{"gene":"ATXN2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2006,"finding":"Ataxin-2 and its Drosophila homolog ATX2 physically assemble with polyribosomes and poly(A)-binding protein (PABP). Assembly with polyribosomes is mediated independently by two distinct conserved regions: an N-terminal Lsm/LsmAD domain and a PAM2 motif. The PAM2 motif mediates physical interaction with PABP and also promotes polyribosome assembly, suggesting ATX2 binds mRNA directly through its Lsm/LsmAD domain and indirectly via PABP.","method":"Co-immunoprecipitation, polyribosome sedimentation assays, domain deletion/mutation analysis in Drosophila and human cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (sedimentation, Co-IP, domain mutagenesis) in two organisms; replicated across Drosophila and human ataxin-2","pmids":["16835262"],"is_preprint":false},{"year":2004,"finding":"C. elegans ATX-2 (ortholog of human ataxin-2) forms a complex with PAB-1 (cytoplasmic poly(A)-binding protein) and is required for germline development. Loss of ATX-2 causes reduced germline stem cell proliferation and abnormal masculinization, resulting from inappropriate translational regulation normally mediated by GLD-1 and MEX-3 KH-domain proteins.","method":"Co-immunoprecipitation, genetic loss-of-function (RNAi/mutant), phenotypic analysis in C. elegans germline","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis with defined cellular phenotype, replicated across multiple C. elegans studies","pmids":["15342467"],"is_preprint":false},{"year":2002,"finding":"Drosophila Datx2 (ataxin-2 homolog) is a dosage-sensitive regulator of actin filament formation. Loss-of-function or overexpression results in actin filament formation defects, female sterility, and tissue degeneration. Datx2 does not assemble with actin filaments, indicating its role in actin regulation is indirect.","method":"Genetic loss-of-function and overexpression transgenic analysis, immunostaining of actin filaments in Drosophila","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/OE with specific cellular phenotype in Drosophila, single lab, two genetic approaches","pmids":["12524342"],"is_preprint":false},{"year":2013,"finding":"Drosophila ATX2 is required for circadian locomotor behavior and PER accumulation in circadian pacemaker neurons. ATX2 functions as an activator of PER translation by forming a complex with TWENTY-FOUR (TYF) and promoting TYF's interaction with poly(A)-binding protein (PABP).","method":"Genetic loss-of-function, co-immunoprecipitation, behavioral assays, immunostaining in Drosophila","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis with TYF, defined cellular and behavioral phenotype, multiple orthogonal methods","pmids":["23687048"],"is_preprint":false},{"year":2005,"finding":"Ataxin-2 knockout mice are viable but show adult-onset obesity on a fat-enriched diet, and female Sca2-/- mice show reduced birth frequency (segregation distortion). No major histological abnormalities were observed in surviving knockout mice, indicating ataxin-2 is not essential for development but affects metabolic regulation.","method":"Gene knockout (homologous recombination), genotypic analysis, weight measurement, histological analysis in mice","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with specific metabolic phenotype, single lab","pmids":["16293225"],"is_preprint":false},{"year":2012,"finding":"Expanded ATXN2 (CAG42 knock-in) sequesters PABPC1 into insolubility in mouse cerebellum. In vitro, ATXN2 overexpression reduces PABPC1 levels. FBXW8 is selectively induced in old CAG42 knock-in cerebellum and decreases the level of expanded insoluble ATXN2 protein in vitro, suggesting FBXW8 partially alleviates ATXN2 aggregation.","method":"Knock-in mouse model, immunoblot (soluble/insoluble fractionation), cell culture ATXN2 overexpression, transcriptome profiling, in vitro FBXW8 degradation assay","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse plus in vitro validation, single lab, multiple orthogonal methods","pmids":["22956915"],"is_preprint":false},{"year":2015,"finding":"ATXN2 interacts selectively with RGS8 mRNA as shown by RNA immunoprecipitation. Expanded polyglutamine ATXN2 impairs this interaction, reduces RGS8 mRNA levels, and reduces RGS8 protein levels more severely than mRNA levels. Mutant ATXN2 reduces RGS8 expression in an in vitro coupled translation assay, supporting a role for ATXN2 in translational regulation of RGS8.","method":"RNA immunoprecipitation, transcriptome analysis by deep RNA-sequencing, in vitro coupled translation assay, BAC transgenic mouse model","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — RNA-IP, in vitro translation assay, and transgenic mouse model with multiple orthogonal methods in single rigorous study","pmids":["25902068"],"is_preprint":false},{"year":2010,"finding":"ZBRK1 (a KRAB zinc-finger transcriptional regulator) is an interaction partner of ataxin-2, and elevated ZBRK1 levels increase ataxin-2 levels. A ZBRK1/ataxin-2 complex regulates SCA2 gene transcription via ZBRK1-binding sites in the SCA2 promoter. Ataxin-2 thus acts as a co-activator of ZBRK1 to upregulate its own transcription.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase promoter assay, siRNA knockdown, overexpression in cell culture","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional promoter assay; single lab with multiple orthogonal methods","pmids":["20926453"],"is_preprint":false},{"year":2012,"finding":"ETS1 transcription factor binds the ATXN2 promoter at an ETS-binding site and is required for ATXN2 expression. ETS1 overexpression increases endogenous ATXN2 expression; dominant-negative ETS1 or ETS1 shRNA reduces ATXN2-luciferase expression. The second of two possible start codons is confirmed as the functional start codon in ATXN2.","method":"Electromobility supershift assay, chromatin immunoprecipitation PCR, luciferase promoter deletion analysis, transgenic mice, shRNA knockdown","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, EMSA, functional promoter assay with multiple methods; single lab","pmids":["22914732"],"is_preprint":false},{"year":2016,"finding":"C. elegans ATX-2 (ataxin-2 ortholog) regulates centrosome size and microtubule dynamics. ATX-2 forms a complex with SZY-20 in an RNA-independent manner. Depletion of ATX-2 causes embryonic lethality and cytokinesis failure, increases centrosome size and levels of centrosome factors (ZYG-1, SPD-5, γ-Tubulin), and impairs MT growth. ATX-2 influences MT behavior through γ-Tubulin at the centrosome.","method":"Co-immunoprecipitation (RNA-independent), RNAi depletion, live imaging, quantitative immunofluorescence in C. elegans embryos","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RNAi with defined cellular phenotype and live imaging; single lab, multiple orthogonal methods","pmids":["27689799"],"is_preprint":false},{"year":2016,"finding":"C. elegans ATX-2 regulates cytokinesis by targeting ZEN-4 to the spindle midzone through modulation of PAR-5 levels. Preventing ATX-2 function elevates PAR-5 at mitotic structures (spindle, centrosomes, midbody), reducing ZEN-4-GFP at the spindle midzone. Codepletion of ATX-2 and PAR-5 rescues ZEN-4 localization, placing ATX-2 upstream of PAR-5 in this