{"gene":"ATXN7","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2001,"finding":"Ataxin-7 interacts with the cone-rod homeobox protein CRX (yeast two-hybrid, co-immunoprecipitation, colocalization), and polyglutamine-expanded ataxin-7 suppresses CRX transactivation activity, leading to reduced CRX DNA-binding and decreased expression of CRX-regulated photoreceptor genes in SCA7 transgenic mice.","method":"Yeast two-hybrid, co-immunoprecipitation, electrophoretic mobility shift assay, RT-PCR in transgenic mice","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Y2H, CoIP, EMSA, RT-PCR) in a single study with transgenic mouse validation","pmids":["11580893"],"is_preprint":false},{"year":2009,"finding":"Yeast Sgf73 (ortholog of human ataxin-7/ATXN7) is required to recruit the histone deubiquitination module (DUBm) into both the SAGA and Slik(SALSA) HAT complexes; loss of Sgf73 disrupts histone H2B deubiquitination and alters transcription at multiple genes.","method":"Genetic deletion, biochemical fractionation, histone modification assays in yeast","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 1-2 — direct genetic and biochemical demonstration of DUBm anchoring function, replicated in two complexes","pmids":["19226466"],"is_preprint":false},{"year":2014,"finding":"STAGA complex (containing ATXN7) is required for transcription initiation of miR-124, which mediates post-transcriptional cross-talk between lnc-SCA7 (a conserved long noncoding RNA) and ATXN7 mRNA; polyQ expansion in ATXN7 disrupts this regulatory feedback, causing neuron-specific increase in ATXN7 expression most prominent in retina and cerebellum.","method":"ChIP, RNA knockdown/overexpression, luciferase reporter assays, mouse model analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing a regulatory circuit, validated in mouse tissue","pmids":["25306109"],"is_preprint":false},{"year":2011,"finding":"Reducing Gcn5 (the HAT catalytic subunit of SAGA) expression accelerates both cerebellar and retinal degeneration in a SCA7 mouse model, demonstrating that Gcn5 HAT function within the SAGA complex contributes to the severity of ATXN7-driven neurodegeneration.","method":"Conditional Gcn5 knockout in Purkinje cells in SCA7 transgenic mice, behavioral and histological analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with defined cellular phenotype and transcriptional readouts","pmids":["22002997"],"is_preprint":false},{"year":2012,"finding":"Polyglutamine-expanded ATXN7 decreases ATXN7 occupancy at the reelin promoter, correlating with increased histone H2B monoubiquitination at that locus; trichostatin A treatment partially restores reelin transcription, identifying reelin as an ATXN7 target gene in human astrocytes.","method":"ChIP, human astrocyte cell culture model, pharmacological rescue with TSA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and pharmacological rescue in human cell model; single lab","pmids":["23236151"],"is_preprint":false},{"year":2015,"finding":"Caspase-7 cleaves ataxin-7 at aspartate 266; blocking this cleavage (D266N mutation) in transgenic SCA7 mice improves motor performance, reduces neurodegeneration, and extends lifespan, establishing proteolysis at D266 as a critical mediator of ataxin-7 neurotoxicity.","method":"Site-directed mutagenesis (D266N), transgenic mouse comparison, behavioral tests, histology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with in vivo rescue demonstrating causal role of cleavage site","pmids":["25859008"],"is_preprint":false},{"year":2019,"finding":"Endogenous ATXN7 is modified by SUMO2/3; polyQ-ATXN7 co-localizes and interacts with SUMO2 in inclusions, and RNF4 (a SUMO-targeted ubiquitin ligase) is recruited to SUMO2/3-decorated inclusions, leading to polyubiquitination and proteasomal degradation of polyQ-ATXN7; overexpression of RNF4 and/or SUMO2 significantly decreases polyQ-ATXN7 levels.","method":"Co-immunoprecipitation, proximity ligation assay, immunofluorescence, overexpression, SCA7 knock-in mouse model","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (CoIP, PLA, IF, overexpression) validated in mouse model","pmids":["30559154"],"is_preprint":false},{"year":2013,"finding":"Mutant ATXN7 (polyQ-expanded) reduces autophagic activity through a p53-mediated mechanism: increased p53-FIP200 interaction and co-aggregation into ATXN7 aggregates deplete soluble FIP200, destabilizing ULK1 and impairing ULK1-FIP200-Atg13-Atg101 complex-mediated autophagy initiation; p53 inhibition or ATXN7 aggregation blockers restore FIP200/ULK1 levels and autophagic flux.","method":"Stable inducible SCA7 cell model, co-immunoprecipitation, filter trap, pharmacological rescue","journal":"Journal of molecular neuroscience : MN","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic pathway defined in cell model with pharmacological rescue; single lab","pmids":["23592174"],"is_preprint":false},{"year":2012,"finding":"Polyglutamine-expanded ATXN7 causes oxidative stress by increasing superoxide anion production from NADPH oxidase (NOX) complexes and reducing catalase levels; NOX inhibition or antioxidant treatment reduces both ATXN7 aggregation and toxicity.","method":"Stable inducible SCA7 cell model, ROS measurement, NOX inhibition, antioxidant treatment","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological dissection in a cell model; single lab, single method class","pmids":["22827889"],"is_preprint":false},{"year":2013,"finding":"Interferon beta induces PML protein expression and PML nuclear body formation, which mediates clearance of mutant ataxin-7 (polyQ-ATXN7) in SCA7 knock-in mice; IFN-β treatment reduces ATXN7-positive neuronal intranuclear inclusions and improves motor function.","method":"SCA7 knock-in mouse model, immunohistochemistry, behavioral testing, cell culture","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — defined molecular pathway (IFN-β→PML→ATXN7 clearance) with in vivo rescue; single lab","pmids":["23518714"],"is_preprint":false},{"year":2002,"finding":"Ataxin-7 is primarily nuclear in most brain regions, but in cerebellar Purkinje cells, subcellular distribution differs between SCA7 patients and controls of different ages, suggesting that nuclear localization is linked to its pathological function; ataxin-7 expression is not restricted to regions of pathology.","method":"Immunohistochemistry, fractionation in CNS tissue from SCA7 patients and controls","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 3 — localization study in patient vs. control tissue without direct functional manipulation","pmids":["12070661"],"is_preprint":false},{"year":2001,"finding":"In SCA7 transgenic mice, mutant ataxin-7 undergoes cytoplasm-to-nucleus translocation and accumulates as