{"gene":"ATXN7","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2001,"finding":"Ataxin-7 physically interacts with the cone-rod homeobox protein CRX, as demonstrated by yeast two-hybrid assay and co-immunoprecipitation; polyglutamine-expanded ataxin-7 colocalizes with CRX and dramatically suppresses CRX transactivation activity, leading to reduced CRX DNA-binding activity and decreased expression of CRX-regulated photoreceptor genes in SCA7 transgenic mice.","method":"Yeast two-hybrid, co-immunoprecipitation, electrophoretic mobility shift assay, RT-PCR, transgenic mouse model","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, yeast two-hybrid, EMSA functional assay, and in vivo transgenic mouse data, multiple orthogonal methods in one study","pmids":["11580893"],"is_preprint":false},{"year":2009,"finding":"Yeast Sgf73 (ortholog of human ATXN7) is required to recruit the histone deubiquitination module (DUBm) into both the SAGA and Slik(SALSA) HAT complexes, and loss of Sgf73 impairs histone H2B deubiquitination and regulation of transcription at multiple genes.","method":"Genetic deletion, complex fractionation, histone modification assays, biochemical reconstitution studies in yeast","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast genetic deletion with histone modification readout, demonstrated in two separate complexes (SAGA and SLIK), replicated by multiple subsequent studies","pmids":["19226466"],"is_preprint":false},{"year":2014,"finding":"Sgf73 point mutations (yeast ATXN7 ortholog) that disrupt DUBm deubiquitinating activity do so by impairing the ubiquitin-binding fingers region of Ubp8 and destabilizing overall DUBm folding, demonstrating that Sgf73 maintains the organization and ubiquitin-binding conformation of the catalytic subunit Ubp8.","method":"X-ray crystallography, solution studies, site-directed mutagenesis, deubiquitinating activity assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination combined with mutagenesis and in vitro activity assays in a single rigorous study","pmids":["25526805"],"is_preprint":false},{"year":2010,"finding":"The N-terminal zinc finger motif of yeast Sgf73 (residues 1-104) requires a zinc ion to maintain stable folding and conformation, as demonstrated by NMR backbone assignment, secondary structure analysis, and circular dichroism after zinc chelation with EDTA.","method":"Solution NMR, circular dichroism, zinc chelation with EDTA","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro structural NMR with zinc removal, single lab, single study","pmids":["20510875"],"is_preprint":false},{"year":2013,"finding":"C-terminus of yeast Sgf73 (residues 373-402) is essential for heterochromatin boundary function, and this boundary function depends on the HAT module components Ada2, Ada3, and Gcn5 of the SAGA/SLIK complex, but is independent of the deubiquitinase-anchoring domain of Sgf73.","method":"Domain deletion analysis, boundary function assays, genetic deletion of SAGA subunits in yeast","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis with defined phenotypic readout (boundary function), single lab","pmids":["23819448"],"is_preprint":false},{"year":2015,"finding":"In fission yeast, Sgf73 (ATXN7 ortholog) is physically associated with Ago1 and Chp1 subunits of the RITS complex and is required for RITS complex assembly, pericentromeric heterochromatin silencing, and siRNA generation; this function is independent of SAGA enzymatic activities or structural integrity.","method":"Co-immunoprecipitation, genetic deletion, chromatin immunoprecipitation, siRNA quantification in fission yeast","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and genetic epistasis with functional chromatin readout, single lab, two orthogonal methods","pmids":["26443059"],"is_preprint":false},{"year":2015,"finding":"Proteolytic cleavage of ataxin-7 by caspase-7 at residue D266 is a critical mediator of SCA7 neurotoxicity in vivo; transgenic mice expressing caspase-7-resistant ataxin-7 (D266N mutation) show improved motor performance, reduced neurodegeneration, and substantial lifespan extension compared to SCA7 mice without the D266N mutation.","method":"Transgenic mouse model with site-directed caspase cleavage-site mutation (D266N), behavioral testing, neuropathology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mutagenesis of cleavage site with multiple functional readouts (motor behavior, neurodegeneration, lifespan), single lab, multiple orthogonal phenotypic measures","pmids":["25859008"],"is_preprint":false},{"year":2019,"finding":"Endogenous ATXN7 and polyQ-expanded ATXN7 are modified by SUMO2/3; RNF4 (a SUMO-targeted ubiquitin ligase) is recruited by SUMO2/3-modified polyQ-ATXN7, leading to its polyubiquitination and proteasomal degradation. Overexpression of RNF4 and/or SUMO2 significantly decreased levels of polyQ-ATXN7, and SUMO2/3 co-localizes with polyQ-ATXN7 inclusions in SCA7 knock-in mouse cerebellum and retina.","method":"Co-immunoprecipitation, immunofluorescence, proximity ligation assay, proteasome inhibition, overexpression studies, SCA7 knock-in mouse model, immunohistochemistry","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, PLA, immunofluorescence, functional overexpression), validated in both cell models and knock-in mouse, confirmed in patient tissue","pmids":["30559154"],"is_preprint":false},{"year":2023,"finding":"Yeast Sgf73 (ATXN7 ortholog) undergoes ubiquitylation and proteasomal degradation; impaired Sgf73 degradation increases its abundance, enhances TBP recruitment to promoters but impairs transcription elongation, while decreased Sgf73 reduces PIC formation. Similarly, human ataxin-7 undergoes ubiquitylation and proteasomal degradation, alteration of which changes ataxin-7 abundance and is associated with altered transcription.","method":"Ubiquitylation assays, proteasome inhibition, chromatin immunoprecipitation, transcription assays in yeast and mammalian cells","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — demonstrated in both yeast and mammalian cells with multiple biochemical methods, single lab","pmids":["37075097"],"is_preprint":false},{"year":2012,"finding":"Polyglutamine-expanded ATXN7 (mutant) decreases ATXN7 occupancy at the reelin promoter, which correlates with increased histone H2B monoubiquitination at that locus, reducing reelin transcription in human SCA7 astrocytes. TSA treatment partially restores reelin transcription.","method":"Human astrocyte cell culture model, chromatin immunoprecipitation, histone modification analysis, pharmacological treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with histone modification readout and functional rescue, human astrocyte model, single lab","pmids":["23236151"],"is_preprint":false},{"year":2011,"finding":"Reducing Gcn5 expression (the HAT catalytic subunit of SAGA) accelerates both cerebellar and retinal degeneration in SCA7 mice, demonstrating that Gcn5 HAT activity within the SAGA complex in which ATXN7 resides contributes to SCA7 disease onset and severity; however, Gcn5 depletion does not further alter known ATXN7 transcriptional targets, suggesting non-transcriptional SAGA functions are involved.","method":"Genetic epistasis in transgenic/conditional knockout mouse, behavioral testing, neuropathological analysis, gene expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with multiple phenotypic readouts, single lab","pmids":["22002997"],"is_preprint":false},{"year":2013,"finding":"STAGA complex (containing ATXN7) is required for transcription initiation of miR-124, which post-transcriptionally regulates ATXN7 mRNA via cross-talk with lnc-SCA7; polyQ expansion in ATXN7 disrupts this regulatory feedback, resulting in neuron-specific increases in ATXN7 expression most prominent in disease-relevant tissues (retina and cerebellum).","method":"STAGA ChIP, miRNA expression analysis, lncRNA functional experiments, SCA7 patient and mouse tissue analysis","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for STAGA occupancy, miRNA and lncRNA functional assays, validated in mouse models, single lab","pmids":["25306109"],"is_preprint":false},{"year":2001,"finding":"Mutant ataxin-7 undergoes cytoplasm-to-nucleus translocation and accumulates as N-terminal fragments in neuronal nuclei in SCA7 transgenic mice; mouse TAFII30 (a subunit of TFIID) is markedly sequestered into nuclear inclusions; mutant ataxin-7 is selectively stabilized at the protein level relative to wild-type, as evidenced by discrepancy between mRNA and protein levels in transgenic mice expressing mutant but not wild-type ataxin-7.","method":"Transgenic mouse models, immunohistochemistry, confocal microscopy, western