pathway.","method":"RNAi depletion, live fluorescence imaging (GFP reporters), genetic epistasis in C. elegans","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined localization phenotype and live imaging; single lab","pmids":["27559134"],"is_preprint":false},{"year":2016,"finding":"C. elegans atx-2 acts as an mTOR repressor, regulating cell size and fat content under dietary restriction. ATX-2 functions downstream of AMPK and upstream of ribosomal S6 kinase and TORC1 by direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP- and GTP-bound forms.","method":"RNAi knockdown, overexpression, genetic pathway analysis, direct interaction assay in C. elegans","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis, overexpression, and direct interaction assay; single lab with multiple approaches","pmids":["27457958"],"is_preprint":false},{"year":2000,"finding":"In SCA2 human brains, ataxin-2 forms cytoplasmic (not nuclear) microaggregates. In transgenic mice expressing ataxin-2[Q58], the protein remains cytoplasmic without detectable ubiquitination, despite causing progressive Purkinje cell dendritic arbor loss and Purkinje cell death. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis.","method":"Immunohistochemistry of human SCA2 brain tissue, transgenic mouse model with behavioral and neuropathological analysis, subcellular fractionation/immunofluorescence","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in human tissue and transgenic mice with defined neuropathological phenotype; single lab","pmids":["10973246"],"is_preprint":false},{"year":2015,"finding":"FBXW8 (an SCF-type E3 ubiquitin ligase component) co-immunoprecipitates with ATXN2 both in vitro and in vivo, and FBXW8 protein is sequestered into insolubility by expanded ATXN2. PARK2 also co-immunoprecipitates with ATXN2 and FBXW8 and is similarly driven into insolubility by expanded ATXN2. FBXW8 transcript is upregulated by ATXN2 expansion, suggesting FBXW8 mediates degradation of both wildtype and mutant ATXN2.","method":"Co-immunoprecipitation in vitro and in vivo, soluble/insoluble fractionation immunoblot, qPCR in patient fibroblasts and blood","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in vitro and in vivo with fractionation; single lab, multiple sample types","pmids":["25790475"],"is_preprint":false},{"year":2019,"finding":"ATXN2 selectively regulates Nat8l mRNA (encoding the enzyme responsible for N-acetylaspartate synthesis) in an Atxn2-CAG100 knock-in mouse model, with early and strong downregulation of Nat8l transcript before onset of motor deficits. This is associated with reduced N-acetylaspartate brain metabolites detectable by in vivo MR spectroscopy.","method":"Knock-in mouse model, RT-qPCR, in vivo MR spectroscopy, transcriptome profiling at pre-symptomatic stages","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse with in vivo metabolic readout and transcriptome analysis; single lab","pmids":["31376479"],"is_preprint":false},{"year":2021,"finding":"In an Atxn2-CAG100 knock-in mouse spinal cord, cytosolic ATXN2 aggregates sequester TDP-43 and TIA1 from the nucleus. This is accompanied by elevated CASP3, RIPK1, and PQBP1 protein levels, and progressive downregulation of cholesterol biosynthesis enzymes (Dhcr24, Msmo1, Idi1, Hmgcs1), with gas chromatography confirming loss of cholesterol precursor metabolites.","method":"Knock-in mouse model, triple immunofluorescence, immunoblot, RT-qPCR, transcriptome profiling, gas chromatography","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse with multiple orthogonal methods; single lab","pmids":["33577922"],"is_preprint":false},{"year":2017,"finding":"ATXN2 acts as a strong modifier of PINK1 levels. ATXN2 knockout mouse cerebellum and liver show severe decrease in Pink1 expression alongside effects on Opa1 and Ghitm (mitochondrial dynamics regulators). In human neuroblastoma cells, starvation stress induces ATXN2 and PINK1 in parallel, and knockdown of one enhances expression of the other during stress response.","method":"Knockout mouse transcriptome (RNA-seq), RT-qPCR, immunoblot, siRNA knockdown in SH-SY5Y cells, stress induction assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse transcriptome plus in vitro knockdown with reciprocal effects; single lab, multiple orthogonal methods","pmids":["27597528"],"is_preprint":false},{"year":2022,"finding":"ATXN2 augments translation of TNFRSF1A (TNFR1) by binding to m6A-modified TNFRSF1A mRNA, upregulating TNFR1 protein levels and consequently activating NF-κB and MAPK pathways in esophageal squamous cell carcinoma cells.","method":"Transcriptome-wide m6A sequencing, RNA immunoprecipitation, functional overexpression/knockdown assays, pathway activation readouts (immunoblot) in ESCC cells","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-seq plus RNA-IP and functional assays; single lab, multiple methods","pmids":["34995801"],"is_preprint":false},{"year":2015,"finding":"Repeat-associated non-AUG (RAN) translation occurs for ATXN2 but is weak compared to AUG-dependent translation, does not increase with longer CAG repeat lengths, and is dependent on ATXN2 sequences downstream of the CAG repeat. RAN translation was detected with CMV but not ATXN2 endogenous promoter constructs.","method":"Luciferase reporter constructs lacking the ATXN2 AUG start codon, Western blot with anti-polyglutamine antibody, various promoter and truncation constructs in cell culture","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro reporter assay with multiple construct variants; single lab","pmids":["26086378"],"is_preprint":false},{"year":2017,"finding":"Atxn2 knockout mouse cerebellum shows dysregulation of calcium homeostasis pathway genes including downregulation of Rora, Itpr1, Atp2a2, and Inpp5a. ITPR1 protein accumulates in membrane-associated fractions in the SCA2 CAG42 knock-in model but not in knockout. Co-immunoprecipitation showed no association of ITPR1 with either Q42-expanded or wild-type ATXN2, indicating the effect on calcium signaling is indirect.","method":"Knockout and knock-in mouse models, microarray, RT-qPCR, co-immunoprecipitation, subcellular fractionation immunoblot","journal":"Cerebellum (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two mouse models, multiple methods; single lab; negative Co-IP result explicitly confirmed","pmids":["26868665"],"is_preprint":false}],"current_model":"ATXN2 is an RNA-binding protein that associates with polyribosomes and poly(A)-binding protein (PABP) via its Lsm/LsmAD and PAM2 domains to regulate mRNA translation; it selectively binds target mRNAs (e.g., RGS8, Nat8l, TNFR1) to control their translation, interacts with partners including PABP/PABPC1, ZBRK1, FBXW8, and TYF to modulate gene expression and protein homeostasis, participates in stress-responsive regulation of the PINK1/mitochondrial quality control pathway, and contributes to cytokinesis and centrosome size regulation in model organisms, with polyglutamine expansion causing progressive sequestration of PABPC1 and TDP-43 into insolubility, indirect disruption of calcium homeostasis, and cholesterol biosynthesis suppression in neurons."