N-terminal fragments; mutant ataxin-7 is selectively stabilized compared to wild-type protein (based on discrepancy between mRNA and protein levels only in mutant-expressing mice), and nuclear inclusions recruit TAF(II)30 (a TFIID subunit) even though it lacks a polyglutamine stretch.","method":"Transgenic mouse models, immunohistochemistry, Western blot, mRNA/protein level comparison","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple mouse lines showing selective stabilization of mutant protein and nuclear accumulation of TFIID subunit","pmids":["11487572"],"is_preprint":false},{"year":2006,"finding":"Polyglutamine-ataxin-7 activates the JNK/c-Jun stress pathway in rod photoreceptors; genetic reduction of c-Jun activation (JunAA knock-in) improves SCA7 retinopathy and partially restores expression of Nrl and its downstream phototransduction targets; c-Jun can directly repress Nrl transcription.","method":"Genetic epistasis (JunAA x R7E SCA7 mice), gene expression analysis, retinal phenotyping","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in vivo with defined transcriptional mechanism","pmids":["17189700"],"is_preprint":false},{"year":2014,"finding":"The autophagy/lysosome pathway is impaired in SCA7: mutant ataxin-7 accumulates with autophagy markers (mTOR, beclin-1, p62, ubiquitin, LC3, LAMP-1, LAMP-2, cathepsin-D) in cerebellar neurons of SCA7 knock-in mice; autophagic flux is impaired in cells overexpressing full-length mutant ataxin-7.","method":"Immunohistochemistry in knock-in mouse and patient tissue, autophagic flux assays in cell culture","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2-3 — convergent in vivo and in vitro evidence from mouse model and patient tissue","pmids":["24859968"],"is_preprint":false},{"year":2010,"finding":"Amyloid precursor-like protein 2 (APLP2) is a binding partner of ataxin-7; caspase-3 cleavage of APLP2 releases intracellular C-terminal domains (ICDs) that translocate to the nucleus and accumulate in neuronal intranuclear inclusions in SCA7 brain; co-expression of APLP2 ICD with mutant ataxin-7 produces cumulative toxicity.","method":"Co-immunoprecipitation, immunohistochemistry in SCA7 brain, co-expression toxicity assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 3 — single CoIP plus IHC in patient tissue and cell toxicity assay","pmids":["20732423"],"is_preprint":false},{"year":2011,"finding":"In SCA7 rod photoreceptor nuclei, the linker histone H1c is strongly reduced in nuclear extracts and its distribution is altered specifically in the facultative heterochromatin compartment, causing chromatin decondensation (fragmentation of the outer heterochromatin ring); acetylated histone H3/H4 levels are unchanged.","method":"Immunogold labeling, stereology, electron tomography, Western blot of nuclear extracts from SCA7 retinas","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple structural and biochemical methods linking H1c loss to chromatin decondensation in vivo","pmids":["21970987"],"is_preprint":false},{"year":2023,"finding":"Ataxin-7 (and its yeast homolog Sgf73) undergo ubiquitylation and proteasomal degradation; impaired Sgf73 degradation increases its abundance, enhancing TBP recruitment to promoters but impairing transcription elongation; decreased Sgf73 reduces PIC (preinitiation complex) formation. This UPS regulation fine-tunes SAGA complex activity in transcription.","method":"Ubiquitylation assays, proteasome inhibition, promoter occupancy (ChIP), transcription assays in yeast; ataxin-7 validation in mammalian cells","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 — multiple biochemical assays in yeast with mammalian validation; single lab","pmids":["37075097"],"is_preprint":false},{"year":2012,"finding":"Reduction of mutant ataxin-7 expression by ~50% (via tamoxifen-induced Cre-mediated excision) in SCA7 mice halts or reverses motor symptoms, reduces ataxin-7 aggregation in Purkinje cells, and prevents loss of climbing fiber-Purkinje cell synapses, demonstrating that ongoing mutant gene expression is required to maintain disease phenotypes.","method":"Conditional transgenic mouse model with tamoxifen-inducible Cre, behavioral testing, histology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — conditional genetic suppression with defined cellular and behavioral rescue; clean KO with specific phenotypic readout","pmids":["23197655"],"is_preprint":false},{"year":2019,"finding":"Loss of ATXN7 (an SAGA subunit) in zebrafish causes ocular coloboma via elevated 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 (a transcription factor for photoreceptor outer segment formation).","method":"Zebrafish atxn7 knockdown/knockout, immunofluorescence, Hedgehog pathway analysis, crx expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function in vertebrate model with defined pathway (Hh signaling) and downstream effector (crx)","pmids":["30445451"],"is_preprint":false},{"year":2021,"finding":"In the SCA7-140Q/5Q knock-in mouse, Purkinje cells show preferential downregulation of 83 cell-type identity genes (involved in spontaneous firing and synaptic function) that precedes morphological changes and motor symptoms; gene deregulation correlates with alterations in SAGA-dependent epigenetic marks (histone modifications).","method":"Cerebellar transcriptome analysis by RNA-seq, cell-type assignment, epigenetic mark analysis, behavioral phenotyping in knock-in mouse","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptomic and epigenomic correlation in a knock-in model; single study but comprehensive methodology","pmids":["33888607"],"is_preprint":false},{"year":2015,"finding":"Polyglutamine-expanded ATXN7 co-aggregates with p53, reducing p53 transcriptional activity and decreasing p53 target proteins (AIF, TIGAR) by ~50%, while increasing NOX1 expression ~2-fold; together these alterations decrease respiratory capacity, increase glycolytic dependence, and reduce ATP by ~20% in SCA7 cells; restoring p53 function or suppressing NOX1 reverses metabolic dysfunction and reduces mutant ATXN7 toxicity.","method":"Stable inducible PC12 SCA7 model, co-immunoprecipitation/aggregation assays, metabolic flux assays, pharmacological rescue","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic pathway defined in cell model with pharmacological validation; single lab","pmids":["25647692"],"is_preprint":false},{"year":2005,"finding":"A novel SCA7 isoform (ataxin-7b) contains an alternative exon (12b) encoding a different C-terminus; insertion of exon 12b shifts the reading frame to produce an alternative C-terminus that directs the protein to a more cytoplasmic localization compared to the canonical nuclear ataxin-7.","method":"Northern blot, quantitative RT-PCR, subcellular