blotting, comparative analysis of mRNA vs. protein levels","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mouse models with immunohistochemistry and protein/mRNA comparison, single lab","pmids":["11487572"],"is_preprint":false},{"year":2006,"finding":"Polyglutamine-expanded ataxin-7 in rod photoreceptors activates the JNK/c-Jun stress pathway; genetic prevention of c-Jun activation (JunAA knock-in) improves SCA7 retinopathy and partially restores expression of rod-specific genes including the transcription factor Nrl and its downstream phototransduction targets. c-Jun directly represses Nrl transcription.","method":"Genetic epistasis (JunAA knock-in × SCA7 transgenic mice), gene expression analysis, transcriptional reporter assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with functional gene expression rescue, single lab, two complementary methods","pmids":["17189700"],"is_preprint":false},{"year":2013,"finding":"Interferon-beta induces PML protein expression and PML nuclear body formation, which mediates clearance of mutant ataxin-7 from neuronal intranuclear inclusions in SCA7 knock-in mice; this is accompanied by improved motor function on behavioral tests and improved Purkinje cell survival in cell culture.","method":"SCA7 knock-in mouse model, IFN-β treatment, immunohistochemistry, behavioral testing (Locotronic, Beam Walking), primary cell culture","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological intervention with cellular and behavioral readouts, validated in patient tissue, single lab","pmids":["23518714"],"is_preprint":false},{"year":2013,"finding":"Mutant ATXN7 inhibits autophagy via a p53-mediated mechanism: increased p53-FIP200 interaction and co-aggregation of p53 and FIP200 into ATXN7 aggregates decreases soluble FIP200, destabilizing ULK1 and reducing capacity for autophagy induction through the ULK1-FIP200-Atg13-Atg101 complex. p53 inhibitor treatment or blocking ATXN7 aggregation restores FIP200/ULK1 levels and increases autophagic activity.","method":"Co-immunoprecipitation, co-aggregation assays, western blotting, pharmacological rescue (p53 inhibitor, aggregation blocker), autophagy flux assays in stable inducible SCA7 cell model","journal":"Journal of molecular neuroscience : MN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, co-aggregation, and pharmacological rescue with multiple readouts, single lab","pmids":["23592174"],"is_preprint":false},{"year":2012,"finding":"Polyglutamine-expanded ATXN7 induces reactive oxygen species (ROS) production from NADPH oxidase (NOX) complexes; NOX inhibition completely prevents the ROS increase, and both antioxidant treatment and NOX inhibition reduce ATXN7 aggregation and toxicity. Mutant ATXN7 also decreases catalase levels, contributing to oxidative stress.","method":"Stable inducible SCA7 cell model, ROS measurement, NOX inhibitor treatment, antioxidant treatment, aggregation assays, cell viability assays","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological intervention with mechanistic specificity, multiple readouts, single lab","pmids":["22827889"],"is_preprint":false},{"year":2015,"finding":"Mutant ATXN7 causes bioenergetic defects through disruption of p53 and NOX1 activity: p53 co-aggregates with mutant ATXN7 reducing its transcriptional activity (50% decrease in AIF and TIGAR), while NOX1 expression increases ~2-fold, collectively resulting in decreased respiratory capacity, increased glycolytic reliance, and 20% reduction in ATP. Restoring p53 function or suppressing NOX1 activity reverses metabolic dysfunction.","method":"Stable inducible SCA7 PC12 cell model, co-aggregation assays, p53 transcriptional reporter assays, metabolic flux analysis, pharmacological rescue","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-aggregation with transcriptional readouts and metabolic measurements, pharmacological rescue, single lab","pmids":["25647692"],"is_preprint":false},{"year":2010,"finding":"Ataxin-7 physically interacts with APLP2 (amyloid precursor-like protein 2); caspase-3-mediated cleavage of APLP2 generates intracellular C-terminal domains that translocate to the nucleus, and abnormal nuclear relocation of APLP2 N-terminal fragments is detected in SCA7 neuronal intranuclear inclusions. Co-expression of APLP2 ICDs with mutant ataxin-7 causes cumulative cytotoxicity.","method":"Yeast two-hybrid (interaction identification), immunohistochemistry in SCA7 brain tissue, co-expression toxicity assays in cells","journal":"Neurobiology of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction identified by yeast two-hybrid with partial cell-based follow-up, single lab","pmids":["20732423"],"is_preprint":false},{"year":2011,"finding":"In SCA7 rod photoreceptor nuclei, the amount of linker histone H1c is strongly reduced and its distribution in facultative heterochromatin is altered, accompanied by fragmentation and decondensation of the most external heterochromatin ring. Acetylated histones H3 and H4 are unchanged in nuclear extracts.","method":"Immunogold labeling, stereology, electron tomography, western blotting of nuclear extracts from SCA7 mouse retinas","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation and ultrastructural localization with quantitative comparison between wild-type and SCA7 mice, single lab","pmids":["21970987"],"is_preprint":false},{"year":2019,"finding":"Loss-of-function of ATXN7 in zebrafish causes ocular coloboma by elevating Hedgehog signaling in the forebrain, altering proximo-distal patterning of the optic vesicle; at later stages, photoreceptor outer segment formation is incomplete, correlating with altered expression of crx. This demonstrates ATXN7 plays an essential role in vertebrate eye morphogenesis and photoreceptor differentiation.","method":"Zebrafish ATXN7 knockdown/knockout, in situ hybridization, Hedgehog pathway analysis, photoreceptor morphology analysis, crx expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway placement (Hedgehog signaling), validated in zebrafish model, single lab","pmids":["30445451"],"is_preprint":false},{"year":2012,"finding":"In a stable inducible SCA7 cell model, the ubiquitin-proteasome system (UPS) is essential for degradation of full-length ATXN7 (both normal and expanded), whereas cleaved ATXN7 fragments are degraded by both UPS and autophagy. Inhibition of either pathway worsens mutant ATXN7 toxicity; pharmacological autophagy activation ameliorates toxicity.","method":"Stable inducible PC12 and HEK293T cell models, proteasome inhibition, autophagy inhibition/activation, western blotting, cell viability assays","journal":"Journal of molecular neuroscience : MN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — differential degradation pathways established by pharmacological inhibition with multiple protein forms tested, single lab","pmids":["22367614"],"is_preprint":false},{"year":2002,"finding":"Ataxin-7 expression is primarily nuclear in most brain regions studied; in cerebellar Purkinje cells, differences in subcellular distribution were observed between SCA7 patients and controls of different ages, suggesting disease-related redistribution.","method":"Immunohistochemistry of CNS and non-CNS tissue from SCA7 patients and controls, subcellular localization analysis","journal":"Acta neuropathologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — immunohistochemistry without direct functional consequence established, single compilation study","pmids":["12070661"],"is_preprint":false},{"year":2005,"finding":"An alternative ataxin-7 isoform (ataxin-7b), generated by inclusion of exon 12b causing a frameshift and novel 58-amino acid C-terminus, localizes to a more cytoplasmic location compared to the canonical nuclear ataxin-7a isoform.","method":"Northern blot, quantitative RT-PCR, subcellular localization analysis in transfected cells","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — subcellular localization by overexpression without direct functional consequence, single lab","pmids":["16297465"],"is_preprint":false},{"year":2022,"finding":"TDP-43 and TIA1 are sequestered into aggregates formed by polyQ-expanded ATXN7 in SCA7 cells; mutant ATXN7 also localizes to stress granules induced by arsenite and alters their shape; mutant ATXN7 expression increases speckling of stress granule-nucleating protein G3BP1. The dynamics of stress granule assembly and disassembly are not significantly impaired in SCA7 cells.","method":"Immunofluorescence, filter trap assay, arsenite-induced stress granule assay, stable SCA7 cell model","journal":"Molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization by immunofluorescence, single lab, limited mechanistic follow-up","pmids":["35689166"],"is_preprint":false}],"current_model":"ATXN7 is a subunit of the SAGA/STAGA transcriptional coactivator complex where its yeast ortholog Sgf73 anchors the histone H2B deubiquitination module (DUBm) by maintaining the active conformation of the catalytic subunit Ubp8 through its zinc finger domain; polyglutamine expansion in ATXN7 impairs these transcriptional coactivator functions—including suppression of CRX-dependent photoreceptor gene expression, reduced occupancy at target gene promoters with concomitant increases in H2B ubiquitination, and disruption of noncoding RNA-mediated feedback regulation—while also causing gain-of-toxic-function through caspase-7 cleavage at D266, SUMO2/RNF4-mediated proteasomal clearance of misfolded protein, autophagy impairment via p53-FIP200-ULK1 disruption, and NADPH oxidase-dependent oxidative stress, collectively resulting in selective neurodegeneration of cerebellar Purkinje cells and retinal photoreceptors."