},"narrative":{"mechanistic_narrative":"ATXN2 is a cytoplasmic RNA-binding protein that functions in post-transcriptional control by assembling with polyribosomes and poly(A)-binding protein (PABP) to regulate the translation and stability of selected mRNAs [PMID:16835262]. It engages polyribosomes through two independent conserved elements — an N-terminal Lsm/LsmAD domain that contacts mRNA directly and a PAM2 motif that binds PABP and promotes polyribosome assembly [PMID:16835262]. Through this machinery ATXN2 acts as a selective translational regulator: it binds and controls specific transcripts including RGS8 [PMID:25902068], the N-acetylaspartate-synthesis enzyme transcript Nat8l [PMID:31376479], and m6A-modified TNFRSF1A (TNFR1), the last driving NF-κB and MAPK activation in esophageal carcinoma cells [PMID:34995801]. In model organisms it operates within RNA-regulatory complexes — with PAB-1 in the C. elegans germline [PMID:15342467] and with TWENTY-FOUR (TYF) to activate PER translation in Drosophila circadian neurons by promoting TYF–PABP interaction [PMID:23687048]. Beyond translation, ATXN2 has broader roles in cell physiology: it regulates centrosome size, microtubule dynamics and cytokinesis in C. elegans via complexes with SZY-20 and modulation of PAR-5 and γ-Tubulin [PMID:27689799, PMID:27559134], acts as an mTOR repressor downstream of AMPK [PMID:27457958], and modifies metabolic and mitochondrial-quality-control programs, including parallel stress-induced regulation with PINK1 [PMID:27597528] and lipid metabolism [PMID:16293225]. ATXN2 expression is autoregulated and transcription-factor controlled, serving as a ZBRK1 co-activator on its own promoter [PMID:20926453] and requiring ETS1 for expression [PMID:22914732]. CAG-repeat (polyglutamine) expansion in ATXN2 causes spinocerebellar ataxia type 2, in which cytoplasmic mutant protein progressively sequesters PABPC1, TDP-43 and TIA1 into insolubility, suppresses cholesterol biosynthesis, and indirectly perturbs calcium homeostasis in neurons [PMID:22956915, PMID:10973246, PMID:33577922, PMID:26868665].","teleology":[{"year":2000,"claim":"Establishing where mutant ataxin-2 acts addressed whether polyQ pathology required nuclear inclusions, as for other polyQ diseases; it showed SCA2 pathology is cytoplasmic.","evidence":"Immunohistochemistry of human SCA2 brain and transgenic ataxin-2[Q58] mice with neuropathological analysis","pmids":["10973246"],"confidence":"Medium","gaps":["Does not define the molecular target whose disruption kills Purkinje cells","Mechanism linking cytoplasmic microaggregates to dendritic loss unresolved"]},{"year":2004,"claim":"The first physiological role was defined by showing the ortholog complexes with PABP to control germline translation, framing ATXN2 as a translational regulator rather than a structural protein.","evidence":"Co-IP and genetic loss-of-function with germline phenotyping in C. elegans","pmids":["15342467"],"confidence":"High","gaps":["Direct mRNA targets not identified","Whether the human ortholog uses the same KH-protein circuitry untested"]},{"year":2006,"claim":"The molecular basis of ATXN2's translational function was mapped, showing two separable domains tether it to polyribosomes and PABP — defining how it accesses mRNA.","evidence":"Polyribosome sedimentation, Co-IP, and domain mutagenesis in Drosophila and human cells","pmids":["16835262"],"confidence":"High","gaps":["Sequence specificity of Lsm/LsmAD mRNA binding undefined","Does not show whether binding activates or represses translation"]},{"year":2010,"claim":"Discovery of ZBRK1 partnership revealed a feedback loop in which ATXN2 co-activates its own transcription, addressing how ATXN2 levels are set.","evidence":"Co-IP, ChIP, luciferase promoter assays with knockdown/overexpression in cell culture","pmids":["20926453"],"confidence":"Medium","gaps":["Physiological relevance of autoregulation in neurons untested","Single lab, no in vivo confirmation"]},{"year":2012,"claim":"Identifying ETS1 as a required transcriptional activator extended ATXN2 expression control and resolved which start codon is functional.","evidence":"EMSA, ChIP-PCR, promoter luciferase deletions, transgenic mice, shRNA","pmids":["22914732"],"confidence":"Medium","gaps":["Tissue/context dependence of ETS1 regulation unclear","Upstream signals controlling ETS1 at the ATXN2 promoter unknown"]},{"year":2012,"claim":"Linking expansion to PABPC1 loss and FBXW8 induction connected polyQ ATXN2 to disrupted RNA-binding partner availability and to a candidate clearance route.","evidence":"CAG42 knock-in mouse, soluble/insoluble fractionation, in vitro FBXW8 degradation assay","pmids":["22956915"],"confidence":"Medium","gaps":["Whether PABPC1 sequestration is the proximal cause of toxicity untested","FBXW8's role only partial in vitro"]},{"year":2015,"claim":"RNA-IP identification of RGS8 as a selective target provided direct evidence that ATXN2 controls specific mRNA translation and that expansion impairs this function.","evidence":"RNA-IP, deep RNA-seq, in vitro coupled translation, BAC transgenic mice","pmids":["25902068"],"confidence":"High","gaps":["Recognition determinants on RGS8 mRNA not mapped","Whether RGS8 loss drives the neuronal phenotype not established"]},{"year":2015,"claim":"Reciprocal Co-IP placed ATXN2 in a complex with FBXW8 and PARK2 and showed expansion co-sequesters these partners, extending the aggregation pathology to ubiquitin-pathway components.","evidence":"In vitro and in vivo Co-IP, fractionation immunoblot, qPCR in patient fibroblasts/blood","pmids":["25790475"],"confidence":"Medium","gaps":["Whether FBXW8-mediated degradation is functionally protective in vivo untested","Stoichiometry of co-sequestration unknown"]},{"year":2015,"claim":"Testing repeat-associated non-AUG translation clarified that RAN products are a minor, length-independent contributor relative to canonical ATXN2 translation.","evidence":"Luciferase reporters lacking the AUG, anti-polyQ Western, promoter/truncation variants in cells","pmids":["26086378"],"confidence":"Medium","gaps":["In vitro reporter only; endogenous RAN product abundance in patient tissue not measured","Pathological contribution untested"]},{"year":2016,"claim":"C. elegans studies defined a cell-division role, showing ATX-2 complexes with SZY-20 and controls centrosome size, microtubule dynamics, and ZEN-4 midzone targeting via PAR-5.","evidence":"RNA-independent Co-IP, RNAi, live imaging, genetic epistasis in C. elegans embryos","pmids":["27689799","27559134"],"confidence":"Medium","gaps":["Whether mammalian ATXN2 performs an analogous mitotic function untested","Molecular link between RNA-regulatory and centrosomal roles unclear"]},{"year":2016,"claim":"Genetic placement of ATX-2 as an mTOR repressor downstream of AMPK connected ATXN2 to nutrient-sensing and cell-size/fat control.","evidence":"RNAi, overexpression, pathway epistasis, direct interaction assay with Rab-GDIβ in C. elegans","pmids":["27457958"],"confidence":"Medium","gaps":["RHEB-shuttling mechanism inferred, not directly demonstrated","Conservation in mammals not shown"]},{"year":2017,"claim":"Loss-of-function transcriptomics revealed ATXN2 as a modifier of PINK1 and calcium-homeostasis genes, broadening its role to mitochondrial quality control and stress signaling.","evidence":"KO mouse RNA-seq/qPCR/immunoblot, SH-SY5Y siRNA and starvation stress; two mouse