localization by immunofluorescence in mice","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 — localization linked to sequence change; single lab, limited functional follow-up","pmids":["16297465"],"is_preprint":false},{"year":2022,"finding":"Key stress granule modulators TDP-43 and TIA1 are sequestered into aggregates formed by polyQ-expanded ATXN7 in SCA7 cells; mutant ATXN7 also localizes to induced stress granules and alters their shape; mutant ATXN7 expression increases speckling of the SG-nucleating protein G3BP1.","method":"Immunofluorescence, co-localization, filter trap assay in SCA7 cell models","journal":"Molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 — co-localization/sequestration without direct mechanistic rescue; single lab","pmids":["35689166"],"is_preprint":false}],"current_model":"ATXN7 is a subunit of the SAGA transcriptional coactivator complex where it anchors the histone H2B deubiquitination module (DUBm) and is regulated by ubiquitin-proteasome-mediated degradation; polyglutamine expansion of ATXN7 disrupts CRX-mediated photoreceptor gene transcription, impairs SAGA-dependent epigenetic regulation and miR-124-mediated feedback control of ATXN7 expression, activates JNK/c-Jun stress signaling, promotes caspase-7 cleavage of ATXN7 to generate toxic fragments, and impairs autophagy through p53-FIP200 co-aggregation, with SUMO2/RNF4-mediated ubiquitination serving as a clearance mechanism for misfolded polyQ-ATXN7."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that ATXN7 is a transcriptional co-regulator: its direct interaction with CRX and the ability of polyQ-expanded ATXN7 to suppress CRX transactivation and DNA binding provided the first mechanistic link between ATXN7 and photoreceptor gene regulation.","evidence":"Yeast two-hybrid, co-IP, EMSA, and RT-PCR in SCA7 transgenic mice","pmids":["11580893"],"confidence":"High","gaps":["Whether ATXN7-CRX interaction occurs within or outside the SAGA complex was not determined","Direct transcriptional targets beyond photoreceptor genes were unknown"]},{"year":2001,"claim":"Demonstrating that mutant ATXN7 undergoes cytoplasm-to-nucleus translocation and is selectively stabilized as N-terminal fragments that recruit TFIID subunits into inclusions revealed the pathogenic importance of nuclear accumulation and general transcription machinery sequestration.","evidence":"Multiple SCA7 transgenic mouse lines, immunohistochemistry, Western blot, mRNA vs. protein level analysis","pmids":["11487572"],"confidence":"Medium","gaps":["The protease responsible for N-terminal fragment generation was unidentified","Functional consequence of TFIID recruitment to inclusions was not tested"]},{"year":2009,"claim":"Defining ATXN7's molecular function within SAGA: the yeast ortholog Sgf73 was shown to be the anchor subunit that recruits the DUBm into both SAGA and SLIK complexes, directly linking ATXN7 to histone H2B deubiquitination and transcriptional regulation.","evidence":"Genetic deletion, biochemical fractionation, and histone modification assays in yeast","pmids":["19226466"],"confidence":"High","gaps":["Whether the anchoring function is fully conserved in human SAGA was inferred but not directly reconstituted","Structural basis of DUBm attachment was unknown"]},{"year":2006,"claim":"Identifying a stress signaling axis downstream of polyQ-ATXN7: genetic reduction of c-Jun activity partially rescued SCA7 retinopathy and restored Nrl expression, establishing the JNK/c-Jun pathway as a mediator of photoreceptor degeneration distinct from direct SAGA dysfunction.","evidence":"Genetic epistasis using JunAA knock-in crossed with R7E SCA7 mice, retinal phenotyping and gene expression analysis","pmids":["17189700"],"confidence":"Medium","gaps":["How polyQ-ATXN7 activates JNK was not resolved","Whether JNK inhibition is additive with SAGA restoration was untested"]},{"year":2011,"claim":"Establishing that SAGA HAT activity modulates polyQ-ATXN7 neurotoxicity: reducing Gcn5 in SCA7 mice worsened cerebellar and retinal degeneration, proving that loss of SAGA enzymatic function contributes to — rather than merely accompanies — disease progression.","evidence":"Conditional Gcn5 knockout in Purkinje cells of SCA7 transgenic mice with behavioral and histological analysis","pmids":["22002997"],"confidence":"High","gaps":["Relative contributions of HAT vs. DUB dysfunction within SAGA were not separated","Whether Gcn5 loss sensitizes non-neuronal cells similarly was unknown"]},{"year":2012,"claim":"Showing that polyQ-ATXN7 reduces its occupancy at the reelin promoter with concomitant H2B monoubiquitination increase linked ATXN7's DUBm-anchoring role to specific target-gene epigenetic dysregulation in human astrocytes.","evidence":"ChIP in human astrocyte culture, pharmacological rescue with trichostatin A","pmids":["23236151"],"confidence":"Medium","gaps":["Genome-wide identification of ATXN7-occupied loci was lacking","TSA rescue may reflect HDAC-dependent rather than DUB-specific effects"]},{"year":2012,"claim":"Conditional reduction of mutant ATXN7 expression by ~50% halted and partially reversed motor symptoms, aggregation, and synapse loss, demonstrating that disease phenotypes require ongoing mutant protein expression and are not irreversible once initiated.","evidence":"Tamoxifen-inducible Cre-mediated transgene excision in SCA7 mice, behavioral and histological rescue","pmids":["23197655"],"confidence":"High","gaps":["Threshold of reduction needed for clinical benefit was not defined","Long-term durability of rescue was not assessed"]},{"year":2013,"claim":"Revealing that polyQ-ATXN7 impairs autophagy by co-aggregating with p53 and FIP200, thereby depleting soluble FIP200 and destabilizing the ULK1 initiation complex, identified a non-transcriptional gain-of-function toxicity mechanism.","evidence":"Stable inducible SCA7 cell model, co-IP, filter trap assay, pharmacological rescue of p53 and aggregation","pmids":["23592174"],"confidence":"Medium","gaps":["In vivo validation of p53-FIP200 co-aggregation was not performed","Relative contribution of autophagy impairment vs. transcriptional dysregulation to disease was untested"]},{"year":2014,"claim":"Discovery of a miR-124-mediated autoregulatory circuit: the SAGA complex drives miR-124 transcription, which post-transcriptionally represses ATXN7 mRNA via lnc-SCA7 cross-talk; polyQ disruption of this circuit causes neuron-specific ATXN7 overaccumulation, explaining tissue selectivity of SCA7.","evidence":"ChIP, RNA knockdown/overexpression, luciferase reporters, mouse retina and cerebellum analysis","pmids":["25306109"],"confidence":"High","gaps":["Whether restoring miR-124 is therapeutically sufficient was not tested","Mechanism by which polyQ-ATXN7 