{"gene":"ATN1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1994,"finding":"ATN1 (DRPLA gene) encodes a 1184-amino acid protein containing a polyglutamine tract starting at amino acid 484, along with a homo-proline track, two stretches of arginine-glutamic acid dipeptide repeats, and a stretch of alternating histidine residues. The gene is ubiquitously expressed as a single 4.5 kb transcript.","method":"cDNA cloning, sequencing, and Northern blot analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — foundational cDNA sequencing and expression analysis replicated across multiple labs in the same year","pmids":["7842016"],"is_preprint":false},{"year":1995,"finding":"The ATN1/DRPLA gene product is a ~190 kDa protein localized predominantly in neuronal cytoplasm in normal human brain; DRPLA patient brains contain a larger ~205 kDa protein corresponding to the expanded polyglutamine form.","method":"Immunoblotting with antibodies against DRPLA C-terminus peptide; immunohistochemistry of human brain sections","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein identification with specific antibodies combined with immunohistochemistry, replicated in follow-up studies","pmids":["7647802"],"is_preprint":false},{"year":1996,"finding":"ATN1/atrophin-1 protein selectively interacts with GAPDH, an interaction mediated by the polyglutamine domain.","method":"Protein–protein binding assays identifying GAPDH as a polyglutamine-domain interacting protein in brain","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding assay demonstrated, but single lab and limited orthogonal validation for ATN1 specifically","pmids":["8612237"],"is_preprint":false},{"year":1997,"finding":"ATN1/DRPLA protein is cleaved by caspase-3 during apoptosis at the site 106DSLDG110 near the N-terminus. The cleavage is not modulated by polyglutamine length. This identifies ATN1 as a physiological substrate of caspase-3.","method":"In vitro cleavage assay with recombinant caspase-3; site-directed mutagenesis of cleavage site; apoptosis induction by VP-16, staurosporine, or glucocorticoid in cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant enzyme plus mutagenesis to map cleavage site","pmids":["9361003"],"is_preprint":false},{"year":1998,"finding":"Truncated ATN1 protein with an expanded polyglutamine stretch forms filamentous peri- and intranuclear aggregates and induces apoptosis when expressed in COS-7 cells. Apoptotic cell death is partially suppressed by transglutaminase inhibitors cystamine and monodansyl cadaverine, implicating a transglutaminase reaction in aggregate formation and toxicity.","method":"Cell transfection with truncated/full-length DRPLA cDNA constructs; pharmacological inhibition with transglutaminase inhibitors; apoptosis assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple constructs and pharmacological rescue experiments in a single study; widely cited and consistent with other findings","pmids":["9462738"],"is_preprint":false},{"year":1998,"finding":"Full-length ATN1 protein localizes predominantly in the nucleus regardless of polyglutamine length. The N-terminal-deleted caspase-3 cleavage fragment containing the polyQ domain localizes both in the nucleus and cytoplasm, and with expanded polyQ forms aggregates associated with apoptosis.","method":"GFP-fusion protein subcellular localization in transfected cells; fluorescence microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — GFP-tagging approach in transfected cells, single lab, consistent with other localization data","pmids":["9705838"],"is_preprint":false},{"year":1998,"finding":"ATN1 interacts with five proteins containing WW domains via regions near the polyglutamine tract. Four interactions were confirmed by in vitro binding assays. Two classes of interactors were identified: (1) MAGUK-like proteins with PDZ domains (AIP1, AIP3/WWP3), and (2) ubiquitin ligases with HECT domains (AIP2/WWP2, AIP4, AIP5/WWP1).","method":"Yeast two-hybrid screen; in vitro binding assays (4 of 5 interactions confirmed)","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus in vitro binding confirmation, single lab","pmids":["9647693"],"is_preprint":false},{"year":1998,"finding":"ATN1 protein forms disulfide-bond complexes in human brain, and this complex formation is enhanced in DRPLA brains with expanded polyglutamine. The complex is found in the neuronal