id":"PMC_7553854","title":"SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7553854","citation_count":498,"is_preprint":false},{"pmid":"11448943","id":"PMC_11448943","title":"Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice.","date":"2001","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11448943","citation_count":378,"is_preprint":false},{"pmid":"9083054","id":"PMC_9083054","title":"A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9083054","citation_count":315,"is_preprint":false},{"pmid":"12086639","id":"PMC_12086639","title":"A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration.","date":"2002","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/12086639","citation_count":278,"is_preprint":false},{"pmid":"7731983","id":"PMC_7731983","title":"The ATX1 gene of Saccharomyces cerevisiae encodes a small metal homeostasis factor that protects cells against reactive oxygen toxicity.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7731983","citation_count":232,"is_preprint":false},{"pmid":"21258123","id":"PMC_21258123","title":"Unification of the copper(I) binding affinities of the metallo-chaperones Atx1, Atox1, and related proteins: detection probes and affinity standards.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21258123","citation_count":208,"is_preprint":false},{"pmid":"10404590","id":"PMC_10404590","title":"Crystal structure of the Atx1 metallochaperone protein at 1.02 A resolution.","date":"1999","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/10404590","citation_count":196,"is_preprint":false},{"pmid":"17110330","id":"PMC_17110330","title":"RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17110330","citation_count":194,"is_preprint":false},{"pmid":"16732294","id":"PMC_16732294","title":"The Atx1-Ccc2 complex is a metal-mediated protein-protein interaction.","date":"2006","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/16732294","citation_count":181,"is_preprint":false},{"pmid":"18758459","id":"PMC_18758459","title":"miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis.","date":"2008","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18758459","citation_count":179,"is_preprint":false},{"pmid":"10764731","id":"PMC_10764731","title":"Energetics of copper trafficking between the Atx1 metallochaperone and the intracellular copper transporter, Ccc2.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10764731","citation_count":173,"is_preprint":false},{"pmid":"11327811","id":"PMC_11327811","title":"Solution structure of the Cu(I) and apo forms of the yeast metallochaperone, Atx1.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11327811","citation_count":146,"is_preprint":false},{"pmid":"15317756","id":"PMC_15317756","title":"Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15317756","citation_count":142,"is_preprint":false},{"pmid":"25768905","id":"PMC_25768905","title":"Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25768905","citation_count":134,"is_preprint":false},{"pmid":"2063871","id":"PMC_2063871","title":"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.","date":"1991","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2063871","citation_count":126,"is_preprint":false},{"pmid":"25980517","id":"PMC_25980517","title":"PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25980517","citation_count":120,"is_preprint":false},{"pmid":"15016912","id":"PMC_15016912","title":"Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15016912","citation_count":119,"is_preprint":false},{"pmid":"31883835","id":"PMC_31883835","title":"Arterial Sca1+ Vascular Stem Cells Generate De Novo Smooth Muscle for Artery Repair and Regeneration.","date":"2019","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/31883835","citation_count":118,"is_preprint":false},{"pmid":"23719381","id":"PMC_23719381","title":"RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23719381","citation_count":118,"is_preprint":false},{"pmid":"30385727","id":"PMC_30385727","title":"Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles.","date":"2018","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/30385727","citation_count":105,"is_preprint":false},{"pmid":"29526553","id":"PMC_29526553","title":"ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/29526553","citation_count":96,"is_preprint":false},{"pmid":"22014525","id":"PMC_22014525","title":"ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization.","date":"2011","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22014525","citation_count":90,"is_preprint":false},{"pmid":"23284292","id":"PMC_23284292","title":"ATX1-generated H3K4me3 is required for efficient elongation of transcription, not initiation, at ATX1-regulated genes.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23284292","citation_count":87,"is_preprint":false},{"pmid":"26948890","id":"PMC_26948890","title":"Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/26948890","citation_count":85,"is_preprint":false},{"pmid":"2460547","id":"PMC_2460547","title":"The stem cell antigens Sca-1 and Sca-2 subdivide thymic and peripheral T lymphocytes into unique subsets.","date":"1988","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2460547","citation_count":76,"is_preprint":false},{"pmid":"21900557","id":"PMC_21900557","title":"Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21900557","citation_count":70,"is_preprint":false},{"pmid":"23935513","id":"PMC_23935513","title":"The role of interruptions in polyQ in the pathology of SCA1.