disrupts miR-124 transcription was not detailed"]},{"year":2015,"claim":"Identification of caspase-7 cleavage at Asp266 as a critical step in ATXN7 neurotoxicity: blocking this site (D266N) in SCA7 mice improved motor function, reduced neurodegeneration, and extended lifespan, establishing proteolytic processing as a therapeutic target.","evidence":"Site-directed mutagenesis, transgenic mouse behavioral and histological comparison","pmids":["25859008"],"confidence":"High","gaps":["Whether the N-terminal fragment itself is toxic or whether cleavage destabilizes the full-length protein was not resolved","Caspase-7 activation mechanism in SCA7 neurons was not defined"]},{"year":2019,"claim":"Demonstrating that SUMO2/RNF4-mediated ubiquitination targets polyQ-ATXN7 for proteasomal clearance revealed an endogenous quality-control pathway for misfolded ATXN7 and a potential therapeutic axis.","evidence":"Co-IP, proximity ligation assay, immunofluorescence, overexpression of RNF4/SUMO2 in SCA7 knock-in mouse model and cell culture","pmids":["30559154"],"confidence":"High","gaps":["Specific SUMO2 attachment sites on ATXN7 were not mapped","Whether RNF4 pathway is saturated in disease was unknown"]},{"year":2019,"claim":"Loss of ATXN7 in zebrafish caused ocular coloboma via elevated Hedgehog signaling and later disrupted photoreceptor outer segment formation with altered crx expression, establishing a developmental (non-polyQ) requirement for ATXN7 in eye morphogenesis.","evidence":"Zebrafish atxn7 knockdown/knockout, Hedgehog pathway and crx expression analysis","pmids":["30445451"],"confidence":"Medium","gaps":["Whether SAGA integrity is required for Hedgehog pathway regulation was not tested","Relevance to mammalian eye development was not demonstrated"]},{"year":2021,"claim":"Transcriptomic analysis of SCA7 knock-in Purkinje cells showed that 83 cell-type identity genes (synaptic and firing genes) are preferentially downregulated before morphological changes, with correlated changes in SAGA-dependent histone marks, providing a direct link between SAGA epigenetic dysfunction and early disease.","evidence":"RNA-seq, cell-type gene assignment, epigenetic mark analysis in SCA7-140Q/5Q knock-in mouse cerebellum","pmids":["33888607"],"confidence":"Medium","gaps":["Causal direction — whether histone mark changes drive or follow transcriptional downregulation — was not established","Whether these identity genes are direct ATXN7/SAGA-occupied targets was not confirmed by ChIP"]},{"year":2023,"claim":"Ubiquitin-proteasome regulation of ATXN7/Sgf73 abundance was shown to fine-tune SAGA transcriptional output: impaired degradation increased Sgf73 levels, boosting TBP recruitment but impairing elongation, revealing that ATXN7 turnover is integral to the SAGA transcription cycle.","evidence":"Ubiquitylation assays, proteasome inhibition, ChIP for promoter occupancy, and transcription assays in yeast with mammalian cell validation","pmids":["37075097"],"confidence":"Medium","gaps":["The E3 ligase responsible for wild-type ATXN7 turnover was not identified","How polyQ expansion affects this turnover pathway specifically was not tested"]},{"year":null,"claim":"Major unresolved questions include the structural basis of ATXN7-mediated DUBm anchoring in human SAGA, the identity of the E3 ubiquitin ligase controlling wild-type ATXN7 turnover, the relative in vivo contributions of SAGA transcriptional dysfunction versus autophagy impairment and proteolytic toxicity in SCA7, and whether restoring the miR-124 autoregulatory circuit or RNF4/SUMO2 clearance pathway is therapeutically viable.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of human ATXN7 within the DUBm","Relative contribution of HAT vs. DUB dysfunction to SCA7 pathology not separated in vivo","Therapeutic potential of SUMO2/RNF4 or miR-124 restoration not validated in mammalian disease models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,16]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,4,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,4,15,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,5,17]}],"complexes":["SAGA","SAGA DUB module"],"partners":["CRX","GCN5","RNF4","SUMO2","FIP200","TP53","APLP2","CASP7"],"other_free_text":[]},"mechanistic_narrative":"ATXN7 is a subunit of the SAGA transcriptional coactivator complex that anchors the histone H2B deubiquitination module (DUBm), coupling chromatin remodeling to gene expression control. Loss of ATXN7/Sgf73 disrupts DUBm incorporation into SAGA, elevating H2B monoubiquitination at target promoters such as reelin and photoreceptor genes, while its proteasomal turnover fine-tunes TBP recruitment and transcription elongation [PMID:19226466, PMID:23236151, PMID:37075097]. ATXN7 interacts with the photoreceptor transcription factor CRX and participates in a miR-124-dependent autoregulatory circuit that controls its own mRNA levels in neurons [PMID:11580893, PMID:25306109]. Polyglutamine expansion in ATXN7 causes spinocerebellar ataxia type 7 (SCA7), in which caspase-7 cleavage at Asp266 generates toxic N-terminal fragments, the mutant protein sequesters p53 and FIP200 to impair autophagy, and SAGA-dependent epigenetic dysregulation preferentially silences Purkinje-cell identity genes; SUMO2/RNF4-mediated ubiquitination promotes clearance of misfolded polyQ-ATXN7 [PMID:25859008, PMID:23592174, PMID:33888607, PMID:30559154]."},"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). Involved in neurodegeneration (PubMed:9288099)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O15265/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN7","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ENY2","stoichiometry":0.2},{"gene":"RAB3D","stoichiometry":0.2},{"gene":"SF3B3","stoichiometry":0.2},{"gene":"TAF12","stoichiometry":0.2},{"gene":"TRRAP","stoichiometry":0.2},{"gene":"USP22","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATXN7","total_profiled":1310},"omim":[{"mim_id":"621377","title":"HAREL-TORA NEURODEVELOPMENTAL SYNDROME; HATONS","url":"https://www.omim.org/entry/621377"},{"mim_id":"619015","title":"ENY2 TRANSCRIPTION AND EXPORT COMPLEX 2 SUBUNIT; ENY2","url":"https://www.omim.org/entry/619015"},{"mim_id":"619010","title":"ATXN7-LIKE 3; ATXN7L3","url":"https://www.omim.org/entry/619010"},{"mim_id":"614481","title":"ATXN7 ANTISENSE RNA 1; ATXN7AS1","url":"https://www.omim.org/entry/614481"},{"mim_id":"612116","title":"UBIQUITIN-SPECIFIC PROTEASE 22; USP22","url":"https://www.omim.org/entry/612116"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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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":48937,"output_tokens":5422,"usd":0.114071},"stage2":{"model":"claude-opus-4-6","input_tokens":8979,"output_tokens":3822,"usd":0.210668},"total_usd":0.324739,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Ataxin-7 interacts with the cone-rod homeobox protein CRX (yeast two-hybrid, co-immunoprecipitation, colocalization), and polyglutamine-expanded ataxin-7 suppresses CRX transactivation activity, leading to reduced CRX DNA-binding 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 in transgenic mice\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Y2H, CoIP, EMSA, RT-PCR) in a single study with transgenic mouse validation\",\n      \"pmids\": [\"11580893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Sgf73 (ortholog of human ataxin-7/ATXN7) is required to recruit the histone deubiquitination module (DUBm) into both the SAGA and Slik(SALSA) HAT complexes; loss of Sgf73 disrupts histone H2B deubiquitination and alters transcription at multiple genes.