cytoplasm.","method":"Immunoblotting under reducing and non-reducing conditions; immunohistochemistry of human brain tissue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunoblot with/without reduction as distinguishing method, single lab","pmids":["9735324"],"is_preprint":false},{"year":1999,"finding":"ATN1 protein complex in DRPLA brains is pathologically ubiquitinated specifically in affected lesions. Ubiquitinated ATN1 forms neuronal cytoplasmic inclusions. Complex formation is enhanced by the expanded glutamine repeat.","method":"Immunoblotting with and without reduction; double-labeling immunohistochemistry with anti-DRPLA and anti-ubiquitin antibodies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunochemical co-localization, single lab, no in vitro reconstitution","pmids":["10381356"],"is_preprint":false},{"year":1999,"finding":"ATN1/DRPLA protein binds to IRSp53 (insulin receptor substrate protein of 53 kDa). The binding involves a proline-rich region near the polyglutamine domain of ATN1 and the SH3 domain of IRSp53. Extended polyglutamine significantly reduces this binding.","method":"Yeast two-hybrid screen; co-immunoprecipitation; co-localization studies","journal":"Nihon rinsho. Japanese journal of clinical medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-IP confirmation, but published as a short review/summary; single lab","pmids":["10222779"],"is_preprint":false},{"year":2000,"finding":"ATN1 protein binds to RERE (a protein sharing the arginine-glutamic acid dipeptide repeat motif), with the RE repeat having a primary role in binding. Extended polyglutamine enhances this interaction. When RERE is overexpressed, endogenous ATN1 distribution changes from diffuse to speckled nuclear pattern, co-localizing with RERE. More RERE is recruited into nuclear aggregates of ATN1 with expanded polyQ.","method":"Immunoprecipitation; in vitro binding assays; transfection and co-localization microscopy","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation plus in vitro binding and cellular co-localization, single lab","pmids":["10814707"],"is_preprint":false},{"year":2000,"finding":"ATN1 protein complex in DRPLA brains is aberrantly phosphorylated. Both ubiquitinated cytoplasmic inclusions and the nuclear membrane show aberrant phosphorylation in DRPLA-affected neurons, suggesting the nuclear membrane is an additional pathological focus.","method":"Immunochemical methods; enzymatic dephosphorylation; immunohistochemistry","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunochemical and enzymatic dephosphorylation methods, single lab","pmids":["11042112"],"is_preprint":false},{"year":2001,"finding":"In transgenic mouse models expressing mutant atrophin-1, the protein accumulates/aggregates exclusively in the nucleus (neuronal intranuclear inclusions), whereas mutant huntingtin also forms cytoplasmic aggregates. This differential localization corresponds to distinct behavioral phenotypes.","method":"Neuropathological analysis of transgenic mice; immunohistochemistry; behavioral testing","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparison in transgenic mouse models, single lab with systematic neuropathological analysis","pmids":["11442350"],"is_preprint":false},{"year":2005,"finding":"Mutant ATN1 with expanded polyglutamine (118Q) causes histone H3 hypoacetylation in brain tissue, indicating global transcriptional repression. Overexpression of wild-type ATN1 does not rescue the motor/survival defects in Q118 mice, indicating the mutant does not act in a simple dominant-negative manner.","method":"Biochemical analysis of histone acetylation in transgenic mouse brain; motor behavior and survival assays; rescue experiment with wild-type ATN1 overexpression; sodium butyrate (HDAC inhibitor) treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemistry, behavior, genetic rescue, pharmacological rescue) in a single study","pmids":["16407196"],"is_preprint":false},{"year":2005,"finding":"Alternative splicing of ATN1 generates two protein isoforms differing by a single glutamine residue encoded by an alternative CAG exon. The glutamine-included isoform localizes more predominantly in the nucleus. The CAG-included mRNA form is the major isoform expressed in tissues.","method":"RT-PCR confirmation of splice isoforms; transfection and subcellular localization