models with negative ITPR1 Co-IP","pmids":["27597528","26868665"],"confidence":"Medium","gaps":["Whether PINK1 regulation is transcriptional or translational unresolved","Calcium-gene effects shown to be indirect; intermediary unknown"]},{"year":2019,"claim":"Pre-symptomatic Nat8l downregulation in CAG100 knock-in mice linked ATXN2 dysfunction to an early, in-vivo-measurable metabolic deficit.","evidence":"CAG100 knock-in mouse, RT-qPCR, in vivo MR spectroscopy, transcriptome profiling","pmids":["31376479"],"confidence":"Medium","gaps":["Direct binding of ATXN2 to Nat8l mRNA not demonstrated here","Causal contribution of NAA loss to disease untested"]},{"year":2021,"claim":"Spinal-cord analysis showed mutant ATXN2 aggregates sequester TDP-43 and TIA1 and suppress cholesterol biosynthesis, tying SCA2 to ALS-related RNA pathology and lipid metabolism.","evidence":"CAG100 knock-in mouse, triple immunofluorescence, immunoblot, RT-qPCR, gas chromatography","pmids":["33577922"],"confidence":"Medium","gaps":["Order of events between sequestration and cholesterol loss unresolved","Whether cholesterol restoration is protective untested"]},{"year":2022,"claim":"Identification of m6A-modified TNFRSF1A as a target connected ATXN2 translational activation to inflammatory NF-κB/MAPK signaling in cancer cells.","evidence":"m6A-seq, RNA-IP, overexpression/knockdown, pathway immunoblots in ESCC cells","pmids":["34995801"],"confidence":"Medium","gaps":["Whether m6A recognition is direct or via a reader untested","Relevance to neuronal ATXN2 function unclear"]},{"year":null,"claim":"It remains unresolved how ATXN2's sequence-specific mRNA selection works mechanistically and how its diverse cellular roles (translation, centrosome/cytokinesis, mTOR, mitochondrial QC) are coordinated by a single protein.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of target-mRNA recognition by the Lsm/LsmAD domain","Unifying biochemical logic across translational and non-translational roles undefined","Proximal toxic species in polyQ expansion not pinpointed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6,14,17]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,3,6,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,12]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,6,17]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[10]}],"complexes":["ATXN2-PABP polyribosome complex"],"partners":["PABPC1","ZBRK1","FBXW8","PARK2","SZY-20","TYF","TDP-43","TIA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99700","full_name":"Ataxin-2","aliases":["Spinocerebellar ataxia type 2 protein","Trinucleotide repeat-containing gene 13 protein"],"length_aa":1313,"mass_kda":140.3,"function":"Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99700/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN2","classification":"Not Classified","n_dependent_lines":40,"n_total_lines":1208,"dependency_fraction":0.033112582781456956},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX6","stoichiometry":10.0},{"gene":"ABCE1","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2},{"gene":"EIF3B","stoichiometry":0.2},{"gene":"EIF3G","stoichiometry":0.2},{"gene":"EIF4A1","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATXN2","total_profiled":1310},"omim":[{"mim_id":"620636","title":"NEURODEGENERATION, CHILDHOOD-ONSET, WITH CEREBELLAR ATAXIA AND COGNITIVE DECLINE; CONDCAC","url":"https://www.omim.org/entry/620636"},{"mim_id":"619798","title":"E74-LIKE ETS TRANSCRIPTION FACTOR 2; ELF2","url":"https://www.omim.org/entry/619798"},{"mim_id":"614260","title":"CHROMOSOME 9 OPEN READING FRAME 72; C9ORF72","url":"https://www.omim.org/entry/614260"},{"mim_id":"613096","title":"SPASTIC PARAPLEGIA 36, AUTOSOMAL DOMINANT; SPG36","url":"https://www.omim.org/entry/613096"},{"mim_id":"612876","title":"SPINOCEREBELLAR ATAXIA 9; SCA9","url":"https://www.omim.org/entry/612876"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Clinical and molecular study in 36 Italian families including a comparison between SCA1 and SCA2 phenotypes.","date":"1996","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8902734","citation_count":33,"is_preprint":false},{"pmid":"31376479","id":"PMC_31376479","title":"Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation.","date":"2019","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/31376479","citation_count":31,"is_preprint":false},{"pmid":"29101844","id":"PMC_29101844","title":"Early corticospinal tract damage in prodromal SCA2 revealed by EEG-EMG and EMG-EMG coherence.","date":"2017","source":"Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/29101844","citation_count":31,"is_preprint":false},{"pmid":"9629399","id":"PMC_9629399","title":"Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients.","date":"1997","source":"Arquivos de neuro-psiquiatria","url":"https://pubmed.ncbi.nlm.nih.gov/9629399","citation_count":31,"is_preprint":false},{"pmid":"22914732","id":"PMC_22914732","title":"ETS1 regulates the expression of ATXN2.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22914732","citation_count":30,"is_preprint":false},{"pmid":"27597528","id":"PMC_27597528","title":"Search for SCA2 blood RNA biomarkers highlights Ataxin-2 as strong modifier of the mitochondrial factor PINK1 levels.","date":"2016","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/27597528","citation_count":30,"is_preprint":false},{"pmid":"27689799","id":"PMC_27689799","title":"ATX-2, the C. elegans Ortholog of Human Ataxin-2, Regulates Centrosome Size and Microtubule Dynamics.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27689799","citation_count":30,"is_preprint":false},{"pmid":"38877004","id":"PMC_38877004","title":"The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38877004","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":"27417041","id":"PMC_27417041","title":"Abnormal corticospinal tract function and motor cortex excitability in non-ataxic SCA2 mutation carriers: A TMS study.","date":"2016","source":"Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/27417041","citation_count":29,"is_preprint":false},{"pmid":"34995801","id":"PMC_34995801","title":"ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m6A-dependent manner.","date":"2022","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34995801","citation_count":28,"is_preprint":false},{"pmid":"21128038","id":"PMC_21128038","title":"Spinocerebellar ataxia type 2 (SCA2): identification of early brain degeneration in one monozygous twin in the initial disease stage.","date":"2011","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21128038","citation_count":28,"is_preprint":false},{"pmid":"32307524","id":"PMC_32307524","title":"ALS-associated genes in SCA2 mouse spinal cord transcriptomes.