\",\n      \"method\": \"Genetic deletion, biochemical fractionation, histone modification assays in yeast\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct genetic and biochemical demonstration of DUBm anchoring function, replicated in two complexes\",\n      \"pmids\": [\"19226466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STAGA complex (containing ATXN7) is required for transcription initiation of miR-124, which mediates post-transcriptional cross-talk between lnc-SCA7 (a conserved long noncoding RNA) and ATXN7 mRNA; polyQ expansion in ATXN7 disrupts this regulatory feedback, causing neuron-specific increase in ATXN7 expression most prominent in retina and cerebellum.\",\n      \"method\": \"ChIP, RNA knockdown/overexpression, luciferase reporter assays, mouse model analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing a regulatory circuit, validated in mouse tissue\",\n      \"pmids\": [\"25306109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Reducing Gcn5 (the HAT catalytic subunit of SAGA) expression accelerates both cerebellar and retinal degeneration in a SCA7 mouse model, demonstrating that Gcn5 HAT function within the SAGA complex contributes to the severity of ATXN7-driven neurodegeneration.\",\n      \"method\": \"Conditional Gcn5 knockout in Purkinje cells in SCA7 transgenic mice, behavioral and histological analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with defined cellular phenotype and transcriptional readouts\",\n      \"pmids\": [\"22002997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Polyglutamine-expanded ATXN7 decreases ATXN7 occupancy at the reelin promoter, correlating with increased histone H2B monoubiquitination at that locus; trichostatin A treatment partially restores reelin transcription, identifying reelin as an ATXN7 target gene in human astrocytes.\",\n      \"method\": \"ChIP, human astrocyte cell culture model, pharmacological rescue with TSA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and pharmacological rescue in human cell model; single lab\",\n      \"pmids\": [\"23236151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Caspase-7 cleaves ataxin-7 at aspartate 266; blocking this cleavage (D266N mutation) in transgenic SCA7 mice improves motor performance, reduces neurodegeneration, and extends lifespan, establishing proteolysis at D266 as a critical mediator of ataxin-7 neurotoxicity.\",\n      \"method\": \"Site-directed mutagenesis (D266N), transgenic mouse comparison, behavioral tests, histology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with in vivo rescue demonstrating causal role of cleavage site\",\n      \"pmids\": [\"25859008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endogenous ATXN7 is modified by SUMO2/3; polyQ-ATXN7 co-localizes and interacts with SUMO2 in inclusions, and RNF4 (a SUMO-targeted ubiquitin ligase) is recruited to SUMO2/3-decorated inclusions, leading to polyubiquitination and proteasomal degradation of polyQ-ATXN7; overexpression of RNF4 and/or SUMO2 significantly decreases polyQ-ATXN7 levels.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, immunofluorescence, overexpression, SCA7 knock-in mouse model\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (CoIP, PLA, IF, overexpression) validated in mouse model\",\n      \"pmids\": [\"30559154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mutant ATXN7 (polyQ-expanded) reduces autophagic activity through a p53-mediated mechanism: increased p53-FIP200 interaction and co-aggregation into ATXN7 aggregates deplete soluble FIP200, destabilizing ULK1 and impairing ULK1-FIP200-Atg13-Atg101 complex-mediated autophagy initiation; p53 inhibition or ATXN7 aggregation blockers restore FIP200/ULK1 levels and autophagic flux.\",\n      \"method\": \"Stable inducible SCA7 cell model, co-immunoprecipitation, filter trap, pharmacological rescue\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic pathway defined in cell model with pharmacological rescue; single lab\",\n      \"pmids\": [\"23592174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Polyglutamine-expanded ATXN7 causes oxidative stress by increasing superoxide anion production from NADPH oxidase (NOX) complexes and reducing catalase levels; NOX inhibition or antioxidant treatment reduces both ATXN7 aggregation and toxicity.\",\n      \"method\": \"Stable inducible SCA7 cell model, ROS measurement, NOX inhibition, antioxidant treatment\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological dissection in a cell model; single lab, single method class\",\n      \"pmids\": [\"22827889\"],\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 (polyQ-ATXN7) in SCA7 knock-in mice; IFN-β treatment reduces ATXN7-positive neuronal intranuclear inclusions and improves motor function.\",\n      \"method\": \"SCA7 knock-in mouse model, immunohistochemistry, behavioral testing, cell culture\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined molecular pathway (IFN-β→PML→ATXN7 clearance) with in vivo rescue; single lab\",\n      \"pmids\": [\"23518714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ataxin-7 is primarily nuclear in most brain regions, but in cerebellar Purkinje cells, subcellular distribution differs between SCA7 patients and controls of different ages, suggesting that nuclear localization is linked to its pathological function; ataxin-7 expression is not restricted to regions of pathology.\",\n      \"method\": \"Immunohistochemistry, fractionation in CNS tissue from SCA7 patients and controls\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization study in patient vs. control tissue without direct functional manipulation\",\n      \"pmids\": [\"12070661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In SCA7 transgenic mice, mutant ataxin-7 undergoes cytoplasm-to-nucleus translocation and accumulates as N-terminal fragments; mutant ataxin-7 is selectively stabilized compared to wild-type protein (based on discrepancy between mRNA and protein levels only in mutant-expressing mice), and nuclear inclusions recruit TAF(II)30 (a TFIID subunit) even though it lacks a polyglutamine stretch.