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23935513","citation_count":69,"is_preprint":false},{"pmid":"29358280","id":"PMC_29358280","title":"Cytokine- and TCR-Mediated Regulation of T Cell Expression of Ly6C and Sca-1.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29358280","citation_count":64,"is_preprint":false},{"pmid":"20176791","id":"PMC_20176791","title":"The Rickettsia conorii autotransporter protein Sca1 promotes adherence to nonphagocytic mammalian cells.","date":"2010","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20176791","citation_count":63,"is_preprint":false},{"pmid":"32600379","id":"PMC_32600379","title":"SRSF10 inhibits biogenesis of circ-ATXN1 to regulate glioma angiogenesis via miR-526b-3p/MMP2 pathway.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32600379","citation_count":58,"is_preprint":false},{"pmid":"9613852","id":"PMC_9613852","title":"Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families.","date":"1998","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9613852","citation_count":53,"is_preprint":false},{"pmid":"17957393","id":"PMC_17957393","title":"Interplay between glutathione, Atx1 and copper. 1. Copper(I) glutathionate induced dimerization of Atx1.","date":"2007","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17957393","citation_count":52,"is_preprint":false},{"pmid":"11673415","id":"PMC_11673415","title":"SCA1 molecular genetics: a history of a 13 year collaboration against glutamines.","date":"2001","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11673415","citation_count":51,"is_preprint":false},{"pmid":"21427130","id":"PMC_21427130","title":"Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21427130","citation_count":50,"is_preprint":false},{"pmid":"20097758","id":"PMC_20097758","title":"Loss of function of ATXN1 increases amyloid beta-protein levels by potentiating beta-secretase processing of beta-amyloid precursor protein.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20097758","citation_count":49,"is_preprint":false},{"pmid":"19500214","id":"PMC_19500214","title":"Phosphorylation of ATXN1 at Ser776 in the cerebellum.","date":"2009","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19500214","citation_count":45,"is_preprint":false},{"pmid":"22480366","id":"PMC_22480366","title":"Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders.","date":"2012","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/22480366","citation_count":43,"is_preprint":false},{"pmid":"17225061","id":"PMC_17225061","title":"Atx1-like chaperones and their cognate P-type ATPases: copper-binding and transfer.","date":"2007","source":"Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17225061","citation_count":40,"is_preprint":false},{"pmid":"24926741","id":"PMC_24926741","title":"Sca-1+ cardiac progenitor cells and heart-making: a critical synopsis.","date":"2014","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/24926741","citation_count":40,"is_preprint":false},{"pmid":"26748090","id":"PMC_26748090","title":"Impaired mTORC1-Dependent Expression of Homer-3 Influences SCA1 Pathophysiology.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/26748090","citation_count":39,"is_preprint":false},{"pmid":"32954321","id":"PMC_32954321","title":"ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.","date":"2020","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/32954321","citation_count":39,"is_preprint":false},{"pmid":"8101039","id":"PMC_8101039","title":"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.","date":"1993","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8101039","citation_count":38,"is_preprint":false},{"pmid":"31810584","id":"PMC_31810584","title":"Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease.","date":"2019","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/31810584","citation_count":37,"is_preprint":false},{"pmid":"29274668","id":"PMC_29274668","title":"ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis.","date":"2017","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/29274668","citation_count":37,"is_preprint":false},{"pmid":"23376683","id":"PMC_23376683","title":"Altered Purkinje cell miRNA expression and SCA1 pathogenesis.","date":"2013","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/23376683","citation_count":35,"is_preprint":false},{"pmid":"16647585","id":"PMC_16647585","title":"Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice.","date":"2006","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/16647585","citation_count":35,"is_preprint":false},{"pmid":"22140470","id":"PMC_22140470","title":"Stem cell antigen-1 (sca-1) regulates mammary tumor development and cell migration.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22140470","citation_count":32,"is_preprint":false},{"pmid":"28757161","id":"PMC_28757161","title":"Adventitial SCA-1+ Progenitor Cell Gene Sequencing Reveals the Mechanisms of Cell Migration in Response to Hyperlipidemia.","date":"2017","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28757161","citation_count":32,"is_preprint":false},{"pmid":"38016472","id":"PMC_38016472","title":"Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/38016472","citation_count":31,"is_preprint":false},{"pmid":"33495447","id":"PMC_33495447","title":"SCA-1 micro-heterogeneity in the fate decision of dystrophic fibro/adipogenic progenitors.