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32307524","citation_count":27,"is_preprint":false},{"pmid":"29581194","id":"PMC_29581194","title":"Role of Sca2 and RickA in the Dissemination of Rickettsia parkeri in Amblyomma maculatum.","date":"2018","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29581194","citation_count":27,"is_preprint":false},{"pmid":"19676102","id":"PMC_19676102","title":"Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2).","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/19676102","citation_count":27,"is_preprint":false},{"pmid":"24718895","id":"PMC_24718895","title":"FTLD-ALS of TDP-43 type and SCA2 in a family with a full ataxin-2 polyglutamine expansion.","date":"2014","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/24718895","citation_count":27,"is_preprint":false},{"pmid":"30342763","id":"PMC_30342763","title":"ATXN2 intermediate repeat expansions influence the clinical phenotype in frontotemporal dementia.","date":"2018","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/30342763","citation_count":26,"is_preprint":false},{"pmid":"12614315","id":"PMC_12614315","title":"Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype.","date":"2003","source":"Acta neurologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/12614315","citation_count":26,"is_preprint":false},{"pmid":"33660796","id":"PMC_33660796","title":"LINC00941 promotes proliferation and metastasis of pancreatic adenocarcinoma by competitively binding miR-873-3p and thus upregulates ATXN2.","date":"2021","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33660796","citation_count":25,"is_preprint":false},{"pmid":"25790475","id":"PMC_25790475","title":"Both ubiquitin ligases FBXW8 and PARK2 are sequestrated into insolubility by ATXN2 PolyQ expansions, but only FBXW8 expression is dysregulated.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25790475","citation_count":25,"is_preprint":false},{"pmid":"26208502","id":"PMC_26208502","title":"ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry.","date":"2015","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/26208502","citation_count":25,"is_preprint":false},{"pmid":"11804332","id":"PMC_11804332","title":"Molecular analysis of Spinocerebellar ataxias in Koreans: frequencies and reference ranges of SCA1, SCA2, SCA3, SCA6, and SCA7.","date":"2001","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/11804332","citation_count":25,"is_preprint":false},{"pmid":"31619481","id":"PMC_31619481","title":"TDP-43 levels in the brain tissue of ALS cases with and without C9ORF72 or ATXN2 gene expansions.","date":"2019","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31619481","citation_count":23,"is_preprint":false},{"pmid":"27559134","id":"PMC_27559134","title":"The RNA-binding protein ATX-2 regulates cytokinesis through PAR-5 and ZEN-4.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/27559134","citation_count":21,"is_preprint":false},{"pmid":"22612237","id":"PMC_22612237","title":"Identification and characterization of the mammalian association and actin-nucleating domains in the Rickettsia conorii autotransporter protein, Sca2.","date":"2012","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22612237","citation_count":21,"is_preprint":false},{"pmid":"8994121","id":"PMC_8994121","title":"Central phenotype and related varieties of spinocerebellar ataxia 2 (SCA2): a clinical and genetic study with a pedigree in the Japanese.","date":"1996","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8994121","citation_count":20,"is_preprint":false},{"pmid":"28462804","id":"PMC_28462804","title":"SCA2 family presenting as typical Parkinson's disease: 34 year follow up.","date":"2017","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/28462804","citation_count":18,"is_preprint":false},{"pmid":"36213324","id":"PMC_36213324","title":"ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity.","date":"2022","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/36213324","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52620,"output_tokens":5340,"usd":0.11898,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13614,"output_tokens":4755,"usd":0.093473,"stage2_stop_reason":"end_turn"},"total_usd":0.212453,"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\": 2006,\n      \"finding\": \"Ataxin-2 and its Drosophila homolog ATX2 physically assemble with polyribosomes and poly(A)-binding protein (PABP). Assembly with polyribosomes is mediated independently by two distinct conserved regions: an N-terminal Lsm/LsmAD domain and a PAM2 motif. The PAM2 motif mediates physical interaction with PABP and also promotes polyribosome assembly, suggesting ATX2 binds mRNA directly through its Lsm/LsmAD domain and indirectly via PABP.\",\n      \"method\": \"Co-immunoprecipitation, polyribosome sedimentation assays, domain deletion/mutation analysis in Drosophila and human cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (sedimentation, Co-IP, domain mutagenesis) in two organisms; replicated across Drosophila and human ataxin-2\",\n      \"pmids\": [\"16835262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"C. elegans ATX-2 (ortholog of human ataxin-2) forms a complex with PAB-1 (cytoplasmic poly(A)-binding protein) and is required for germline development. Loss of ATX-2 causes reduced germline stem cell proliferation and abnormal masculinization, resulting from inappropriate translational regulation normally mediated by GLD-1 and MEX-3 KH-domain proteins.\",\n      \"method\": \"Co-immunoprecipitation, genetic loss-of-function (RNAi/mutant), phenotypic analysis in C. elegans germline\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis with defined cellular phenotype, replicated across multiple C. elegans studies\",\n      \"pmids\": [\"15342467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Drosophila Datx2 (ataxin-2 homolog) is a dosage-sensitive regulator of actin filament formation. Loss-of-function or overexpression results in actin filament formation defects, female sterility, and tissue degeneration. Datx2 does not assemble with actin filaments, indicating its role in actin regulation is indirect.\",\n      \"method\": \"Genetic loss-of-function and overexpression transgenic analysis, immunostaining of actin filaments in Drosophila\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/OE with specific cellular phenotype in Drosophila, single lab, two genetic approaches\",\n      \"pmids\": [\"12524342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila ATX2 is required for circadian locomotor behavior and PER accumulation in circadian pacemaker neurons. ATX2 functions as an activator of PER translation by forming a complex with TWENTY-FOUR (TYF) and promoting TYF's interaction with poly(A)-binding protein (PABP).\",\n      \"method\": \"Genetic loss-of-function, co-immunoprecipitation, behavioral assays, immunostaining in Drosophila\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis with TYF, defined cellular and behavioral phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"23687048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ataxin-2 knockout mice are viable but show adult-onset obesity on a fat-enriched diet, and female Sca2-/- mice show reduced birth frequency (segregation distortion). No major histological abnormalities were observed in surviving knockout mice, indicating ataxin-2 is not essential for development but affects metabolic regulation.\",\n      \"method\": \"Gene knockout (homologous recombination), genotypic analysis, weight measurement, histological analysis in mice\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with specific metabolic phenotype, single lab\",\n      \"pmids\": [\"16293225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Expanded ATXN2 (CAG42 knock-in) sequesters PABPC1 into insolubility in mouse cerebellum. In vitro, ATXN2 overexpression reduces PABPC1 levels. FBXW8 is selectively induced in old CAG42 knock-in cerebellum and decreases the level of expanded insoluble ATXN2 protein in vitro, suggesting FBXW8 partially alleviates ATXN2 aggregation.