\",\n      \"method\": \"Transgenic mouse models, immunohistochemistry, Western blot, mRNA/protein level comparison\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple mouse lines showing selective stabilization of mutant protein and nuclear accumulation of TFIID subunit\",\n      \"pmids\": [\"11487572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Polyglutamine-ataxin-7 activates the JNK/c-Jun stress pathway in rod photoreceptors; genetic reduction of c-Jun activation (JunAA knock-in) improves SCA7 retinopathy and partially restores expression of Nrl and its downstream phototransduction targets; c-Jun can directly repress Nrl transcription.\",\n      \"method\": \"Genetic epistasis (JunAA x R7E SCA7 mice), gene expression analysis, retinal phenotyping\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with defined transcriptional mechanism\",\n      \"pmids\": [\"17189700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The autophagy/lysosome pathway is impaired in SCA7: mutant ataxin-7 accumulates with autophagy markers (mTOR, beclin-1, p62, ubiquitin, LC3, LAMP-1, LAMP-2, cathepsin-D) in cerebellar neurons of SCA7 knock-in mice; autophagic flux is impaired in cells overexpressing full-length mutant ataxin-7.\",\n      \"method\": \"Immunohistochemistry in knock-in mouse and patient tissue, autophagic flux assays in cell culture\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — convergent in vivo and in vitro evidence from mouse model and patient tissue\",\n      \"pmids\": [\"24859968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Amyloid precursor-like protein 2 (APLP2) is a binding partner of ataxin-7; caspase-3 cleavage of APLP2 releases intracellular C-terminal domains (ICDs) that translocate to the nucleus and accumulate in neuronal intranuclear inclusions in SCA7 brain; co-expression of APLP2 ICD with mutant ataxin-7 produces cumulative toxicity.\",\n      \"method\": \"Co-immunoprecipitation, immunohistochemistry in SCA7 brain, co-expression toxicity assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single CoIP plus IHC in patient tissue and cell toxicity assay\",\n      \"pmids\": [\"20732423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In SCA7 rod photoreceptor nuclei, the linker histone H1c is strongly reduced in nuclear extracts and its distribution is altered specifically in the facultative heterochromatin compartment, causing chromatin decondensation (fragmentation of the outer heterochromatin ring); acetylated histone H3/H4 levels are unchanged.\",\n      \"method\": \"Immunogold labeling, stereology, electron tomography, Western blot of nuclear extracts from SCA7 retinas\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple structural and biochemical methods linking H1c loss to chromatin decondensation in vivo\",\n      \"pmids\": [\"21970987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ataxin-7 (and its yeast homolog Sgf73) undergo ubiquitylation and proteasomal degradation; impaired Sgf73 degradation increases its abundance, enhancing TBP recruitment to promoters but impairing transcription elongation; decreased Sgf73 reduces PIC (preinitiation complex) formation. This UPS regulation fine-tunes SAGA complex activity in transcription.\",\n      \"method\": \"Ubiquitylation assays, proteasome inhibition, promoter occupancy (ChIP), transcription assays in yeast; ataxin-7 validation in mammalian cells\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple biochemical assays in yeast with mammalian validation; single lab\",\n      \"pmids\": [\"37075097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Reduction of mutant ataxin-7 expression by ~50% (via tamoxifen-induced Cre-mediated excision) in SCA7 mice halts or reverses motor symptoms, reduces ataxin-7 aggregation in Purkinje cells, and prevents loss of climbing fiber-Purkinje cell synapses, demonstrating that ongoing mutant gene expression is required to maintain disease phenotypes.\",\n      \"method\": \"Conditional transgenic mouse model with tamoxifen-inducible Cre, behavioral testing, histology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic suppression with defined cellular and behavioral rescue; clean KO with specific phenotypic readout\",\n      \"pmids\": [\"23197655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of ATXN7 (an SAGA subunit) in zebrafish causes ocular coloboma via elevated 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 (a transcription factor for photoreceptor outer segment formation).\",\n      \"method\": \"Zebrafish atxn7 knockdown/knockout, immunofluorescence, Hedgehog pathway analysis, crx expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in vertebrate model with defined pathway (Hh signaling) and downstream effector (crx)\",\n      \"pmids\": [\"30445451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In the SCA7-140Q/5Q knock-in mouse, Purkinje cells show preferential downregulation of 83 cell-type identity genes (involved in spontaneous firing and synaptic function) that precedes morphological changes and motor symptoms; gene deregulation correlates with alterations in SAGA-dependent epigenetic marks (histone modifications).\",\n      \"method\": \"Cerebellar transcriptome analysis by RNA-seq, cell-type assignment, epigenetic mark analysis, behavioral phenotyping in knock-in mouse\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptomic and epigenomic correlation in a knock-in model; single study but comprehensive methodology\",\n      \"pmids\": [\"33888607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Polyglutamine-expanded ATXN7 co-aggregates with p53, reducing p53 transcriptional activity and decreasing p53 target proteins (AIF, TIGAR) by ~50%, while increasing NOX1 expression ~2-fold; together these alterations decrease respiratory capacity, increase glycolytic dependence, and reduce ATP by ~20% in SCA7 cells; restoring p53 function or suppressing NOX1 reverses metabolic dysfunction and reduces mutant ATXN7 toxicity.\",\n      \"method\": \"Stable inducible PC12 SCA7 model, co-immunoprecipitation/aggregation assays, metabolic flux assays, pharmacological rescue\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic pathway defined in cell model with pharmacological validation; single lab\",\n      \"pmids\": [\"25647692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel SCA7 isoform (ataxin-7b) contains an alternative exon (12b) encoding a different C-terminus; insertion of exon 12b shifts the reading frame to produce an alternative C-terminus that directs the protein to a more cytoplasmic localization compared to the canonical nuclear ataxin-7.