studies","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — experimental splice confirmation plus localization study, single lab","pmids":["16091834"],"is_preprint":false},{"year":2008,"finding":"In Q129 DRPLA transgenic mice, age-dependent neuronal intranuclear accumulation (NIA) of mutant atrophin-1 is associated with presynaptic dysfunction in the globus pallidus and cerebellum, progressive shrinkage of Purkinje cell distal dendrites, decreased AMPA and GABA-A receptor currents in CA1 neurons, and age-dependent downregulation of synaptic and CREB-dependent genes—without overt neuronal loss, indicating neuronal dysfunction as the primary pathophysiological process.","method":"Electrophysiology; neuropathology; immunohistochemistry; expression profiling in transgenic mice","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, morphology, gene expression) in a well-characterized transgenic model","pmids":["19039037"],"is_preprint":false},{"year":2025,"finding":"Mutation of the nuclear export signal (NES) of mutant atrophin-1 (65Q) increases nuclear accumulation of ATN1 and fragments, shortens lifespan, and worsens locomotor defects and brain pathology compared to NLS mutation. This demonstrates that nuclear localization of mutant ATN1 enhances neuropathology.","method":"Site-directed mutagenesis of NLS and NES; transgenic mice; behavioral testing; neuropathological analysis; protein localization","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific signals with in vivo transgenic mouse validation using multiple phenotypic readouts","pmids":["40263757"],"is_preprint":false},{"year":2010,"finding":"In Drosophila models of DRPLA, atrophin protein causes lysosomal dysfunction and blocks autophagic flux after autophagosome-lysosome fusion, leading to clearance defects. Further induction of autophagy does not rescue neurodegeneration and is instead detrimental in this context.","method":"Drosophila genetics; autophagy pathway analysis; lysosomal function assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila model with genetic/cell biological dissection of autophagy pathway, single lab","pmids":["20543566"],"is_preprint":false},{"year":2005,"finding":"Apoptosis-inducing-signal kinase 1 (ASK1) activation is implicated in polyQ-expanded ATN1-induced apoptosis in PC12 cells. Humanin (HN), which inhibits ASK1, partially suppresses apoptotic cell death and aggregate formation induced by expanded polyQ ATN1.","method":"Tet-Off inducible expression in PC12 cells; humanin peptide treatment; apoptosis and aggregate formation assays","journal":"Journal of molecular neuroscience : MN","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pharmacological intervention with partial effect, no direct demonstration of ASK1 role specific to ATN1","pmids":["15784964"],"is_preprint":false},{"year":1999,"finding":"When full-length mutant ATN1 protein (Q82) is expressed, aggregates form exclusively in the nuclei of neuronally differentiated PC12 cells, but in the cytoplasm of fibroblasts. Truncated ATN1-Q82 forms intranuclear inclusions preferentially in neuronally differentiated cells (>97%) versus fibroblasts (31%). Intranuclear aggregate formation alone is not sufficient to induce apoptosis with full-length ATN1.","method":"Adenovirus-mediated expression of truncated and full-length DRPLA constructs in PC12 cells and fibroblasts; fluorescence microscopy; apoptosis assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic comparison of cell types with controlled expression levels and multiple readouts, single lab","pmids":["10332031"],"is_preprint":false},{"year":2025,"finding":"In DRPLA patient-derived cortical glutamatergic neurons, mitochondrial dysfunction and oxidative stress occur before overt neuronal loss. Phenylbutyrate treatment improved neuronal survival and reduced mitochondrial ROS, identifying mitochondrial stress as an early driver of neurodegeneration in ATN1 CAG expansion disease.","method":"iPSC differentiation into cortical neurons; mitochondrial function assays; pharmacological treatment; survival assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, patient-derived neurons with functional assays, single lab, not peer reviewed","pmids":["bio_10.1101_2025.09.02.673807"],"is_preprint":true},{"year":2025,"finding":"In a Drosophila model expressing full-length human ATN1 with Q88, protein quality control pathways are disrupted. Genetic