\",\n      \"method\": \"Knock-in mouse model, immunoblot (soluble/insoluble fractionation), cell culture ATXN2 overexpression, transcriptome profiling, in vitro FBXW8 degradation assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse plus in vitro validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22956915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATXN2 interacts selectively with RGS8 mRNA as shown by RNA immunoprecipitation. Expanded polyglutamine ATXN2 impairs this interaction, reduces RGS8 mRNA levels, and reduces RGS8 protein levels more severely than mRNA levels. Mutant ATXN2 reduces RGS8 expression in an in vitro coupled translation assay, supporting a role for ATXN2 in translational regulation of RGS8.\",\n      \"method\": \"RNA immunoprecipitation, transcriptome analysis by deep RNA-sequencing, in vitro coupled translation assay, BAC transgenic mouse model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — RNA-IP, in vitro translation assay, and transgenic mouse model with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25902068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZBRK1 (a KRAB zinc-finger transcriptional regulator) is an interaction partner of ataxin-2, and elevated ZBRK1 levels increase ataxin-2 levels. A ZBRK1/ataxin-2 complex regulates SCA2 gene transcription via ZBRK1-binding sites in the SCA2 promoter. Ataxin-2 thus acts as a co-activator of ZBRK1 to upregulate its own transcription.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase promoter assay, siRNA knockdown, overexpression in cell culture\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional promoter assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20926453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ETS1 transcription factor binds the ATXN2 promoter at an ETS-binding site and is required for ATXN2 expression. ETS1 overexpression increases endogenous ATXN2 expression; dominant-negative ETS1 or ETS1 shRNA reduces ATXN2-luciferase expression. The second of two possible start codons is confirmed as the functional start codon in ATXN2.\",\n      \"method\": \"Electromobility supershift assay, chromatin immunoprecipitation PCR, luciferase promoter deletion analysis, transgenic mice, shRNA knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, EMSA, functional promoter assay with multiple methods; single lab\",\n      \"pmids\": [\"22914732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C. elegans ATX-2 (ataxin-2 ortholog) regulates centrosome size and microtubule dynamics. ATX-2 forms a complex with SZY-20 in an RNA-independent manner. Depletion of ATX-2 causes embryonic lethality and cytokinesis failure, increases centrosome size and levels of centrosome factors (ZYG-1, SPD-5, γ-Tubulin), and impairs MT growth. ATX-2 influences MT behavior through γ-Tubulin at the centrosome.\",\n      \"method\": \"Co-immunoprecipitation (RNA-independent), RNAi depletion, live imaging, quantitative immunofluorescence in C. elegans embryos\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RNAi with defined cellular phenotype and live imaging; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27689799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C. elegans ATX-2 regulates cytokinesis by targeting ZEN-4 to the spindle midzone through modulation of PAR-5 levels. Preventing ATX-2 function elevates PAR-5 at mitotic structures (spindle, centrosomes, midbody), reducing ZEN-4-GFP at the spindle midzone. Codepletion of ATX-2 and PAR-5 rescues ZEN-4 localization, placing ATX-2 upstream of PAR-5 in this pathway.\",\n      \"method\": \"RNAi depletion, live fluorescence imaging (GFP reporters), genetic epistasis in C. elegans\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined localization phenotype and live imaging; single lab\",\n      \"pmids\": [\"27559134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C. elegans atx-2 acts as an mTOR repressor, regulating cell size and fat content under dietary restriction. ATX-2 functions downstream of AMPK and upstream of ribosomal S6 kinase and TORC1 by direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP- and GTP-bound forms.\",\n      \"method\": \"RNAi knockdown, overexpression, genetic pathway analysis, direct interaction assay in C. elegans\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis, overexpression, and direct interaction assay; single lab with multiple approaches\",\n      \"pmids\": [\"27457958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In SCA2 human brains, ataxin-2 forms cytoplasmic (not nuclear) microaggregates. In transgenic mice expressing ataxin-2[Q58], the protein remains cytoplasmic without detectable ubiquitination, despite causing progressive Purkinje cell dendritic arbor loss and Purkinje cell death. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis.\",\n      \"method\": \"Immunohistochemistry of human SCA2 brain tissue, transgenic mouse model with behavioral and neuropathological analysis, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in human tissue and transgenic mice with defined neuropathological phenotype; single lab\",\n      \"pmids\": [\"10973246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXW8 (an SCF-type E3 ubiquitin ligase component) co-immunoprecipitates with ATXN2 both in vitro and in vivo, and FBXW8 protein is sequestered into insolubility by expanded ATXN2. PARK2 also co-immunoprecipitates with ATXN2 and FBXW8 and is similarly driven into insolubility by expanded ATXN2. FBXW8 transcript is upregulated by ATXN2 expansion, suggesting FBXW8 mediates degradation of both wildtype and mutant ATXN2.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in vivo, soluble/insoluble fractionation immunoblot, qPCR in patient fibroblasts and blood\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in vitro and in vivo with fractionation; single lab, multiple sample types\",\n      \"pmids\": [\"25790475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATXN2 selectively regulates Nat8l mRNA (encoding the enzyme responsible for N-acetylaspartate synthesis) in an Atxn2-CAG100 knock-in mouse model, with early and strong downregulation of Nat8l transcript before onset of motor deficits. This is associated with reduced N-acetylaspartate brain metabolites detectable by in vivo MR spectroscopy.\",\n      \"method\": \"Knock-in mouse model, RT-qPCR, in vivo MR spectroscopy, transcriptome profiling at pre-symptomatic stages\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse with in vivo metabolic readout and transcriptome analysis; single lab\",\n      \"pmids\": [\"31376479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In an Atxn2-CAG100 knock-in mouse spinal cord, cytosolic ATXN2 aggregates sequester TDP-43 and TIA1 from the nucleus. This is accompanied by elevated CASP3, RIPK1, and PQBP1 protein levels, and progressive downregulation of cholesterol biosynthesis enzymes (Dhcr24, Msmo1, Idi1, Hmgcs1), with gas chromatography confirming loss of cholesterol precursor metabolites.