\",\n      \"method\": \"Northern blot, quantitative RT-PCR, subcellular localization by immunofluorescence in mice\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization linked to sequence change; single lab, limited functional follow-up\",\n      \"pmids\": [\"16297465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Key stress granule modulators TDP-43 and TIA1 are sequestered into aggregates formed by polyQ-expanded ATXN7 in SCA7 cells; mutant ATXN7 also localizes to induced stress granules and alters their shape; mutant ATXN7 expression increases speckling of the SG-nucleating protein G3BP1.\",\n      \"method\": \"Immunofluorescence, co-localization, filter trap assay in SCA7 cell models\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — co-localization/sequestration without direct mechanistic rescue; single lab\",\n      \"pmids\": [\"35689166\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATXN7 is a subunit of the SAGA transcriptional coactivator complex where it anchors the histone H2B deubiquitination module (DUBm) and is regulated by ubiquitin-proteasome-mediated degradation; polyglutamine expansion of ATXN7 disrupts CRX-mediated photoreceptor gene transcription, impairs SAGA-dependent epigenetic regulation and miR-124-mediated feedback control of ATXN7 expression, activates JNK/c-Jun stress signaling, promotes caspase-7 cleavage of ATXN7 to generate toxic fragments, and impairs autophagy through p53-FIP200 co-aggregation, with SUMO2/RNF4-mediated ubiquitination serving as a clearance mechanism for misfolded polyQ-ATXN7.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATXN7 is a subunit of the SAGA transcriptional coactivator complex that anchors the histone H2B deubiquitination module (DUBm), coupling chromatin remodeling to gene expression control. Loss of ATXN7/Sgf73 disrupts DUBm incorporation into SAGA, elevating H2B monoubiquitination at target promoters such as reelin and photoreceptor genes, while its proteasomal turnover fine-tunes TBP recruitment and transcription elongation [PMID:19226466, PMID:23236151, PMID:37075097]. ATXN7 interacts with the photoreceptor transcription factor CRX and participates in a miR-124-dependent autoregulatory circuit that controls its own mRNA levels in neurons [PMID:11580893, PMID:25306109]. Polyglutamine expansion in ATXN7 causes spinocerebellar ataxia type 7 (SCA7), in which caspase-7 cleavage at Asp266 generates toxic N-terminal fragments, the mutant protein sequesters p53 and FIP200 to impair autophagy, and SAGA-dependent epigenetic dysregulation preferentially silences Purkinje-cell identity genes; SUMO2/RNF4-mediated ubiquitination promotes clearance of misfolded polyQ-ATXN7 [PMID:25859008, PMID:23592174, PMID:33888607, PMID:30559154].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that ATXN7 is a transcriptional co-regulator: its direct interaction with CRX and the ability of polyQ-expanded ATXN7 to suppress CRX transactivation and DNA binding provided the first mechanistic link between ATXN7 and photoreceptor gene regulation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, EMSA, and RT-PCR in SCA7 transgenic mice\",\n      \"pmids\": [\"11580893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ATXN7-CRX interaction occurs within or outside the SAGA complex was not determined\",\n        \"Direct transcriptional targets beyond photoreceptor genes were unknown\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that mutant ATXN7 undergoes cytoplasm-to-nucleus translocation and is selectively stabilized as N-terminal fragments that recruit TFIID subunits into inclusions revealed the pathogenic importance of nuclear accumulation and general transcription machinery sequestration.\",\n      \"evidence\": \"Multiple SCA7 transgenic mouse lines, immunohistochemistry, Western blot, mRNA vs. protein level analysis\",\n      \"pmids\": [\"11487572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The protease responsible for N-terminal fragment generation was unidentified\",\n        \"Functional consequence of TFIID recruitment to inclusions was not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining ATXN7's molecular function within SAGA: the yeast ortholog Sgf73 was shown to be the anchor subunit that recruits the DUBm into both SAGA and SLIK complexes, directly linking ATXN7 to histone H2B deubiquitination and transcriptional regulation.\",\n      \"evidence\": \"Genetic deletion, biochemical fractionation, and histone modification assays in yeast\",\n      \"pmids\": [\"19226466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the anchoring function is fully conserved in human SAGA was inferred but not directly reconstituted\",\n        \"Structural basis of DUBm attachment was unknown\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying a stress signaling axis downstream of polyQ-ATXN7: genetic reduction of c-Jun activity partially rescued SCA7 retinopathy and restored Nrl expression, establishing the JNK/c-Jun pathway as a mediator of photoreceptor degeneration distinct from direct SAGA dysfunction.\",\n      \"evidence\": \"Genetic epistasis using JunAA knock-in crossed with R7E SCA7 mice, retinal phenotyping and gene expression analysis\",\n      \"pmids\": [\"17189700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How polyQ-ATXN7 activates JNK was not resolved\",\n        \"Whether JNK inhibition is additive with SAGA restoration was untested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that SAGA HAT activity modulates polyQ-ATXN7 neurotoxicity: reducing Gcn5 in SCA7 mice worsened cerebellar and retinal degeneration, proving that loss of SAGA enzymatic function contributes to — rather than merely accompanies — disease progression.\",\n      \"evidence\": \"Conditional Gcn5 knockout in Purkinje cells of SCA7 transgenic mice with behavioral and histological analysis\",\n      \"pmids\": [\"22002997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of HAT vs. DUB dysfunction within SAGA were not separated\",\n        \"Whether Gcn5 loss sensitizes non-neuronal cells similarly was unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that polyQ-ATXN7 reduces its occupancy at the reelin promoter with concomitant H2B monoubiquitination increase linked ATXN7's DUBm-anchoring role to specific target-gene epigenetic dysregulation in human astrocytes.