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33495447","citation_count":31,"is_preprint":false},{"pmid":"31696233","id":"PMC_31696233","title":"Cerebellar contribution to the cognitive alterations in SCA1: evidence from mouse models.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31696233","citation_count":31,"is_preprint":false},{"pmid":"28388654","id":"PMC_28388654","title":"Triplin, a small molecule, reveals copper ion transport in ethylene signaling from ATX1 to RAN1.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28388654","citation_count":31,"is_preprint":false},{"pmid":"32763910","id":"PMC_32763910","title":"miR760 regulates ATXN1 levels via interaction with its 5' untranslated region.","date":"2020","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/32763910","citation_count":30,"is_preprint":false},{"pmid":"22531670","id":"PMC_22531670","title":"SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis.","date":"2012","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22531670","citation_count":30,"is_preprint":false},{"pmid":"29758256","id":"PMC_29758256","title":"Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model.","date":"2018","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29758256","citation_count":29,"is_preprint":false},{"pmid":"28935755","id":"PMC_28935755","title":"Leptin Induces Sca-1+ Progenitor Cell Migration Enhancing Neointimal Lesions in Vessel-Injury Mouse Models.","date":"2017","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28935755","citation_count":29,"is_preprint":false},{"pmid":"33888607","id":"PMC_33888607","title":"SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2.","date":"2021","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33888607","citation_count":29,"is_preprint":false},{"pmid":"21420496","id":"PMC_21420496","title":"Cellular fusion for gene delivery to SCA1 affected Purkinje neurons.","date":"2011","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/21420496","citation_count":28,"is_preprint":false},{"pmid":"19259938","id":"PMC_19259938","title":"Commentary: Sca-1 and Cells of the Lung: A matter of Different Sorts.","date":"2009","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/19259938","citation_count":27,"is_preprint":false},{"pmid":"36577403","id":"PMC_36577403","title":"Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles.","date":"2022","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/36577403","citation_count":26,"is_preprint":false},{"pmid":"19543924","id":"PMC_19543924","title":"Interaction between cyanobacterial copper chaperone Atx1 and zinc homeostasis.","date":"2009","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19543924","citation_count":26,"is_preprint":false},{"pmid":"24726953","id":"PMC_24726953","title":"Fat depot-specific gene signature and ECM remodeling of Sca1(high) adipose-derived stem cells.","date":"2014","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24726953","citation_count":26,"is_preprint":false},{"pmid":"28717241","id":"PMC_28717241","title":"Sca-1 identifies a trophoblast population with multipotent potential in the mid-gestation mouse placenta.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28717241","citation_count":26,"is_preprint":false},{"pmid":"11719254","id":"PMC_11719254","title":"Calcium homeostasis and spinocerebellar ataxia-1 (SCA-1).","date":"2001","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/11719254","citation_count":25,"is_preprint":false},{"pmid":"27174098","id":"PMC_27174098","title":"c-Myb Regulates Proliferation and Differentiation of Adventitial Sca1+ Vascular Smooth Muscle Cell Progenitors by Transactivation of Myocardin.","date":"2016","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27174098","citation_count":24,"is_preprint":false},{"pmid":"36577402","id":"PMC_36577402","title":"Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1.","date":"2022","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/36577402","citation_count":23,"is_preprint":false},{"pmid":"22076800","id":"PMC_22076800","title":"Suppression of calbindin-D28k expression exacerbates SCA1 phenotype in a disease mouse model.","date":"2012","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22076800","citation_count":22,"is_preprint":false},{"pmid":"23308177","id":"PMC_23308177","title":"PECAM1(+)/Sca1(+)/CD38(+) vascular cells transform into myofibroblast-like cells in skin wound repair.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23308177","citation_count":21,"is_preprint":false},{"pmid":"35715887","id":"PMC_35715887","title":"Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma.","date":"2022","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35715887","citation_count":20,"is_preprint":false},{"pmid":"27306906","id":"PMC_27306906","title":"Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1.","date":"2017","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27306906","citation_count":20,"is_preprint":false},{"pmid":"21156809","id":"PMC_21156809","title":"Sca-1 is negatively regulated by TGF-beta1 in myogenic cells.","date":"2010","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/21156809","citation_count":20,"is_preprint":false},{"pmid":"21302343","id":"PMC_21302343","title":"The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: evidence from a large