},"narrative":{"mechanistic_narrative":"ATXN7 is a subunit of the SAGA/STAGA transcriptional coactivator complex that anchors the histone H2B deubiquitination module (DUBm), and through this role governs chromatin organization and photoreceptor/neuronal gene programs [PMID:19226466, PMID:25306109]. Its yeast ortholog Sgf73 is required to recruit the DUBm into the SAGA and SLIK HAT complexes, and an N-terminal zinc-finger domain maintains the active, ubiquitin-binding conformation of the catalytic deubiquitinase Ubp8 [PMID:19226466, PMID:25526805, PMID:20510875]. ATXN7 binds the cone-rod homeobox factor CRX and is required for normal photoreceptor gene expression, and its loss in vertebrates causes eye morphogenesis defects through elevated Hedgehog signaling and altered crx expression [PMID:11580893, PMID:30445451]. Distinct domains of Sgf73 mediate SAGA-independent functions including heterochromatin boundary activity and assembly of the RNAi/RITS silencing complex [PMID:23819448, PMID:26443059]. ATXN7 abundance is itself controlled by ubiquitin-proteasome degradation, which feeds back on transcription, and by a STAGA-dependent miR-124/lnc-SCA7 regulatory loop [PMID:30559154, PMID:37075097, PMID:25306109]. Polyglutamine expansion in ATXN7 produces both loss of these coactivator functions—reduced promoter occupancy with increased local H2B ubiquitination—and a gain of toxic function: caspase-7 cleavage at D266 is a critical in vivo driver of neurotoxicity, while SUMO2/3-RNF4-mediated clearance, autophagy impairment via a p53-FIP200-ULK1 axis, and NADPH oxidase-dependent oxidative and bioenergetic stress collectively produce selective degeneration of cerebellar Purkinje cells and retinal photoreceptors [PMID:25859008, PMID:30559154, PMID:23236151, PMID:23592174, PMID:22827889, PMID:25647692]. Mutations in ATXN7 cause spinocerebellar ataxia type 7 (SCA7) [PMID:25859008].","teleology":[{"year":2001,"claim":"Established a direct molecular link between ataxin-7 and the photoreceptor transcription factor CRX, explaining why polyQ expansion selectively perturbs retinal gene expression.","evidence":"Yeast two-hybrid, co-IP, EMSA, and SCA7 transgenic mice","pmids":["11580893"],"confidence":"High","gaps":["Did not place ataxin-7 within the SAGA complex","Mechanism of CRX transactivation suppression beyond reduced DNA binding unresolved"]},{"year":2001,"claim":"Showed that mutant ataxin-7 mislocalizes to neuronal nuclei as N-terminal fragments, sequesters the TFIID subunit TAFII30, and is selectively stabilized, framing SCA7 as a problem of toxic nuclear accumulation.","evidence":"Transgenic mouse immunohistochemistry, confocal microscopy, mRNA vs protein comparison","pmids":["11487572"],"confidence":"Medium","gaps":["Functional consequence of TAFII30 sequestration not measured","Identity of the protease generating N-terminal fragments unknown at this point"]},{"year":2009,"claim":"Defined the conserved core function of the ATXN7 ortholog Sgf73 as the anchor recruiting the H2B deubiquitination module into SAGA/SLIK complexes.","evidence":"Yeast genetic deletion, complex fractionation, histone modification assays","pmids":["19226466"],"confidence":"High","gaps":["Whether human ATXN7 anchors the DUBm identically not directly shown here","Specific genes whose H2B-ub state is controlled in mammals not defined"]},{"year":2010,"claim":"Determined that an N-terminal zinc-finger of Sgf73 requires a zinc ion for stable folding, identifying the structural basis of the anchoring domain.","evidence":"Solution NMR, circular dichroism, EDTA zinc chelation","pmids":["20510875"],"confidence":"Medium","gaps":["Single in vitro study","Did not test the domain's anchoring function directly"]},{"year":2010,"claim":"Reported a physical interaction between ataxin-7 and APLP2 whose cleavage fragments contribute cumulative cytotoxicity in SCA7.","evidence":"Yeast two-hybrid, SCA7 brain immunohistochemistry, cell co-expression toxicity assays","pmids":["20732423"],"confidence":"Low","gaps":["Interaction identified by yeast two-hybrid with limited orthogonal validation","Physiological relevance to neurodegeneration unestablished"]},{"year":2011,"claim":"Linked SAGA HAT activity to disease by showing Gcn5 reduction accelerates SCA7 degeneration, while implicating non-transcriptional SAGA functions.","evidence":"Genetic epistasis in SCA7 mice, behavior, neuropathology, expression analysis","pmids":["22002997"],"confidence":"Medium","gaps":["Nature of the non-transcriptional SAGA functions undefined","Mechanism connecting Gcn5 loss to faster degeneration unknown"]},{"year":2011,"claim":"Documented altered linker histone H1c and heterochromatin ultrastructure in SCA7 photoreceptors, tying ATXN7 dysfunction to chromatin architecture.","evidence":"Immunogold, electron tomography, stereology, nuclear extract western blots from SCA7 retinas","pmids":["21970987"],"confidence":"Medium","gaps":["Causal mechanism linking ATXN7 to H1c loss not established","Functional readout for the decondensation phenotype absent"]},{"year":2012,"claim":"Connected loss of ATXN7 promoter occupancy to increased local H2B monoubiquitination and reduced target (reelin) transcription in human SCA7 cells, providing direct evidence of impaired DUBm function in disease.","evidence":"Human astrocyte ChIP, histone modification analysis, TSA rescue","pmids":["23236151"],"confidence":"Medium","gaps":["Single target locus examined","Whether DUBm catalytic disruption is general across SCA7 genes unknown"]},{"year":2012,"claim":"Showed polyQ-ATXN7 drives NADPH oxidase-dependent ROS and lowers catalase, implicating oxidative stress as a toxicity pathway amenable to pharmacological reversal.","evidence":"Inducible SCA7 cell model, ROS assays, NOX inhibitor and antioxidant treatment","pmids":["22827889"],"confidence":"Medium","gaps":["Mechanism linking ATXN7 to NOX activation unknown","In vivo validation absent"]},{"year":2012,"claim":"Established that full-length ATXN7 is cleared by the proteasome while cleaved fragments use both proteasome and autophagy, and that autophagy activation reduces toxicity.","evidence":"Inducible PC12/HEK293T models, proteasome and autophagy inhibition/activation","pmids":["22367614"],"confidence":"Medium","gaps":["E3 ligases not identified in this study","In vivo degradation routes not tested"]},{"year":2013,"claim":"Identified a JNK/c-Jun stress pathway repressing Nrl as a driver of SCA7 retinopathy, since blocking c-Jun activation rescues rod gene expression.","evidence":"JunAA knock-in × SCA7 mice genetic epistasis, expression analysis, reporter assays","pmids":["17189700"],"confidence":"Medium","gaps":["How polyQ-ATXN7 activates JNK/c-Jun unresolved","Relevance to cerebellar degeneration untested"]},{"year":2013,"claim":"Defined a p53-dependent autophagy block in which p53 and FIP200 co-aggregate with ATXN7, destabilizing ULK1 and impairing autophagy induction.","evidence":"Co-IP, co-aggregation, autophagy flux assays, p53 inhibitor and aggregation-blocker rescue","pmids":["23592174"],"confidence":"Medium","gaps":["In vivo confirmation lacking","Stoichiometry of FIP200 sequestration not quantified"]},{"year":2013,"claim":"Showed IFN-β-induced PML nuclear bodies clear mutant ataxin-7 inclusions and improve motor function and Purkinje survival, suggesting a clearance-based therapeutic route.","evidence":"SCA7 knock-in mice, IFN-β treatment, immunohistochemistry, behavior, primary culture","pmids":["23518714"],"confidence":"Medium","gaps":["Molecular mechanism of PML-mediated clearance not dissected","Long-term efficacy unknown"]},{"year":2013,"claim":"Revealed a STAGA-dependent miR-124/lnc-SCA7 feedback loop controlling ATXN7 mRNA whose