\",\n      \"method\": \"Knock-in mouse model, triple immunofluorescence, immunoblot, RT-qPCR, transcriptome profiling, gas chromatography\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"33577922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATXN2 acts as a strong modifier of PINK1 levels. ATXN2 knockout mouse cerebellum and liver show severe decrease in Pink1 expression alongside effects on Opa1 and Ghitm (mitochondrial dynamics regulators). In human neuroblastoma cells, starvation stress induces ATXN2 and PINK1 in parallel, and knockdown of one enhances expression of the other during stress response.\",\n      \"method\": \"Knockout mouse transcriptome (RNA-seq), RT-qPCR, immunoblot, siRNA knockdown in SH-SY5Y cells, stress induction assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse transcriptome plus in vitro knockdown with reciprocal effects; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27597528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATXN2 augments translation of TNFRSF1A (TNFR1) by binding to m6A-modified TNFRSF1A mRNA, upregulating TNFR1 protein levels and consequently activating NF-κB and MAPK pathways in esophageal squamous cell carcinoma cells.\",\n      \"method\": \"Transcriptome-wide m6A sequencing, RNA immunoprecipitation, functional overexpression/knockdown assays, pathway activation readouts (immunoblot) in ESCC cells\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-seq plus RNA-IP and functional assays; single lab, multiple methods\",\n      \"pmids\": [\"34995801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Repeat-associated non-AUG (RAN) translation occurs for ATXN2 but is weak compared to AUG-dependent translation, does not increase with longer CAG repeat lengths, and is dependent on ATXN2 sequences downstream of the CAG repeat. RAN translation was detected with CMV but not ATXN2 endogenous promoter constructs.\",\n      \"method\": \"Luciferase reporter constructs lacking the ATXN2 AUG start codon, Western blot with anti-polyglutamine antibody, various promoter and truncation constructs in cell culture\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reporter assay with multiple construct variants; single lab\",\n      \"pmids\": [\"26086378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Atxn2 knockout mouse cerebellum shows dysregulation of calcium homeostasis pathway genes including downregulation of Rora, Itpr1, Atp2a2, and Inpp5a. ITPR1 protein accumulates in membrane-associated fractions in the SCA2 CAG42 knock-in model but not in knockout. Co-immunoprecipitation showed no association of ITPR1 with either Q42-expanded or wild-type ATXN2, indicating the effect on calcium signaling is indirect.\",\n      \"method\": \"Knockout and knock-in mouse models, microarray, RT-qPCR, co-immunoprecipitation, subcellular fractionation immunoblot\",\n      \"journal\": \"Cerebellum (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two mouse models, multiple methods; single lab; negative Co-IP result explicitly confirmed\",\n      \"pmids\": [\"26868665\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATXN2 is an RNA-binding protein that associates with polyribosomes and poly(A)-binding protein (PABP) via its Lsm/LsmAD and PAM2 domains to regulate mRNA translation; it selectively binds target mRNAs (e.g., RGS8, Nat8l, TNFR1) to control their translation, interacts with partners including PABP/PABPC1, ZBRK1, FBXW8, and TYF to modulate gene expression and protein homeostasis, participates in stress-responsive regulation of the PINK1/mitochondrial quality control pathway, and contributes to cytokinesis and centrosome size regulation in model organisms, with polyglutamine expansion causing progressive sequestration of PABPC1 and TDP-43 into insolubility, indirect disruption of calcium homeostasis, and cholesterol biosynthesis suppression in neurons.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATXN2 is a cytoplasmic RNA-binding protein that functions in post-transcriptional control by assembling with polyribosomes and poly(A)-binding protein (PABP) to regulate the translation and stability of selected mRNAs [#0]. It engages polyribosomes through two independent conserved elements — an N-terminal Lsm/LsmAD domain that contacts mRNA directly and a PAM2 motif that binds PABP and promotes polyribosome assembly [#0]. Through this machinery ATXN2 acts as a selective translational regulator: it binds and controls specific transcripts including RGS8 [#6], the N-acetylaspartate-synthesis enzyme transcript Nat8l [#14], and m6A-modified TNFRSF1A (TNFR1), the last driving NF-\\u03baB and MAPK activation in esophageal carcinoma cells [#17]. In model organisms it operates within RNA-regulatory complexes — with PAB-1 in the C. elegans germline [#1] and with TWENTY-FOUR (TYF) to activate PER translation in Drosophila circadian neurons by promoting TYF\\u2013PABP interaction [#3]. Beyond translation, ATXN2 has broader roles in cell physiology: it regulates centrosome size, microtubule dynamics and cytokinesis in C. elegans via complexes with SZY-20 and modulation of PAR-5 and \\u03b3-Tubulin [#9, #10], acts as an mTOR repressor downstream of AMPK [#11], and modifies metabolic and mitochondrial-quality-control programs, including parallel stress-induced regulation with PINK1 [#16] and lipid metabolism [#4]. ATXN2 expression is autoregulated and transcription-factor controlled, serving as a ZBRK1 co-activator on its own promoter [#7] and requiring ETS1 for expression [#8]. CAG-repeat (polyglutamine) expansion in ATXN2 causes spinocerebellar ataxia type 2, in which cytoplasmic mutant protein progressively sequesters PABPC1, TDP-43 and TIA1 into insolubility, suppresses cholesterol biosynthesis, and indirectly perturbs calcium homeostasis in neurons [#5, #12, #15, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing where mutant ataxin-2 acts addressed whether polyQ pathology required nuclear inclusions, as for other polyQ diseases; it showed SCA2 pathology is cytoplasmic.\",\n      \"evidence\": \"Immunohistochemistry of human SCA2 brain and transgenic ataxin-2[Q58] mice with neuropathological analysis\",\n      \"pmids\": [\"10973246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the molecular target whose disruption kills Purkinje cells\", \"Mechanism linking cytoplasmic microaggregates to dendritic loss unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The first physiological role was defined by showing the ortholog complexes with PABP to control germline translation, framing ATXN2 as a translational regulator rather than a structural protein.\",\n      \"evidence\": \"Co-IP and genetic loss-of-function with germline phenotyping in C. elegans\",\n      \"pmids\": [\"15342467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mRNA targets not identified\", \"Whether the human ortholog uses the same KH-protein circuitry untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The molecular basis of ATXN2's translational function was mapped, showing two separable domains tether it to polyribosomes and PABP — defining how it accesses mRNA.