collaborative study totaling 4,963 subjects.","date":"2010","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21302343","citation_count":20,"is_preprint":false},{"pmid":"18723604","id":"PMC_18723604","title":"Copper distributed by Atx1 is available to copper amine oxidase 1 in Schizosaccharomyces pombe.","date":"2008","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/18723604","citation_count":19,"is_preprint":false},{"pmid":"29556355","id":"PMC_29556355","title":"Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/29556355","citation_count":19,"is_preprint":false},{"pmid":"24903464","id":"PMC_24903464","title":"The design and delivery of a PKA inhibitory polypeptide to treat SCA1.","date":"2014","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24903464","citation_count":18,"is_preprint":false},{"pmid":"24481638","id":"PMC_24481638","title":"Sca1⁺ murine pituitary adenoma cells show tumor-growth advantage.","date":"2014","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24481638","citation_count":18,"is_preprint":false},{"pmid":"19085187","id":"PMC_19085187","title":"Characterization of the zebrafish atxn1/axh gene family.","date":"2008","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19085187","citation_count":17,"is_preprint":false},{"pmid":"18175035","id":"PMC_18175035","title":"Cell surface expression of stem cell antigen-1 (Sca-1) distinguishes osteo-, chondro-, and adipoprogenitors in fetal mouse calvaria.","date":"2008","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/18175035","citation_count":17,"is_preprint":false},{"pmid":"10860780","id":"PMC_10860780","title":"The ins and outs of a polyglutamine neurodegenerative disease: spinocerebellar ataxia type 1 (SCA1).","date":"2000","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/10860780","citation_count":17,"is_preprint":false},{"pmid":"28739828","id":"PMC_28739828","title":"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.","date":"2017","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/28739828","citation_count":17,"is_preprint":false},{"pmid":"29860311","id":"PMC_29860311","title":"PAK1 regulates ATXN1 levels providing an opportunity to modify its toxicity in spinocerebellar ataxia type 1.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29860311","citation_count":16,"is_preprint":false},{"pmid":"33554954","id":"PMC_33554954","title":"Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/33554954","citation_count":15,"is_preprint":false},{"pmid":"33724582","id":"PMC_33724582","title":"Region-specific preservation of Purkinje cell morphology and motor behavior in the ATXN1[82Q] mouse model of spinocerebellar ataxia 1.","date":"2021","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33724582","citation_count":15,"is_preprint":false},{"pmid":"28551466","id":"PMC_28551466","title":"Stance instability in preclinical SCA1 mutation carriers: A 4-year prospective posturography study.","date":"2017","source":"Gait & posture","url":"https://pubmed.ncbi.nlm.nih.gov/28551466","citation_count":15,"is_preprint":false},{"pmid":"27193757","id":"PMC_27193757","title":"High relative frequency of SCA1 in Poland reflecting a potential founder effect.","date":"2016","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/27193757","citation_count":15,"is_preprint":false},{"pmid":"37321222","id":"PMC_37321222","title":"Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/37321222","citation_count":14,"is_preprint":false},{"pmid":"35573049","id":"PMC_35573049","title":"Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice.","date":"2022","source":"Molecular therapy. Methods & clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/35573049","citation_count":14,"is_preprint":false},{"pmid":"37918793","id":"PMC_37918793","title":"Adiponectin stimulates Sca1+CD34--adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue.","date":"2023","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/37918793","citation_count":14,"is_preprint":false},{"pmid":"33394333","id":"PMC_33394333","title":"Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis.","date":"2021","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33394333","citation_count":14,"is_preprint":false},{"pmid":"37863037","id":"PMC_37863037","title":"HD and SCA1: Tales from two 30-year journeys since gene discovery.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/37863037","citation_count":13,"is_preprint":false},{"pmid":"10982193","id":"PMC_10982193","title":"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.","date":"2000","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10982193","citation_count":13,"is_preprint":false},{"pmid":"32627901","id":"PMC_32627901","title":"The Sca-1+ and Sca-1- mouse prostatic luminal cell lineages are independently sustained.","date":"2020","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/32627901","citation_count":13,"is_preprint":false},{"pmid":"12062012","id":"PMC_12062012","title":"Toward cell specificity in SCA1.","date":"2002","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/12062012","citation_count":12,"is_preprint":false},{"pmid":"27401861","id":"PMC_27401861","title":"Transcriptomic response of yeast cells to ATX1 deletion under different copper levels.","date":"2016","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/27401861","citation_count":12,"is_preprint":false},{"pmid":"21245040","id":"PMC_21245040","title":"A cytoplasm-specific activity encoded by the Trithorax-like ATX1 gene.