disruption by polyQ expansion causes tissue-specific ATXN7 accumulation.","evidence":"STAGA ChIP, miRNA/lncRNA functional assays, SCA7 patient and mouse tissue","pmids":["25306109"],"confidence":"Medium","gaps":["Quantitative contribution of the feedback loop to disease selectivity unclear","Conservation across cell types not fully mapped"]},{"year":2014,"claim":"Provided the structural mechanism by which Sgf73 maintains the ubiquitin-binding conformation and folding of the catalytic subunit Ubp8 within the DUBm.","evidence":"X-ray crystallography, mutagenesis, deubiquitinating activity assays","pmids":["25526805"],"confidence":"High","gaps":["Human ATXN7-USP22 module not crystallized here","Effect of polyQ tract on DUBm structure not addressed"]},{"year":2015,"claim":"Demonstrated that caspase-7 cleavage of ataxin-7 at D266 is a critical in vivo neurotoxicity event, since a cleavage-resistant mutant improves motor function and lifespan.","evidence":"D266N knock-in SCA7 mice, behavior, neuropathology","pmids":["25859008"],"confidence":"High","gaps":["What activates caspase-7 in SCA7 neurons unknown","Toxic species generated by the fragment not fully characterized"]},{"year":2015,"claim":"Extended SAGA-independent roles of Sgf73 to the RNAi machinery, showing it associates with Ago1/Chp1 and is required for RITS assembly and heterochromatin silencing.","evidence":"Fission yeast co-IP, genetic deletion, ChIP, siRNA quantification","pmids":["26443059"],"confidence":"Medium","gaps":["Whether human ATXN7 has an analogous RNAi role untested","Independence from SAGA shown in one organism only"]},{"year":2015,"claim":"Tied p53 sequestration and NOX1 upregulation to bioenergetic failure in SCA7 cells, linking transcriptional and metabolic dysfunction.","evidence":"Inducible SCA7 PC12 cells, co-aggregation, p53 reporter, metabolic flux, pharmacological rescue","pmids":["25647692"],"confidence":"Medium","gaps":["In vivo metabolic phenotype not confirmed","Causal order of p53 and NOX1 effects unclear"]},{"year":2019,"claim":"Identified SUMO2/3-RNF4 as a SUMO-targeted ubiquitin ligase pathway that ubiquitinates and degrades polyQ-ATXN7, defining a clearance route for the toxic protein.","evidence":"Co-IP, PLA, immunofluorescence, proteasome inhibition, overexpression, SCA7 knock-in mouse, patient tissue","pmids":["30559154"],"confidence":"High","gaps":["Therapeutic exploitation of RNF4 not tested in vivo","Why endogenous clearance is insufficient unresolved"]},{"year":2019,"claim":"Defined an essential developmental role for ATXN7 in vertebrate eye morphogenesis and photoreceptor differentiation via restraint of Hedgehog signaling and control of crx.","evidence":"Zebrafish loss-of-function, in situ hybridization, Hedgehog and photoreceptor analysis","pmids":["30445451"],"confidence":"Medium","gaps":["Direct molecular link between ATXN7 and Hedgehog pathway components unknown","Relevance of loss-of-function to polyQ disease unclear"]},{"year":2022,"claim":"Reported sequestration of RNA-binding proteins TDP-43 and TIA1 and altered stress-granule morphology by polyQ-ATXN7, suggesting interplay with RNA metabolism.","evidence":"Immunofluorescence, filter trap, arsenite stress-granule assay, SCA7 cells","pmids":["35689166"],"confidence":"Low","gaps":["Co-localization only, no functional consequence established","Stress granule dynamics not significantly impaired, weakening mechanistic relevance"]},{"year":2023,"claim":"Showed that ubiquitin-proteasome-controlled abundance of Sgf73/ATXN7 tunes PIC formation and transcription elongation, integrating protein turnover with coactivator output.","evidence":"Ubiquitylation assays, proteasome inhibition, ChIP, transcription assays in yeast and mammalian cells","pmids":["37075097"],"confidence":"Medium","gaps":["E3 ligase for normal ATXN7 turnover not pinned down","Single lab; physiological context of elongation effect in neurons untested"]},{"year":null,"claim":"How polyQ expansion mechanistically converts coactivator loss-of-function into the specific combination of caspase cleavage, impaired clearance, and oxidative/metabolic stress that selectively kills Purkinje cells and photoreceptors remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking transcriptional dysfunction to the multiple toxic pathways","Basis of cell-type selectivity not fully explained","Human DUBm structure with polyQ tract uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,9,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,22]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,9,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,5,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,21]}],"complexes":["SAGA/STAGA","histone deubiquitination module (DUBm)","SLIK/SALSA HAT complex","RITS complex"],"partners":["CRX","USP22/UBP8","GCN5","RNF4","SUMO2","FIP200","TP53","APLP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15265","full_name":"Ataxin-7","aliases":["Spinocerebellar ataxia type 7 protein"],"length_aa":892,"mass_kda":95.5,"function":"Acts as a component of the SAGA (aka STAGA) transcription coactivator-HAT complex (PubMed:15932940, PubMed:18206972). Mediates the interaction of SAGA complex with the CRX and is involved in CRX-dependent gene activation (PubMed:15932940, PubMed:18206972). Probably involved in tethering the deubiquitination module within the SAGA complex (PubMed:24493646). Necessary for microtubule cytoskeleton stabilization (PubMed:22100762). 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Advances in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/25643591","citation_count":7,"is_preprint":false},{"pmid":"37214832","id":"PMC_37214832","title":"Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37214832","citation_count":6,"is_preprint":false},{"pmid":"23100044","id":"PMC_23100044","title":"Genetic variation in ataxia gene ATXN7 influences cerebellar grey matter volume in healthy adults.","date":"2013","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23100044","citation_count":6,"is_preprint":false},{"pmid":"26992556","id":"PMC_26992556","title":"Voice Alterations in Patients With Spinocerebellar Ataxia Type 7 (SCA7): Clinical-Genetic Correlations.","date":"2016","source":"Journal of voice : official journal of the Voice Foundation","url":"https://pubmed.ncbi.nlm.nih.gov/26992556","citation_count":6,"is_preprint":false},{"pmid":"20510875","id":"PMC_20510875","title":"Solution NMR characterization of Sgf73(1-104) indicates that Zn ion is required to stabilize zinc finger motif.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20510875","citation_count":5,"is_preprint":false},{"pmid":"20732423","id":"PMC_20732423","title":"Amyloid precursor-like protein 2 cleavage contributes to neuronal intranuclear inclusions and cytotoxicity in spinocerebellar ataxia-7 (SCA7).","date":"2010","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/20732423","citation_count":5,"is_preprint":false},{"pmid":"34490149","id":"PMC_34490149","title":"Conformation of the Solute-Binding Protein AdcAII Influences Zinc Uptake in Streptococcus pneumoniae.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34490149","citation_count":4,"is_preprint":false},{"pmid":"38637450","id":"PMC_38637450","title":"YTHDC1-Mediated lncRNA MSC-AS1 m6A Modification Potentiates Laryngeal Squamous Cell Carcinoma Development via Repressing ATXN7 Transcription.","date":"2024","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38637450","citation_count":4,"is_preprint":false},{"pmid":"34012225","id":"PMC_34012225","title":"Clinical characterization and the improved molecular diagnosis of autosomal dominant cone-rod dystrophy in patients with SCA7.","date":"2021","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/34012225","citation_count":4,"is_preprint":false},{"pmid":"31202915","id":"PMC_31202915","title":"Loss of function in SAGA deubiquitinating module caused by Sgf73 H93A mutation: A molecular dynamics study.","date":"2019","source":"Journal of molecular graphics & modelling","url":"https://pubmed.ncbi.nlm.nih.gov/31202915","citation_count":3,"is_preprint":false},{"pmid":"38421662","id":"PMC_38421662","title":"ATXN7-Related Cone-Rod Dystrophy: The Integrated Functional Evaluation of the Cerebellum (CERMOI) Study.","date":"2024","source":"JAMA ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/38421662","citation_count":3,"is_preprint":false},{"pmid":"16297465","id":"PMC_16297465","title":"Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice.","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16297465","citation_count":3,"is_preprint":false},{"pmid":"38227598","id":"PMC_38227598","title":"Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38227598","citation_count":2,"is_preprint":false},{"pmid":"39139632","id":"PMC_39139632","title":"The 5HT4R agonist velusetrag efficacy on neuropathic chronic intestinal pseudo-obstruction in PrP-SCA7-92Q transgenic mice.","date":"2024","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39139632","citation_count":2,"is_preprint":false},{"pmid":"30999137","id":"PMC_30999137","title":"A SCA7 premutation may be a novel Mendelian modifier of MS course: A case report.","date":"2019","source":"Multiple sclerosis and related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/30999137","citation_count":2,"is_preprint":false},{"pmid":"25076038","id":"PMC_25076038","title":"Large scale screening of genetic interaction with sgf73(+) in fission yeast.","date":"2014","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/25076038","citation_count":1,"is_preprint":false},{"pmid":"16311960","id":"PMC_16311960","title":"[SCA-7. Cone-rod dystrophy in the context of an hereditary ataxia].","date":"2005","source":"Archivos de la Sociedad Espanola de Oftalmologia","url":"https://pubmed.ncbi.nlm.nih.gov/16311960","citation_count":1,"is_preprint":false},{"pmid":"34870541","id":"PMC_34870541","title":"Amyotrophic lateral sclerosis associated with a pathological expansion in the ATXN7 gene.","date":"2021","source":"Amyotrophic lateral sclerosis & frontotemporal degeneration","url":"https://pubmed.ncbi.nlm.nih.gov/34870541","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.13.669846","title":"Overview of non-coding RNAs with CAG repeats and the case of mutation-containing circRNA in polyglutamine disease patients","date":"2025-08-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.13.669846","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.17.25322412","title":"Unbiased human genomic characterization of polyglutamine disorder genes to guide biological understanding and therapeutic strategies","date":"2025-02-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.17.25322412","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49116,"output_tokens":6312,"usd":0.121014,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15180,"output_tokens":6131,"usd":0.114587,"stage2_stop_reason":"end_turn"},"total_usd":0.235601,"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\": 2001,\n      \"finding\": \"Ataxin-7 physically interacts with the cone-rod homeobox protein CRX, as demonstrated by yeast two-hybrid assay and co-immunoprecipitation; polyglutamine-expanded ataxin-7 colocalizes with CRX and dramatically suppresses CRX transactivation activity, leading to reduced CRX DNA-binding activity and decreased expression of CRX-regulated photoreceptor genes in SCA7 transgenic mice.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, electrophoretic mobility shift assay, RT-PCR, transgenic mouse model\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, yeast two-hybrid, EMSA functional assay, and in vivo transgenic mouse data, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11580893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Sgf73 (ortholog of human ATXN7) is required to recruit the histone deubiquitination module (DUBm) into both the SAGA and Slik(SALSA) HAT complexes, and loss of Sgf73 impairs histone H2B deubiquitination and regulation of transcription at multiple genes.\",\n      \"method\": \"Genetic deletion, complex fractionation, histone modification assays, biochemical reconstitution studies in yeast\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast genetic deletion with histone modification readout, demonstrated in two separate complexes (SAGA and SLIK), replicated by multiple subsequent studies\",\n      \"pmids\": [\"19226466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sgf73 point mutations (yeast ATXN7 ortholog) that disrupt DUBm deubiquitinating activity do so by impairing the ubiquitin-binding fingers region of Ubp8 and destabilizing overall DUBm folding, demonstrating that Sgf73 maintains the organization and ubiquitin-binding conformation of the catalytic subunit Ubp8.\",\n      \"method\": \"X-ray crystallography, solution studies, site-directed mutagenesis, deubiquitinating activity assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination combined with mutagenesis and in vitro activity assays in a single rigorous study\",\n      \"pmids\": [\"25526805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The N-terminal zinc finger motif of yeast Sgf73 (residues 1-104) requires a zinc ion to maintain stable folding and conformation, as demonstrated by NMR backbone assignment, secondary structure analysis, and circular dichroism after zinc chelation with EDTA.\",\n      \"method\": \"Solution NMR, circular dichroism, zinc chelation with EDTA\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro structural NMR with zinc removal, single lab, single study\",\n      \"pmids\": [\"20510875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C-terminus of yeast Sgf73 (residues 373-402) is essential for heterochromatin boundary function, and this boundary function depends on the HAT module components Ada2, Ada3, and Gcn5 of the SAGA/SLIK complex, but is independent of the deubiquitinase-anchoring domain of Sgf73.\",\n      \"method\": \"Domain deletion analysis, boundary function assays, genetic deletion of SAGA subunits in yeast\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis with defined phenotypic readout (boundary function), single lab\",\n      \"pmids\": [\"23819448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In fission yeast, Sgf73 (ATXN7 ortholog) is physically associated with Ago1 and Chp1 subunits of the RITS complex and is required for RITS complex assembly, pericentromeric heterochromatin silencing, and siRNA generation; this function is independent of SAGA enzymatic activities or structural integrity.\",\n      \"method\": \"Co-immunoprecipitation, genetic deletion, chromatin immunoprecipitation, siRNA quantification in fission yeast\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and genetic epistasis with functional chromatin readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"26443059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Proteolytic cleavage of ataxin-7 by caspase-7 at residue D266 is a critical mediator of SCA7 neurotoxicity in vivo; transgenic mice expressing caspase-7-resistant ataxin-7 (D266N mutation) show improved motor performance, reduced neurodegeneration, and substantial lifespan extension compared to SCA7 mice without the D266N mutation.\",\n      \"method\": \"Transgenic mouse model with site-directed caspase cleavage-site mutation (D266N), behavioral testing, neuropathology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mutagenesis of cleavage site with multiple functional readouts (motor behavior, neurodegeneration, lifespan), single lab, multiple orthogonal phenotypic measures\",\n      \"pmids\": [\"25859008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endogenous ATXN7 and polyQ-expanded ATXN7 are modified by SUMO2/3; RNF4 (a SUMO-targeted ubiquitin ligase) is recruited by SUMO2/3-modified polyQ-ATXN7, leading to its polyubiquitination and proteasomal degradation. Overexpression of RNF4 and/or SUMO2 significantly decreased levels of polyQ-ATXN7, and SUMO2/3 co-localizes with polyQ-ATXN7 inclusions in SCA7 knock-in mouse cerebellum and retina.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, proximity ligation assay, proteasome inhibition, overexpression studies, SCA7 knock-in mouse model, immunohistochemistry\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, PLA, immunofluorescence, functional overexpression), validated in both cell models and knock-in mouse, confirmed in patient tissue\",\n      \"pmids\": [\"30559154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Yeast Sgf73 (ATXN7 ortholog) undergoes ubiquitylation and proteasomal degradation; impaired Sgf73 degradation increases its abundance, enhances TBP recruitment to promoters but impairs transcription elongation, while decreased Sgf73 reduces PIC formation. Similarly, human ataxin-7 undergoes ubiquitylation and proteasomal degradation, alteration of which changes ataxin-7 abundance and is associated with altered transcription.\",\n      \"method\": \"Ubiquitylation assays, proteasome inhibition, chromatin immunoprecipitation, transcription assays in yeast and mammalian cells\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — demonstrated in both yeast and mammalian cells with multiple biochemical methods, single lab\",\n      \"pmids\": [\"37075097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Polyglutamine-expanded ATXN7 (mutant) decreases ATXN7 occupancy at the reelin promoter, which correlates with increased histone H2B monoubiquitination at that locus, reducing reelin transcription in human SCA7 astrocytes. TSA treatment partially restores reelin transcription.