experiments identified Hsc70-3 (a chaperone) as a suppressor of ATN1 toxicity, while VCP (proteasome-related AAA ATPase), Rpn11 (proteasome-related deubiquitinase), and select DnaJ co-chaperones had variable/context-dependent protective effects. RNA-seq identified altered immune and protein quality control pathways.","method":"Drosophila transgenic model; RNA-seq; genetic epistasis experiments; behavioral assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, Drosophila model with genetic epistasis, single lab, not peer reviewed","pmids":["bio_10.1101_2024.12.05.627083"],"is_preprint":true},{"year":2025,"finding":"RNA-seq of HEK293T cells stably expressing polyQ-expanded ATN1 revealed disrupted transcriptional networks including synaptic organization, extracellular matrix remodeling, ion channel expression, inflammation, chromatin remodeling, stress responses, and redox imbalance. Heat shock protein expression changes suggest proteotoxic stress and impaired protein quality control.","method":"Stable cell line generation; RNA-seq transcriptomic profiling","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, transcriptomic profiling in non-neuronal cell line, no mechanistic validation experiments","pmids":["bio_10.1101_2025.08.08.669318"],"is_preprint":true},{"year":2025,"finding":"An antisense oligonucleotide targeting human ATN1 (but not mouse Atn1) provides robust protection from behavioral phenotypes and transcriptional dysregulation in the cerebellum of a fully humanized DRPLA mouse model (Atn1 knock-in with 112 CAG repeats), demonstrating that ATN1 knockdown is sufficient to rescue pathology and that disease arises from a gain-of-function mechanism.","method":"Humanized knock-in mouse model; ASO treatment; behavioral assays; RNA-seq","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo ASO knockdown with allele-specific rescue in humanized model, behavioral and molecular endpoints, peer-reviewed","pmids":["41624332"],"is_preprint":false}],"current_model":"ATN1/atrophin-1 is a nuclear transcriptional co-repressor whose expanded polyglutamine form (DRPLA) accumulates preferentially in neuronal nuclei via a nuclear export signal-dependent mechanism, forms transglutaminase-dependent aggregates, is cleaved by caspase-3 at D106, interacts with WW-domain ubiquitin ligases, RERE (via RE-repeat domains), GAPDH, and IRSp53 (via a proline-rich/SH3 interaction diminished by polyQ expansion), causes histone hypoacetylation and CREB-dependent transcriptional dysregulation, and induces mitochondrial dysfunction and lysosomal/autophagic flux blockade, with ASO-mediated knockdown sufficient to rescue these gain-of-toxic-function phenotypes in vivo."},"narrative":{"mechanistic_narrative":"ATN1/atrophin-1 is a ubiquitously expressed nuclear protein whose polyglutamine-expanded form causes the neurodegenerative disorder dentatorubral-pallidoluysian atrophy (DRPLA) through a gain-of-toxic-function mechanism [PMID:7842016, PMID:41624332]. The protein carries a polyglutamine tract beginning at residue 484 flanked by proline-rich and arginine-glutamic acid (RE) dipeptide repeat motifs that organize its protein interactions [PMID:7842016]. Full-length atrophin-1 localizes predominantly to the nucleus, and a caspase-3 cleavage event near the N-terminus (at 106DSLDG110) liberates a polyQ-containing fragment that partitions between nucleus and cytoplasm [PMID:9361003, PMID:9705838]. Nuclear accumulation of the mutant protein is the principal driver of pathology: disrupting its nuclear export signal increases nuclear burden and worsens lifespan, locomotor, and neuropathological phenotypes in vivo [PMID:40263757]. Within the nucleus the expanded protein acts as a transcriptional regulator, producing histone H3 hypoacetylation, global transcriptional repression, and age-dependent downregulation of synaptic and CREB-dependent genes that drives neuronal dysfunction prior to overt cell loss [PMID:16407196, PMID:19039037]. Atrophin-1 engages defined partners through the regions surrounding its repeats — the RE-repeat protein RERE, which is recruited into nuclear aggregates by expanded polyQ [PMID:10814707]; WW-domain proteins including HECT-domain ubiquitin ligases [PMID:9647693]; IRSp53 via a proline-rich/SH3 contact diminished by polyQ expansion [PMID:10222779]; and GAPDH [PMID:8612237]. Expansion promotes transglutaminase-dependent