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21245040","citation_count":12,"is_preprint":false},{"pmid":"33478569","id":"PMC_33478569","title":"The novel multiple sclerosis susceptibility gene ATXN1 regulates B cell receptor signaling in B-1a cells.","date":"2021","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/33478569","citation_count":11,"is_preprint":false},{"pmid":"36293311","id":"PMC_36293311","title":"Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1+CD31- Cells.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36293311","citation_count":11,"is_preprint":false},{"pmid":"36434031","id":"PMC_36434031","title":"Suppressing gain-of-function proteins via CRISPR/Cas9 system in SCA1 cells.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36434031","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48544,"output_tokens":6659,"usd":0.122759,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15818,"output_tokens":6230,"usd":0.11742,"stage2_stop_reason":"end_turn"},"total_usd":0.240179,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Transgenic mouse generation; behavioral testing (rotarod/ataxia); histopathology of Purkinje cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean transgenic loss/gain-of-function model with specific cellular phenotype, replicated across multiple transgenic lines\",\n      \"pmids\": [\"7553854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Cross-breeding SCA1 transgenic mice with iHSP70 over-expressing mice; behavioral and neuropathological assessment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiment in mammalian model with defined cellular phenotype and behavioral readout\",\n      \"pmids\": [\"11448943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"CAG knock-in mouse model; protein solubility fractionation; behavioral, electrophysiological, and neuropathological analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous knock-in model with multiple orthogonal biochemical and behavioral readouts\",\n      \"pmids\": [\"12086639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; chromatin binding assays; transcriptional reporter assays; Drosophila genetic epistasis (Smrter loss/gain-of-function modifier screen)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis in Drosophila with specific phenotypic readout, multiple orthogonal methods\",\n      \"pmids\": [\"15016912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional transgenic mouse model; Co-immunoprecipitation; gene expression analysis; genetic cross with RORα heterozygous mice; behavioral assessment\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional mouse model, reciprocal Co-IP identifying ATXN1-RORα-Tip60 complex, genetic modifier cross with specific behavioral readout\",\n      \"pmids\": [\"17110330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"miRNA inhibitor transfection in human cells; Western blot for ATXN1 levels; cell viability assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, cell-based assays showing miRNA regulation of ATXN1 levels with cytotoxicity readout, no in vivo validation reported\",\n      \"pmids\": [\"18758459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cerebellar extract-based phosphorylation assay; immunodepletion; pharmacological kinase inhibition; Western blot\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with cerebellar extracts, immunodepletion and pharmacological inhibition, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19500214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"RNA interference knockdown; ATXN1 overexpression; Aβ ELISA; β-secretase activity assays in human neuronal cell line and mouse primary cortical neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with rescue by overexpression, specific enzymatic pathway (β-secretase) assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"20097758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mouse generation (Atxn1L−/−, Atxn1−/−;Atxn1L−/−); Co-immunoprecipitation; gene expression analysis; CIC protein stability assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific developmental phenotype, Co-IP identifying ATXN1/ATXN1L-CIC complex, epistasis via double knockout\",\n      \"pmids\": [\"22014525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; genetic cross (ATXN1[82Q] × Tip60+/− mice); behavioral and neuropathological assessment; gene expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction mapped to AXH domain, genetic rescue experiment with specific phenotypic readout, multiple methods\",\n      \"pmids\": [\"21427130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Flavoprotein autofluorescence optical imaging; extracellular field potential recordings; immunostaining for VGluT2; transgenic mouse models including nuclear localization mutants\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo circuit imaging with multiple transgenic lines including nuclear localization mutant controls, specific mechanistic requirement for nuclear ATXN1\",\n      \"pmids\": [\"21900557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Review/synthesis of prior experimental evidence including phosphomimetic and phosphonull mutant analyses in cell and animal models\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review article synthesizing prior mutagenesis