\",\n      \"method\": \"Human astrocyte cell culture model, chromatin immunoprecipitation, histone modification analysis, pharmacological treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with histone modification readout and functional rescue, human astrocyte model, single lab\",\n      \"pmids\": [\"23236151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Reducing Gcn5 expression (the HAT catalytic subunit of SAGA) accelerates both cerebellar and retinal degeneration in SCA7 mice, demonstrating that Gcn5 HAT activity within the SAGA complex in which ATXN7 resides contributes to SCA7 disease onset and severity; however, Gcn5 depletion does not further alter known ATXN7 transcriptional targets, suggesting non-transcriptional SAGA functions are involved.\",\n      \"method\": \"Genetic epistasis in transgenic/conditional knockout mouse, behavioral testing, neuropathological analysis, gene expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"22002997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STAGA complex (containing ATXN7) is required for transcription initiation of miR-124, which post-transcriptionally regulates ATXN7 mRNA via cross-talk with lnc-SCA7; polyQ expansion in ATXN7 disrupts this regulatory feedback, resulting in neuron-specific increases in ATXN7 expression most prominent in disease-relevant tissues (retina and cerebellum).\",\n      \"method\": \"STAGA ChIP, miRNA expression analysis, lncRNA functional experiments, SCA7 patient and mouse tissue analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for STAGA occupancy, miRNA and lncRNA functional assays, validated in mouse models, single lab\",\n      \"pmids\": [\"25306109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Mutant ataxin-7 undergoes cytoplasm-to-nucleus translocation and accumulates as N-terminal fragments in neuronal nuclei in SCA7 transgenic mice; mouse TAFII30 (a subunit of TFIID) is markedly sequestered into nuclear inclusions; mutant ataxin-7 is selectively stabilized at the protein level relative to wild-type, as evidenced by discrepancy between mRNA and protein levels in transgenic mice expressing mutant but not wild-type ataxin-7.\",\n      \"method\": \"Transgenic mouse models, immunohistochemistry, confocal microscopy, western blotting, comparative analysis of mRNA vs. protein levels\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mouse models with immunohistochemistry and protein/mRNA comparison, single lab\",\n      \"pmids\": [\"11487572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Polyglutamine-expanded ataxin-7 in rod photoreceptors activates the JNK/c-Jun stress pathway; genetic prevention of c-Jun activation (JunAA knock-in) improves SCA7 retinopathy and partially restores expression of rod-specific genes including the transcription factor Nrl and its downstream phototransduction targets. c-Jun directly represses Nrl transcription.\",\n      \"method\": \"Genetic epistasis (JunAA knock-in × SCA7 transgenic mice), gene expression analysis, transcriptional reporter assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with functional gene expression rescue, single lab, two complementary methods\",\n      \"pmids\": [\"17189700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Interferon-beta induces PML protein expression and PML nuclear body formation, which mediates clearance of mutant ataxin-7 from neuronal intranuclear inclusions in SCA7 knock-in mice; this is accompanied by improved motor function on behavioral tests and improved Purkinje cell survival in cell culture.\",\n      \"method\": \"SCA7 knock-in mouse model, IFN-β treatment, immunohistochemistry, behavioral testing (Locotronic, Beam Walking), primary cell culture\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological intervention with cellular and behavioral readouts, validated in patient tissue, single lab\",\n      \"pmids\": [\"23518714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mutant ATXN7 inhibits autophagy via a p53-mediated mechanism: increased p53-FIP200 interaction and co-aggregation of p53 and FIP200 into ATXN7 aggregates decreases soluble FIP200, destabilizing ULK1 and reducing capacity for autophagy induction through the ULK1-FIP200-Atg13-Atg101 complex. p53 inhibitor treatment or blocking ATXN7 aggregation restores FIP200/ULK1 levels and increases autophagic activity.\",\n      \"method\": \"Co-immunoprecipitation, co-aggregation assays, western blotting, pharmacological rescue (p53 inhibitor, aggregation blocker), autophagy flux assays in stable inducible SCA7 cell model\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, co-aggregation, and pharmacological rescue with multiple readouts, single lab\",\n      \"pmids\": [\"23592174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Polyglutamine-expanded ATXN7 induces reactive oxygen species (ROS) production from NADPH oxidase (NOX) complexes; NOX inhibition completely prevents the ROS increase, and both antioxidant treatment and NOX inhibition reduce ATXN7 aggregation and toxicity. Mutant ATXN7 also decreases catalase levels, contributing to oxidative stress.\",\n      \"method\": \"Stable inducible SCA7 cell model, ROS measurement, NOX inhibitor treatment, antioxidant treatment, aggregation assays, cell viability assays\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological intervention with mechanistic specificity, multiple readouts, single lab\",\n      \"pmids\": [\"22827889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mutant ATXN7 causes bioenergetic defects through disruption of p53 and NOX1 activity: p53 co-aggregates with mutant ATXN7 reducing its transcriptional activity (50% decrease in AIF and TIGAR), while NOX1 expression increases ~2-fold, collectively resulting in decreased respiratory capacity, increased glycolytic reliance, and 20% reduction in ATP. Restoring p53 function or suppressing NOX1 activity reverses metabolic dysfunction.\",\n      \"method\": \"Stable inducible SCA7 PC12 cell model, co-aggregation assays, p53 transcriptional reporter assays, metabolic flux analysis, pharmacological rescue\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-aggregation with transcriptional readouts and metabolic measurements, pharmacological rescue, single lab\",\n      \"pmids\": [\"25647692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ataxin-7 physically interacts with APLP2 (amyloid precursor-like protein 2); caspase-3-mediated cleavage of APLP2 generates intracellular C-terminal domains that translocate to the nucleus, and abnormal nuclear relocation of APLP2 N-terminal fragments is detected in SCA7 neuronal intranuclear inclusions. Co-expression of APLP2 ICDs with mutant ataxin-7 causes cumulative cytotoxicity.\",\n      \"method\": \"Yeast two-hybrid (interaction identification), immunohistochemistry in SCA7 brain tissue, co-expression toxicity assays in cells\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction identified by yeast two-hybrid with partial cell-based follow-up, single lab\",\n      \"pmids\": [\"20732423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In SCA7 rod photoreceptor nuclei, the amount of linker histone H1c is strongly reduced and its distribution in facultative heterochromatin is altered, accompanied by fragmentation and decondensation of the most external heterochromatin ring. Acetylated histones H3 and H4 are unchanged in nuclear extracts.\",\n      \"method\": \"Immunogold labeling, stereology, electron tomography, western blotting of nuclear extracts from SCA7 mouse retinas\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation and ultrastructural localization with quantitative comparison between wild-type and SCA7 mice, single lab\",\n      \"pmids\": [\"21970987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function of ATXN7 in zebrafish causes ocular coloboma by elevating Hedgehog signaling in the forebrain, altering proximo-distal patterning of the optic vesicle; at later stages, photoreceptor outer segment formation is incomplete, correlating with altered expression of crx. This demonstrates ATXN7 plays an essential role in vertebrate eye morphogenesis and photoreceptor differentiation.