\",\n      \"evidence\": \"ChIP in human astrocyte culture, pharmacological rescue with trichostatin A\",\n      \"pmids\": [\"23236151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genome-wide identification of ATXN7-occupied loci was lacking\",\n        \"TSA rescue may reflect HDAC-dependent rather than DUB-specific effects\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Conditional reduction of mutant ATXN7 expression by ~50% halted and partially reversed motor symptoms, aggregation, and synapse loss, demonstrating that disease phenotypes require ongoing mutant protein expression and are not irreversible once initiated.\",\n      \"evidence\": \"Tamoxifen-inducible Cre-mediated transgene excision in SCA7 mice, behavioral and histological rescue\",\n      \"pmids\": [\"23197655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Threshold of reduction needed for clinical benefit was not defined\",\n        \"Long-term durability of rescue was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing that polyQ-ATXN7 impairs autophagy by co-aggregating with p53 and FIP200, thereby depleting soluble FIP200 and destabilizing the ULK1 initiation complex, identified a non-transcriptional gain-of-function toxicity mechanism.\",\n      \"evidence\": \"Stable inducible SCA7 cell model, co-IP, filter trap assay, pharmacological rescue of p53 and aggregation\",\n      \"pmids\": [\"23592174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo validation of p53-FIP200 co-aggregation was not performed\",\n        \"Relative contribution of autophagy impairment vs. transcriptional dysregulation to disease was untested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of a miR-124-mediated autoregulatory circuit: the SAGA complex drives miR-124 transcription, which post-transcriptionally represses ATXN7 mRNA via lnc-SCA7 cross-talk; polyQ disruption of this circuit causes neuron-specific ATXN7 overaccumulation, explaining tissue selectivity of SCA7.\",\n      \"evidence\": \"ChIP, RNA knockdown/overexpression, luciferase reporters, mouse retina and cerebellum analysis\",\n      \"pmids\": [\"25306109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether restoring miR-124 is therapeutically sufficient was not tested\",\n        \"Mechanism by which polyQ-ATXN7 disrupts miR-124 transcription was not detailed\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of caspase-7 cleavage at Asp266 as a critical step in ATXN7 neurotoxicity: blocking this site (D266N) in SCA7 mice improved motor function, reduced neurodegeneration, and extended lifespan, establishing proteolytic processing as a therapeutic target.\",\n      \"evidence\": \"Site-directed mutagenesis, transgenic mouse behavioral and histological comparison\",\n      \"pmids\": [\"25859008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the N-terminal fragment itself is toxic or whether cleavage destabilizes the full-length protein was not resolved\",\n        \"Caspase-7 activation mechanism in SCA7 neurons was not defined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that SUMO2/RNF4-mediated ubiquitination targets polyQ-ATXN7 for proteasomal clearance revealed an endogenous quality-control pathway for misfolded ATXN7 and a potential therapeutic axis.\",\n      \"evidence\": \"Co-IP, proximity ligation assay, immunofluorescence, overexpression of RNF4/SUMO2 in SCA7 knock-in mouse model and cell culture\",\n      \"pmids\": [\"30559154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific SUMO2 attachment sites on ATXN7 were not mapped\",\n        \"Whether RNF4 pathway is saturated in disease was unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Loss of ATXN7 in zebrafish caused ocular coloboma via elevated Hedgehog signaling and later disrupted photoreceptor outer segment formation with altered crx expression, establishing a developmental (non-polyQ) requirement for ATXN7 in eye morphogenesis.\",\n      \"evidence\": \"Zebrafish atxn7 knockdown/knockout, Hedgehog pathway and crx expression analysis\",\n      \"pmids\": [\"30445451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SAGA integrity is required for Hedgehog pathway regulation was not tested\",\n        \"Relevance to mammalian eye development was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Transcriptomic analysis of SCA7 knock-in Purkinje cells showed that 83 cell-type identity genes (synaptic and firing genes) are preferentially downregulated before morphological changes, with correlated changes in SAGA-dependent histone marks, providing a direct link between SAGA epigenetic dysfunction and early disease.\",\n      \"evidence\": \"RNA-seq, cell-type gene assignment, epigenetic mark analysis in SCA7-140Q/5Q knock-in mouse cerebellum\",\n      \"pmids\": [\"33888607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal direction — whether histone mark changes drive or follow transcriptional downregulation — was not established\",\n        \"Whether these identity genes are direct ATXN7/SAGA-occupied targets was not confirmed by ChIP\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Ubiquitin-proteasome regulation of ATXN7/Sgf73 abundance was shown to fine-tune SAGA transcriptional output: impaired degradation increased Sgf73 levels, boosting TBP recruitment but impairing elongation, revealing that ATXN7 turnover is integral to the SAGA transcription cycle.\",\n      \"evidence\": \"Ubiquitylation assays, proteasome inhibition, ChIP for promoter occupancy, and transcription assays in yeast with mammalian cell validation\",\n      \"pmids\": [\"37075097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ligase responsible for wild-type ATXN7 turnover was not identified\",\n        \"How polyQ expansion affects this turnover pathway specifically was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of ATXN7-mediated DUBm anchoring in human SAGA, the identity of the E3 ubiquitin ligase controlling wild-type ATXN7 turnover, the relative in vivo contributions of SAGA transcriptional dysfunction versus autophagy impairment and proteolytic toxicity in SCA7, and whether restoring the miR-124 autoregulatory circuit or RNF4/SUMO2 clearance pathway is therapeutically viable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of human ATXN7 within the DUBm\",\n        \"Relative contribution of HAT vs. DUB dysfunction to SCA7 pathology not separated in vivo\",\n        \"Therapeutic potential of SUMO2/RNF4 or miR-124 restoration not validated in mammalian disease models\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 4, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 4, 15, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 5, 17]}\n    ],\n    \"complexes\": [\n      \"SAGA\",\n      \"SAGA DUB module\"\n    ],\n    \"partners\": [\n      \"CRX\",\n      \"GCN5\",\n      \"RNF4\",\n      \"SUMO2\",\n      \"FIP200\",\n      \"TP53\",\n      \"APLP2\",\n      \"CASP7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}