\",\n      \"evidence\": \"Polyribosome sedimentation, Co-IP, and domain mutagenesis in Drosophila and human cells\",\n      \"pmids\": [\"16835262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence specificity of Lsm/LsmAD mRNA binding undefined\", \"Does not show whether binding activates or represses translation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery of ZBRK1 partnership revealed a feedback loop in which ATXN2 co-activates its own transcription, addressing how ATXN2 levels are set.\",\n      \"evidence\": \"Co-IP, ChIP, luciferase promoter assays with knockdown/overexpression in cell culture\",\n      \"pmids\": [\"20926453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of autoregulation in neurons untested\", \"Single lab, no in vivo confirmation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying ETS1 as a required transcriptional activator extended ATXN2 expression control and resolved which start codon is functional.\",\n      \"evidence\": \"EMSA, ChIP-PCR, promoter luciferase deletions, transgenic mice, shRNA\",\n      \"pmids\": [\"22914732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue/context dependence of ETS1 regulation unclear\", \"Upstream signals controlling ETS1 at the ATXN2 promoter unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking expansion to PABPC1 loss and FBXW8 induction connected polyQ ATXN2 to disrupted RNA-binding partner availability and to a candidate clearance route.\",\n      \"evidence\": \"CAG42 knock-in mouse, soluble/insoluble fractionation, in vitro FBXW8 degradation assay\",\n      \"pmids\": [\"22956915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PABPC1 sequestration is the proximal cause of toxicity untested\", \"FBXW8's role only partial in vitro\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"RNA-IP identification of RGS8 as a selective target provided direct evidence that ATXN2 controls specific mRNA translation and that expansion impairs this function.\",\n      \"evidence\": \"RNA-IP, deep RNA-seq, in vitro coupled translation, BAC transgenic mice\",\n      \"pmids\": [\"25902068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recognition determinants on RGS8 mRNA not mapped\", \"Whether RGS8 loss drives the neuronal phenotype not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reciprocal Co-IP placed ATXN2 in a complex with FBXW8 and PARK2 and showed expansion co-sequesters these partners, extending the aggregation pathology to ubiquitin-pathway components.\",\n      \"evidence\": \"In vitro and in vivo Co-IP, fractionation immunoblot, qPCR in patient fibroblasts/blood\",\n      \"pmids\": [\"25790475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FBXW8-mediated degradation is functionally protective in vivo untested\", \"Stoichiometry of co-sequestration unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Testing repeat-associated non-AUG translation clarified that RAN products are a minor, length-independent contributor relative to canonical ATXN2 translation.\",\n      \"evidence\": \"Luciferase reporters lacking the AUG, anti-polyQ Western, promoter/truncation variants in cells\",\n      \"pmids\": [\"26086378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reporter only; endogenous RAN product abundance in patient tissue not measured\", \"Pathological contribution untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"C. elegans studies defined a cell-division role, showing ATX-2 complexes with SZY-20 and controls centrosome size, microtubule dynamics, and ZEN-4 midzone targeting via PAR-5.\",\n      \"evidence\": \"RNA-independent Co-IP, RNAi, live imaging, genetic epistasis in C. elegans embryos\",\n      \"pmids\": [\"27689799\", \"27559134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mammalian ATXN2 performs an analogous mitotic function untested\", \"Molecular link between RNA-regulatory and centrosomal roles unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic placement of ATX-2 as an mTOR repressor downstream of AMPK connected ATXN2 to nutrient-sensing and cell-size/fat control.\",\n      \"evidence\": \"RNAi, overexpression, pathway epistasis, direct interaction assay with Rab-GDI\\u03b2 in C. elegans\",\n      \"pmids\": [\"27457958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RHEB-shuttling mechanism inferred, not directly demonstrated\", \"Conservation in mammals not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Loss-of-function transcriptomics revealed ATXN2 as a modifier of PINK1 and calcium-homeostasis genes, broadening its role to mitochondrial quality control and stress signaling.\",\n      \"evidence\": \"KO mouse RNA-seq/qPCR/immunoblot, SH-SY5Y siRNA and starvation stress; two mouse models with negative ITPR1 Co-IP\",\n      \"pmids\": [\"27597528\", \"26868665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PINK1 regulation is transcriptional or translational unresolved\", \"Calcium-gene effects shown to be indirect; intermediary unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pre-symptomatic Nat8l downregulation in CAG100 knock-in mice linked ATXN2 dysfunction to an early, in-vivo-measurable metabolic deficit.\",\n      \"evidence\": \"CAG100 knock-in mouse, RT-qPCR, in vivo MR spectroscopy, transcriptome profiling\",\n      \"pmids\": [\"31376479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of ATXN2 to Nat8l mRNA not demonstrated here\", \"Causal contribution of NAA loss to disease untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Spinal-cord analysis showed mutant ATXN2 aggregates sequester TDP-43 and TIA1 and suppress cholesterol biosynthesis, tying SCA2 to ALS-related RNA pathology and lipid metabolism.\",\n      \"evidence\": \"CAG100 knock-in mouse, triple immunofluorescence, immunoblot, RT-qPCR, gas chromatography\",\n      \"pmids\": [\"33577922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order of events between sequestration and cholesterol loss unresolved\", \"Whether cholesterol restoration is protective untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of m6A-modified TNFRSF1A as a target connected ATXN2 translational activation to inflammatory NF-\\u03baB/MAPK signaling in cancer cells.\",\n      \"evidence\": \"m6A-seq, RNA-IP, overexpression/knockdown, pathway immunoblots in ESCC cells\",\n      \"pmids\": [\"34995801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m6A recognition is direct or via a reader untested\", \"Relevance to neuronal ATXN2 function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ATXN2's sequence-specific mRNA selection works mechanistically and how its diverse cellular roles (translation, centrosome/cytokinesis, mTOR, mitochondrial QC) are coordinated by a single protein.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of target-mRNA recognition by the Lsm/LsmAD domain\", \"Unifying biochemical logic across translational and non-translational roles undefined\", \"Proximal toxic species in polyQ expansion not pinpointed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6, 14, 17]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 3, 6, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 6, 17]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"ATXN2-PABP polyribosome complex\"],\n    \"partners\": [\"PABPC1\", \"ZBRK1\", \"FBXW8\", \"PARK2\", \"SZY-20\", \"TYF\", \"TDP-43\", \"TIA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}