\",\n      \"method\": \"Zebrafish ATXN7 knockdown/knockout, in situ hybridization, Hedgehog pathway analysis, photoreceptor morphology analysis, crx expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway placement (Hedgehog signaling), validated in zebrafish model, single lab\",\n      \"pmids\": [\"30445451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In a stable inducible SCA7 cell model, the ubiquitin-proteasome system (UPS) is essential for degradation of full-length ATXN7 (both normal and expanded), whereas cleaved ATXN7 fragments are degraded by both UPS and autophagy. Inhibition of either pathway worsens mutant ATXN7 toxicity; pharmacological autophagy activation ameliorates toxicity.\",\n      \"method\": \"Stable inducible PC12 and HEK293T cell models, proteasome inhibition, autophagy inhibition/activation, western blotting, cell viability assays\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — differential degradation pathways established by pharmacological inhibition with multiple protein forms tested, single lab\",\n      \"pmids\": [\"22367614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ataxin-7 expression is primarily nuclear in most brain regions studied; in cerebellar Purkinje cells, differences in subcellular distribution were observed between SCA7 patients and controls of different ages, suggesting disease-related redistribution.\",\n      \"method\": \"Immunohistochemistry of CNS and non-CNS tissue from SCA7 patients and controls, subcellular localization analysis\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunohistochemistry without direct functional consequence established, single compilation study\",\n      \"pmids\": [\"12070661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"An alternative ataxin-7 isoform (ataxin-7b), generated by inclusion of exon 12b causing a frameshift and novel 58-amino acid C-terminus, localizes to a more cytoplasmic location compared to the canonical nuclear ataxin-7a isoform.\",\n      \"method\": \"Northern blot, quantitative RT-PCR, subcellular localization analysis in transfected cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — subcellular localization by overexpression without direct functional consequence, single lab\",\n      \"pmids\": [\"16297465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TDP-43 and TIA1 are sequestered into aggregates formed by polyQ-expanded ATXN7 in SCA7 cells; mutant ATXN7 also localizes to stress granules induced by arsenite and alters their shape; mutant ATXN7 expression increases speckling of stress granule-nucleating protein G3BP1. The dynamics of stress granule assembly and disassembly are not significantly impaired in SCA7 cells.\",\n      \"method\": \"Immunofluorescence, filter trap assay, arsenite-induced stress granule assay, stable SCA7 cell model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization by immunofluorescence, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"35689166\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATXN7 is a subunit of the SAGA/STAGA transcriptional coactivator complex where its yeast ortholog Sgf73 anchors the histone H2B deubiquitination module (DUBm) by maintaining the active conformation of the catalytic subunit Ubp8 through its zinc finger domain; polyglutamine expansion in ATXN7 impairs these transcriptional coactivator functions—including suppression of CRX-dependent photoreceptor gene expression, reduced occupancy at target gene promoters with concomitant increases in H2B ubiquitination, and disruption of noncoding RNA-mediated feedback regulation—while also causing gain-of-toxic-function through caspase-7 cleavage at D266, SUMO2/RNF4-mediated proteasomal clearance of misfolded protein, autophagy impairment via p53-FIP200-ULK1 disruption, and NADPH oxidase-dependent oxidative stress, collectively resulting in selective neurodegeneration of cerebellar Purkinje cells and retinal photoreceptors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATXN7 is a subunit of the SAGA/STAGA transcriptional coactivator complex that anchors the histone H2B deubiquitination module (DUBm), and through this role governs chromatin organization and photoreceptor/neuronal gene programs [#1, #11]. Its yeast ortholog Sgf73 is required to recruit the DUBm into the SAGA and SLIK HAT complexes, and an N-terminal zinc-finger domain maintains the active, ubiquitin-binding conformation of the catalytic deubiquitinase Ubp8 [#1, #2, #3]. ATXN7 binds the cone-rod homeobox factor CRX and is required for normal photoreceptor gene expression, and its loss in vertebrates causes eye morphogenesis defects through elevated Hedgehog signaling and altered crx expression [#0, #20]. Distinct domains of Sgf73 mediate SAGA-independent functions including heterochromatin boundary activity and assembly of the RNAi/RITS silencing complex [#4, #5]. ATXN7 abundance is itself controlled by ubiquitin-proteasome degradation, which feeds back on transcription, and by a STAGA-dependent miR-124/lnc-SCA7 regulatory loop [#7, #8, #11]. Polyglutamine expansion in ATXN7 produces both loss of these coactivator functions—reduced promoter occupancy with increased local H2B ubiquitination—and a gain of toxic function: caspase-7 cleavage at D266 is a critical in vivo driver of neurotoxicity, while SUMO2/3-RNF4-mediated clearance, autophagy impairment via a p53-FIP200-ULK1 axis, and NADPH oxidase-dependent oxidative and bioenergetic stress collectively produce selective degeneration of cerebellar Purkinje cells and retinal photoreceptors [#6, #7, #9, #15, #16, #17]. Mutations in ATXN7 cause spinocerebellar ataxia type 7 (SCA7) [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established a direct molecular link between ataxin-7 and the photoreceptor transcription factor CRX, explaining why polyQ expansion selectively perturbs retinal gene expression.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, EMSA, and SCA7 transgenic mice\",\n      \"pmids\": [\"11580893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not place ataxin-7 within the SAGA complex\", \"Mechanism of CRX transactivation suppression beyond reduced DNA binding unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that mutant ataxin-7 mislocalizes to neuronal nuclei as N-terminal fragments, sequesters the TFIID subunit TAFII30, and is selectively stabilized, framing SCA7 as a problem of toxic nuclear accumulation.\",\n      \"evidence\": \"Transgenic mouse immunohistochemistry, confocal microscopy, mRNA vs protein comparison\",\n      \"pmids\": [\"11487572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TAFII30 sequestration not measured\", \"Identity of the protease generating N-terminal fragments unknown at this point\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the conserved core function of the ATXN7 ortholog Sgf73 as the anchor recruiting the H2B deubiquitination module into SAGA/SLIK complexes.\",\n      \"evidence\": \"Yeast genetic deletion, complex fractionation, histone modification assays\",\n      \"pmids\": [\"19226466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human ATXN7 anchors the DUBm identically not directly shown here\", \"Specific genes whose H2B-ub state is controlled in mammals not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Determined that an N-terminal zinc-finger of Sgf73 requires a zinc ion for stable folding, identifying the structural basis of the anchoring domain.\",\n      \"evidence\": \"Solution NMR, circular dichroism, EDTA zinc chelation\",\n      \"pmids\": [\"20510875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro study\", \"Did not test the domain's anchoring function directly\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reported a physical interaction between ataxin-7 and APLP2 whose cleavage fragments contribute cumulative cytotoxicity in SCA7.\",\n      \"evidence\": \"Yeast two-hybrid, SCA7 brain immunohistochemistry, cell co-expression toxicity assays\",\n      \"pmids\": [\"20732423\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Interaction identified by yeast two-hybrid with limited orthogonal validation\", \"Physiological relevance to neurodegeneration unestablished\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked SAGA HAT activity to disease by showing Gcn5 reduction accelerates SCA7 degeneration, while implicating non-transcriptional SAGA functions.\",\n      \"evidence\": \"Genetic epistasis in SCA7 mice, behavior, neuropathology, expression analysis\",\n      \"pmids\": [\"22002997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nature of the non-transcriptional SAGA functions undefined\", \"Mechanism connecting Gcn5 loss to faster degeneration unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Documented altered linker histone H1c and heterochromatin ultrastructure in SCA7 photoreceptors, tying ATXN7 dysfunction to chromatin architecture.