and mouse model data; confidence limited as this paper itself is a review\",\n      \"pmids\": [\"22531670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based genetic screen; Drosophila genetic screen; pharmacological inhibition in mice; Western blot for ATXN1 levels; Drosophila neurodegeneration assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parallel genetic screens in two organisms plus pharmacological validation in mice, replicated across multiple methods and model systems\",\n      \"pmids\": [\"23719381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"PUM1 knockout/haploinsufficiency mouse models; genetic epistasis crosses (Pum1+/−× Atxn1154Q/+ and Pum1+/− × Atxn1+/−); ATXN1 protein level measurement; behavioral assessment\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with three-way crosses, direct protein level measurement, specific behavioral and neuropathological readouts\",\n      \"pmids\": [\"25768905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo genetic disruption of ATXN1-CIC interaction; Purkinje cell-specific CIC knockout mice; expression profiling; iPSC-derived neurons from SCA1 patients; behavioral assessment\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo interaction disruption with specific genetic controls, human iPSC validation, multiple orthogonal approaches\",\n      \"pmids\": [\"29526553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and genetic approaches in both human iPSC-derived neurons and mouse model, specific protein level and behavioral readouts\",\n      \"pmids\": [\"29758256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Drosophila forward genetic screen; PAK1 knockdown in mammalian cells; pharmacological PAK inhibition in SCA1 mice; Western blot for ATXN1 levels; Drosophila neurodegeneration assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen in Drosophila validated in mammalian cells and mouse model, with pharmacological and genetic approaches\",\n      \"pmids\": [\"29860311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Drosophila ALS phenotype assays; TDP-43 nuclear/cytoplasmic fractionation; population genetic association study\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional Drosophila assay and fractionation from single study; mechanistic detail limited in abstract\",\n      \"pmids\": [\"32954321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"miRNA-target site mutagenesis; luciferase reporter assays; Western blot; AAV delivery in vivo; behavioral assessment in SCA1 mice\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 5' UTR binding validated by mutagenesis and reporter assay, in vivo AAV validation with behavioral readout\",\n      \"pmids\": [\"32763910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — allele-specific knock-in mouse models with multiple physiological readouts, demonstrates mechanistic distinction between alleles\",\n      \"pmids\": [\"33554954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 knock-in of K772T nuclear localization sequence mutation in Atxn1175Q mice; behavioral (motor, cognitive), survival, and RNA-seq analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise CRISPR knock-in targeting nuclear localization sequence with multiple behavioral and transcriptomic readouts\",\n      \"pmids\": [\"36577403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Global ATXN1-CIC interaction disruption in knock-in mice; unbiased proteomics; RNA-seq; ChIP-seq for CIC; human SCA1 patient-derived iNeurons; behavioral assessment\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteomics plus genetic interaction disruption in knock-in mice, validated in human patient-derived neurons\",\n      \"pmids\": [\"36577402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Atxn1 knockout mice; flow cytometry; transcriptomic profiling of B-1a cells; BCR stimulation assays\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockout mouse phenotype with transcriptomics, limited mechanistic detail on molecular pathway in abstract\",\n      \"pmids\": [\"33478569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo two-photon calcium imaging in behaving SCA1 mice; chemogenetic (DREADD) inhibition; synaptic density analysis; behavioral assessment; proteomics of SCA1 MLINs\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo two-photon imaging plus chemogenetic intervention with multiple mechanistic readouts in SCA1 mice\",\n      \"pmids\": [\"37321222\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATXN1 is a nuclear protein whose polyglutamine-expanded form causes SCA1 through gain-of-function mechanisms dependent on nuclear localization and S776 phosphorylation (stabilized by PKA and modulated by RAS-MAPK-MSK1 and PAK1 signaling); in the nucleus, mutant ATXN1 forms toxic complexes with the transcriptional repressor CIC (the primary driver of cerebellar Purkinje cell pathology), as well as with RORα, Tip60, SMRT/HDAC3, and other transcription factors (RFX1, ZBTB5, ZKSCAN1), dysregulating transcriptional programs; wild-type ATXN1 normally stabilizes CIC to repress ETV4/MMP genes and regulate ECM remodeling, modulates β-secretase processing of APP, and influences B cell receptor signaling, while its protein levels are post-transcriptionally regulated by PUM1 and multiple miRNAs (miR-19, miR-101, miR-130, miR760 via the 5' UTR).