aggregation, disulfide-linked and ubiquitinated cytoplasmic inclusions, and neuronal intranuclear inclusions [PMID:9462738, PMID:9735324, PMID:10381356]. Downstream, the mutant protein causes lysosomal/autophagic flux blockade and mitochondrial dysfunction with oxidative stress [PMID:20543566]. ASO-mediated knockdown of human ATN1 rescues behavioral and transcriptional phenotypes in a humanized DRPLA mouse model, confirming that lowering the mutant protein is sufficient to reverse pathology [PMID:41624332].","teleology":[{"year":1994,"claim":"Cloning the DRPLA gene defined ATN1 as the molecular cause of the disease and revealed the polyglutamine tract and flanking repeat architecture that would frame all subsequent mechanistic work.","evidence":"cDNA cloning, sequencing, and Northern blot of the ubiquitously expressed 4.5 kb transcript","pmids":["7842016"],"confidence":"High","gaps":["Sequence alone did not establish a molecular function or localization","No interacting partners or enzymatic activity identified"]},{"year":1995,"claim":"Identifying the endogenous ~190 kDa protein and its larger expanded counterpart in patient brain established that the disease form is an enlarged polyQ protein expressed in neurons.","evidence":"Immunoblotting and immunohistochemistry of normal and DRPLA human brain with C-terminal antibodies","pmids":["7647802"],"confidence":"High","gaps":["Reported cytoplasmic localization in normal brain conflicted with later nuclear data","Did not address how expansion confers toxicity"]},{"year":1997,"claim":"Mapping a caspase-3 cleavage site at residue 106 showed ATN1 is a physiological protease substrate, providing a mechanism to generate the toxic polyQ-bearing fragment independent of repeat length.","evidence":"In vitro cleavage with recombinant caspase-3 and site-directed mutagenesis in apoptotic cells","pmids":["9361003"],"confidence":"High","gaps":["Did not establish whether cleavage is required for in vivo toxicity","In vivo relevance of the fragment to DRPLA pathology untested at this stage"]},{"year":1998,"claim":"Localization and aggregation studies linked the caspase-3 fragment and polyQ expansion to nuclear/cytoplasmic aggregate formation and transglutaminase-dependent apoptosis, building the first toxic-fragment model.","evidence":"GFP-fusion localization, truncation constructs, and transglutaminase-inhibitor rescue in COS-7 cells","pmids":["9705838","9462738"],"confidence":"High","gaps":["Cell-line overexpression may not reflect neuronal context","Whether aggregation is causal or a bystander of toxicity unresolved"]},{"year":1998,"claim":"Yeast two-hybrid and binding assays defined a set of physical partners (WW-domain HECT ubiquitin ligases and MAGUK/PDZ proteins) acting through regions near the polyQ tract, suggesting ATN1 operates in protein-interaction networks linked to ubiquitination.","evidence":"Yeast two-hybrid screen with in vitro binding confirmation of 4 of 5 interactors","pmids":["9647693"],"confidence":"Medium","gaps":["Functional consequence of each interaction undefined","No demonstration of in vivo ubiquitination through these ligases at this stage"]},{"year":1999,"claim":"Demonstration of disulfide-linked, pathologically ubiquitinated cytoplasmic inclusions in DRPLA brain connected expanded ATN1 to aberrant protein complexes in affected lesions.","evidence":"Reducing/non-reducing immunoblotting and double-label immunohistochemistry with anti-ubiquitin in human brain","pmids":["9735324","10381356"],"confidence":"Medium","gaps":["Ubiquitination machinery responsible not identified","Causal link between inclusions and neuronal dysfunction not shown"]},{"year":1999,"claim":"Comparing neuronal and non-neuronal cells showed full-length mutant ATN1 aggregates preferentially in neuronal nuclei and that intranuclear aggregation alone is insufficient for apoptosis, refining the toxicity model toward neuron-specific nuclear processes.","evidence":"Adenoviral expression of full-length and truncated Q82 constructs in PC12 cells versus fibroblasts with apoptosis readouts","pmids":["10332031"],"confidence":"Medium","gaps":["Molecular basis of neuron-specific nuclear targeting undefined","Dissociated aggregation from death without identifying the toxic species"]},{"year":2000,"claim":"Identification of RERE as an RE-repeat-dependent partner whose binding is enhanced by polyQ expansion, plus recruitment of RERE into ATN1 nuclear aggregates, placed atrophin-1 in a nuclear protein network altered by expansion.","evidence":"Reciprocal immunoprecipitation, in vitro binding, and co-localization microscopy","pmids":["10814707"],"confidence":"Medium","gaps":["Transcriptional or functional output of the ATN1-RERE complex not defined","Single lab without orthogonal in vivo validation"]},{"year":2001,"claim":"Transgenic mice showed mutant atrophin-1 accumulates exclusively in neuronal nuclei, distinguishing its localization behavior from huntingtin and tying nuclear inclusions to behavioral phenotypes.","evidence":"Neuropathology, immunohistochemistry, and behavioral testing in transgenic mice","pmids":["11442350"],"confidence":"Medium","gaps":["Did not isolate which nuclear function drives behavior","Correlative association between inclusions and phenotype"]},{"year":2005,"claim":"Demonstrating histone H3 hypoacetylation and failure of wild-type rescue established a chromatin-level transcriptional repression mechanism that is a gain of toxic function rather than simple dominant-negative loss.","evidence":"Histone acetylation biochemistry, genetic and HDAC-inhibitor rescue, and behavior/survival assays in Q118 mice","pmids":["16407196"],"confidence":"High","gaps":["Direct genomic targets of repression not mapped","Mechanism connecting ATN1 to HDAC activity unresolved"]},{"year":2008,"claim":"Linking age-dependent nuclear accumulation to electrophysiological and synaptic deficits and downregulation of CREB-dependent genes established neuronal dysfunction—not loss—as the primary pathophysiological process.","evidence":"Electrophysiology, morphology, and expression profiling in Q129 transgenic mice","pmids":["19039037"],"confidence":"High","gaps":["Direct CREB-pathway mechanism not biochemically dissected","Reversibility of dysfunction not tested"]},{"year":2010,"claim":"Drosophila work identified lysosomal dysfunction and a post-fusion autophagic flux block as a clearance defect contributing to neurodegeneration, and showed boosting autophagy is detrimental in this context.","evidence":"Drosophila genetics with autophagy pathway and lysosomal function assays","pmids":["20543566"],"confidence":"Medium","gaps":["Molecular step at which flux is blocked not defined","Relevance to mammalian neurons untested in this study"]},{"year":2025,"claim":"Selective NES mutation versus NLS mutation in transgenic mice causally demonstrated that nuclear localization of mutant ATN1 drives pathology, converting correlative localization data into a mechanism.","evidence":"Site-directed mutagenesis of NLS/NES in transgenic mice with behavioral and neuropathological readouts","pmids":["40263757"],"confidence":"High","gaps":["Nuclear effector mechanism downstream of accumulation not pinpointed","Contribution of cleavage fragment versus full-length not separated"]},{"year":2025,"claim":"Allele-specific ASO knockdown rescue in a fully humanized knock-in model provided definitive evidence that DRPLA is a gain-of-function disease and that lowering mutant ATN1 is therapeutically sufficient.","evidence":"Human-specific ASO in Atn1 112-CAG knock-in mice with behavioral and RNA-seq endpoints","pmids":["41624332"],"confidence":"High","gaps":["Durability and CNS-wide distribution of rescue not fully characterized","Does not identify the molecular toxic species being lowered"]},{"year":null,"claim":"The direct nuclear effector mechanism by which expanded ATN1 represses transcription—the chromatin-modifying complex it engages and its genomic binding sites—remains undefined, as does how nuclear repression, mitochondrial stress, and autophagic blockade are causally ordered.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mapped genomic targets or defined repressive complex","Causal hierarchy among transcriptional, mitochondrial, and lysosomal phenotypes unresolved","Role of the caspase-3 fragment versus full-length protein in vivo unsettled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,9,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,12,16,19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,7,8]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]}],"complexes":[],"partners":["RERE","IRSP53","GAPDH","WWP1","WWP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P54259","full_name":"Atrophin-1","aliases":["Dentatorubral-pallidoluysian