\",\n      \"evidence\": \"Immunogold, electron tomography, stereology, nuclear extract western blots from SCA7 retinas\",\n      \"pmids\": [\"21970987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking ATXN7 to H1c loss not established\", \"Functional readout for the decondensation phenotype absent\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected loss of ATXN7 promoter occupancy to increased local H2B monoubiquitination and reduced target (reelin) transcription in human SCA7 cells, providing direct evidence of impaired DUBm function in disease.\",\n      \"evidence\": \"Human astrocyte ChIP, histone modification analysis, TSA rescue\",\n      \"pmids\": [\"23236151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single target locus examined\", \"Whether DUBm catalytic disruption is general across SCA7 genes unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed polyQ-ATXN7 drives NADPH oxidase-dependent ROS and lowers catalase, implicating oxidative stress as a toxicity pathway amenable to pharmacological reversal.\",\n      \"evidence\": \"Inducible SCA7 cell model, ROS assays, NOX inhibitor and antioxidant treatment\",\n      \"pmids\": [\"22827889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ATXN7 to NOX activation unknown\", \"In vivo validation absent\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that full-length ATXN7 is cleared by the proteasome while cleaved fragments use both proteasome and autophagy, and that autophagy activation reduces toxicity.\",\n      \"evidence\": \"Inducible PC12/HEK293T models, proteasome and autophagy inhibition/activation\",\n      \"pmids\": [\"22367614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligases not identified in this study\", \"In vivo degradation routes not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a JNK/c-Jun stress pathway repressing Nrl as a driver of SCA7 retinopathy, since blocking c-Jun activation rescues rod gene expression.\",\n      \"evidence\": \"JunAA knock-in × SCA7 mice genetic epistasis, expression analysis, reporter assays\",\n      \"pmids\": [\"17189700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How polyQ-ATXN7 activates JNK/c-Jun unresolved\", \"Relevance to cerebellar degeneration untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a p53-dependent autophagy block in which p53 and FIP200 co-aggregate with ATXN7, destabilizing ULK1 and impairing autophagy induction.\",\n      \"evidence\": \"Co-IP, co-aggregation, autophagy flux assays, p53 inhibitor and aggregation-blocker rescue\",\n      \"pmids\": [\"23592174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation lacking\", \"Stoichiometry of FIP200 sequestration not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed IFN-β-induced PML nuclear bodies clear mutant ataxin-7 inclusions and improve motor function and Purkinje survival, suggesting a clearance-based therapeutic route.\",\n      \"evidence\": \"SCA7 knock-in mice, IFN-β treatment, immunohistochemistry, behavior, primary culture\",\n      \"pmids\": [\"23518714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of PML-mediated clearance not dissected\", \"Long-term efficacy unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a STAGA-dependent miR-124/lnc-SCA7 feedback loop controlling ATXN7 mRNA whose disruption by polyQ expansion causes tissue-specific ATXN7 accumulation.\",\n      \"evidence\": \"STAGA ChIP, miRNA/lncRNA functional assays, SCA7 patient and mouse tissue\",\n      \"pmids\": [\"25306109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of the feedback loop to disease selectivity unclear\", \"Conservation across cell types not fully mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the structural mechanism by which Sgf73 maintains the ubiquitin-binding conformation and folding of the catalytic subunit Ubp8 within the DUBm.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis, deubiquitinating activity assays\",\n      \"pmids\": [\"25526805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human ATXN7-USP22 module not crystallized here\", \"Effect of polyQ tract on DUBm structure not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that caspase-7 cleavage of ataxin-7 at D266 is a critical in vivo neurotoxicity event, since a cleavage-resistant mutant improves motor function and lifespan.\",\n      \"evidence\": \"D266N knock-in SCA7 mice, behavior, neuropathology\",\n      \"pmids\": [\"25859008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What activates caspase-7 in SCA7 neurons unknown\", \"Toxic species generated by the fragment not fully characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SAGA-independent roles of Sgf73 to the RNAi machinery, showing it associates with Ago1/Chp1 and is required for RITS assembly and heterochromatin silencing.\",\n      \"evidence\": \"Fission yeast co-IP, genetic deletion, ChIP, siRNA quantification\",\n      \"pmids\": [\"26443059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether human ATXN7 has an analogous RNAi role untested\", \"Independence from SAGA shown in one organism only\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tied p53 sequestration and NOX1 upregulation to bioenergetic failure in SCA7 cells, linking transcriptional and metabolic dysfunction.\",\n      \"evidence\": \"Inducible SCA7 PC12 cells, co-aggregation, p53 reporter, metabolic flux, pharmacological rescue\",\n      \"pmids\": [\"25647692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo metabolic phenotype not confirmed\", \"Causal order of p53 and NOX1 effects unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SUMO2/3-RNF4 as a SUMO-targeted ubiquitin ligase pathway that ubiquitinates and degrades polyQ-ATXN7, defining a clearance route for the toxic protein.\",\n      \"evidence\": \"Co-IP, PLA, immunofluorescence, proteasome inhibition, overexpression, SCA7 knock-in mouse, patient tissue\",\n      \"pmids\": [\"30559154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic exploitation of RNF4 not tested in vivo\", \"Why endogenous clearance is insufficient unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined an essential developmental role for ATXN7 in vertebrate eye morphogenesis and photoreceptor differentiation via restraint of Hedgehog signaling and control of crx.\",\n      \"evidence\": \"Zebrafish loss-of-function, in situ hybridization, Hedgehog and photoreceptor analysis\",\n      \"pmids\": [\"30445451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between ATXN7 and Hedgehog pathway components unknown\", \"Relevance of loss-of-function to polyQ disease unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported sequestration of RNA-binding proteins TDP-43 and TIA1 and altered stress-granule morphology by polyQ-ATXN7, suggesting interplay with RNA metabolism.\",\n      \"evidence\": \"Immunofluorescence, filter trap, arsenite stress-granule assay, SCA7 cells\",\n      \"pmids\": [\"35689166\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-localization only, no functional consequence established\", \"Stress granule dynamics not significantly impaired, weakening mechanistic relevance\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that ubiquitin-proteasome-controlled abundance of Sgf73/ATXN7 tunes PIC formation and transcription elongation, integrating protein turnover with coactivator output.\",\n      \"evidence\": \"Ubiquitylation assays, proteasome inhibition, ChIP, transcription assays in yeast and mammalian cells\",\n      \"pmids\": [\"37075097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for normal ATXN7 turnover not pinned down\", \"Single lab; physiological context of elongation effect in neurons untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How polyQ expansion mechanistically converts coactivator loss-of-function into the specific combination of caspase cleavage, impaired clearance, and oxidative/metabolic stress that selectively kills Purkinje cells and photoreceptors remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking transcriptional dysfunction to the multiple toxic pathways\", \"Basis of cell-type selectivity not fully explained\", \"Human DUBm structure with polyQ tract uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 9, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 22]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 9, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 5, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 21]}\n    ],\n    \"complexes\": [\"SAGA/STAGA\", \"histone deubiquitination module (DUBm)\", \"SLIK/SALSA HAT complex\", \"RITS complex\"],\n    \"partners\": [\"CRX\", \"USP22/Ubp8\", \"GCN5\", \"RNF4\", \"SUMO2\", \"FIP200\", \"TP53\", \"APLP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}