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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) [#0, #3]. In the nucleus ATXN1 binds DNA and represses transcription through the corepressor SMRT/HDAC3 [#3], 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 [#4, #9]. ATXN1 (redundantly with ATXN1L) stabilizes the transcriptional repressor Capicua (CIC), restraining the ETV4→MMP9 axis and ECM remodeling [#8]; 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 [#14]. Additional ATXN1 partners identified by unbiased proteomics (RFX1, ZBTB5, ZKSCAN1) contribute to SCA1 phenotypes beyond CIC in different cell populations [#21]. Pathogenic ATXN1 toxicity requires nuclear localization [#10, #20] 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 [#6, #15, #19]. 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 [#13, #18, #12, #16]. Beyond the cerebellum, ATXN1 loss-of-function potentiates BACE1 β-secretase processing of APP to raise amyloid-β levels [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Purkinje-cell-targeted expanded-CAG transgenic mice with ataxia and histopathology\",\n      \"pmids\": [\"7553854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular partners through which toxicity is exerted\", \"Did not establish whether wild-type ATXN1 has an essential normal function\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that impaired clearance/misfolding of expanded ATXN1 contributes to pathology, since chaperone augmentation mitigates disease.\",\n      \"evidence\": \"Cross of SCA1 mice with iHSP70-overexpressing mice; behavioral and neuropathological rescue\",\n      \"pmids\": [\"11448943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the degradation machinery normally handling ATXN1\", \"Mechanism of chaperone protection not resolved at the molecular level\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Endogenous knock-in established a faithful disease model and linked neuronal vulnerability to the inability to sequester mutant protein into aggregates.\",\n      \"evidence\": \"154Q CAG knock-in mice; solubility fractionation, behavioral, electrophysiological analysis\",\n      \"pmids\": [\"12086639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether soluble mutant protein is the toxic species mechanistically\", \"Did not identify the downstream effectors of toxicity\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined ATXN1 as a chromatin-binding transcriptional repressor acting through the SMRT/HDAC3 corepressor pathway, providing a molecular function for the protein.\",\n      \"evidence\": \"Co-IP, chromatin binding and reporter assays, Drosophila Smrter genetic epistasis\",\n      \"pmids\": [\"15016912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA-binding specificity of ATXN1 not defined\", \"Relationship of SMRT pathway to Purkinje-cell-specific toxicity unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified an ATXN1-RORα-Tip60 complex and connected RORα-dependent cerebellar development to SCA1, showing that developmental timing of mutant expression shapes disease severity.\",\n      \"evidence\": \"Conditional transgenic mice, Co-IP, RORα heterozygous crosses, behavioral readout\",\n      \"pmids\": [\"17110330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RORα destabilization is direct or secondary not fully resolved\", \"Quantitative contribution of RORα versus other pathways to toxicity unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified PKA, not Akt, as the cerebellar kinase phosphorylating ATXN1 at S776, the modification that stabilizes the protein.\",\n      \"evidence\": \"Cerebellar extract phosphorylation assay with immunodepletion and pharmacological PKA inhibition\",\n      \"pmids\": [\"19500214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro extract assay; cellular PKA-ATXN1 mechanism not directly demonstrated in vivo here\", \"Phosphatase counter-regulating S776 not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established miRNA-mediated dosage control of ATXN1 as a modulator of polyQ toxicity, introducing the theme that ATXN1 protein levels gate disease.\",\n      \"evidence\": \"miR-19/101/130 inhibition in human cells, ATXN1 Western blot, viability assays\",\n      \"pmids\": [\"18758459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation of these miRNAs\", \"Direct binding to ATXN1 transcript not fully mapped in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Atxn1L and Atxn1;Atxn1L knockout mice, Co-IP, CIC stability and expression assays\",\n      \"pmids\": [\"22014525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how the same CIC complex becomes toxic when ATXN1 is polyQ-expanded\", \"Tissue scope of ATXN1/ATXN1L redundancy not fully mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped the ATXN1-Tip60 interaction to the AXH domain and showed S776 phosphomimicry enhances it, linking phosphorylation to complex assembly and disease modification.\",\n      \"evidence\": \"Co-IP, ATXN1[82Q] x Tip60+/- crosses, gene expression and neuropathology\",\n      \"pmids\": [\"21427130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rescue was partial and mid-stage-specific\", \"Structural basis of S776-dependent affinity change not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that nuclear pathogenic ATXN1 selectively disrupts climbing fiber-Purkinje cell synaptic transmission before cell death, establishing a circuit deficit upstream of degeneration.\",\n      \"evidence\": \"Optical imaging, field recordings, VGluT2 staining in nuclear-localization mutant transgenic mice\",\n      \"pmids\": [\"21900557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between nuclear transcriptional dysregulation and the synaptic defect not defined\", \"Reversibility of the circuit deficit not tested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified RAS-MAPK-MSK1 signaling as a druggable regulator of ATXN1 protein levels, providing a pathway-level lever on disease.\",\n      \"evidence\": \"Parallel cell-based and Drosophila genetic screens plus pharmacological inhibition in mice\",\n      \"pmids\": [\"23719381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the pathway sets ATXN1 stability/translation not fully defined\", \"Whether the effect is S776-dependent not resolved here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pum1 knockout/haploinsufficiency mice and three-way epistasis crosses with Atxn1 alleles\",\n      \"pmids\": [\"25768905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PUM1 acts on ATXN1 stability versus translation not fully separated\", \"Other PUM1 targets contributing to phenotype not excluded\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo ATXN1-CIC interaction disruption, Purkinje-cell CIC knockout, expression profiling, patient iPSC neurons\",\n      \"pmids\": [\"29526553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not account for extracerebellar phenotypes\", \"How polyQ expansion alters CIC complex output mechanistically not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"PKA Cα genetic reduction in ATXN1[82Q] mice and pharmacological inhibition in patient iPSC neurons\",\n      \"pmids\": [\"29758256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKA also has essential physiological roles limiting therapeutic window\", \"Did not map the degron exposed by S776 dephosphorylation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PAK1 as an S776-independent regulator of ATXN1 levels, expanding the network of dosage-controlling pathways and showing additive benefit with MSK1 inhibition.\",\n      \"evidence\": \"Drosophila forward genetic screen, mammalian PAK1 knockdown, pharmacological PAK inhibition in SCA1 mice\",\n      \"pmids\": [\"29860311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which PAK1 sets ATXN1 abundance not defined\", \"Whether PAK1 acts on ATXN1 directly or via intermediates unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Target-site mutagenesis, luciferase reporters, Western blot, AAV delivery and behavior in SCA1 mice\",\n      \"pmids\": [\"32763910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and off-target effects of AAV-miR760 not fully addressed\", \"Endogenous regulation of miR760 in disease not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Allele-specific S776 phospho-null knock-in mice with behavioral, respiratory, and survival readouts\",\n      \"pmids\": [\"33554954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of WT-allele protection not resolved\", \"Did not define how WT and mutant ATXN1 functionally interact\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended ATXN1 loss-of-function biology beyond the nervous system, showing it regulates B-1a cell receptor signaling and immunoglobulin gene transcription.\",\n      \"evidence\": \"Atxn1-null mice, flow cytometry, B-1a transcriptomics, BCR stimulation assays\",\n      \"pmids\": [\"33478569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited mechanistic detail on the molecular BCR pathway\", \"Whether ATXN1's nuclear transcriptional role mediates this is not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"CRISPR K772T NLS knock-in in Atxn1175Q mice with behavioral, survival, and RNA-seq analysis\",\n      \"pmids\": [\"36577403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the nuclear effectors responsible for each phenotype\", \"Region-specific transcriptional drivers not individually validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Unbiased proteomics, ATXN1-CIC disruption knock-in mice, RNA-seq, CIC ChIP-seq, patient iNeurons\",\n      \"pmids\": [\"36577402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contributions of RFX1/ZBTB5/ZKSCAN1 not individually dissected\", \"Which interactors drive which extracerebellar phenotypes unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo two-photon calcium imaging, DREADD inhibition, synaptic density and proteomics in SCA1 mice\",\n      \"pmids\": [\"37321222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear ATXN1 dysregulation produces MLIN hyperexcitability not defined\", \"Whether the circuit mechanism generalizes to human SCA1 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 4, 8, 14, 21]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 20]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8, 14, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 14, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13, 18]}\n    ],\n    \"complexes\": [\n      \"ATXN1-CIC complex\",\n      \"ATXN1-RORα-Tip60 complex\",\n      \"ATXN1-SMRT/HDAC3 corepressor complex\"\n    ],\n    \"partners\": [\n      \"CIC\",\n      \"ATXN1L\",\n      \"RORA\",\n      \"KAT5\",\n      \"NCOR2\",\n      \"HDAC3\",\n      \"RFX1\",\n      \"ZKSCAN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}