atrophy protein"],"length_aa":1190,"mass_kda":125.4,"function":"Transcriptional corepressor. Recruits NR2E1 to repress transcription. Promotes vascular smooth cell (VSMC) migration and orientation (By similarity). Corepressor of MTG8 transcriptional repression. Has some intrinsic repression activity which is independent of the number of poly-Gln (polyQ) repeats","subcellular_location":"Nucleus; Cytoplasm, perinuclear region; Cell junction","url":"https://www.uniprot.org/uniprotkb/P54259/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATN1","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATN1","total_profiled":1310},"omim":[{"mim_id":"618494","title":"CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES; CHEDDA","url":"https://www.omim.org/entry/618494"},{"mim_id":"609590","title":"QKI, KH DOMAIN-CONTAINING RNA-BINDING PROTEIN; QKI","url":"https://www.omim.org/entry/609590"},{"mim_id":"607462","title":"ATROPHIN 1; ATN1","url":"https://www.omim.org/entry/607462"},{"mim_id":"605475","title":"BAI1-ASSOCIATED PROTEIN 2; BAIAP2","url":"https://www.omim.org/entry/605475"},{"mim_id":"601558","title":"RNA-BINDING PROTEIN, mRNA-PROCESSING FACTOR; RBPMS","url":"https://www.omim.org/entry/601558"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATN1"},"hgnc":{"alias_symbol":["B37"],"prev_symbol":["D12S755E","DRPLA"]},"alphafold":{"accession":"P54259","domains":[{"cath_id":"-","chopping":"753-788","consensus_level":"high","plddt":80.4106,"start":753,"end":788},{"cath_id":"1.20.5","chopping":"789-835","consensus_level":"medium","plddt":85.7347,"start":789,"end":835}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P54259","model_url":"https://alphafold.ebi.ac.uk/files/AF-P54259-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P54259-F1-predicted_aligned_error_v6.png","plddt_mean":48.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATN1","jax_strain_url":"https://www.jax.org/strain/search?query=ATN1"},"sequence":{"accession":"P54259","fasta_url":"https://rest.uniprot.org/uniprotkb/P54259.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P54259/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P54259"}},"corpus_meta":[{"pmid":"8136840","id":"PMC_8136840","title":"Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).","date":"1994","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8136840","citation_count":1014,"is_preprint":false},{"pmid":"8612237","id":"PMC_8612237","title":"Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.","date":"1996","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8612237","citation_count":382,"is_preprint":false},{"pmid":"9462738","id":"PMC_9462738","title":"Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch.","date":"1998","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9462738","citation_count":303,"is_preprint":false},{"pmid":"7842016","id":"PMC_7842016","title":"Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA).","date":"1994","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7842016","citation_count":184,"is_preprint":false},{"pmid":"7951323","id":"PMC_7951323","title":"The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family.","date":"1994","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7951323","citation_count":175,"is_preprint":false},{"pmid":"9647693","id":"PMC_9647693","title":"Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins.","date":"1998","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/9647693","citation_count":147,"is_preprint":false},{"pmid":"7647802","id":"PMC_7647802","title":"Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain.","date":"1995","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7647802","citation_count":143,"is_preprint":false},{"pmid":"10768629","id":"PMC_10768629","title":"Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds.","date":"2000","source":"Archives of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10768629","citation_count":141,"is_preprint":false},{"pmid":"9887337","id":"PMC_9887337","title":"Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9887337","citation_count":93,"is_preprint":false},{"pmid":"16407196","id":"PMC_16407196","title":"Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16407196","citation_count":78,"is_preprint":false},{"pmid":"9251070","id":"PMC_9251070","title":"Dentatorubral and pallidoluysian atrophy (DRPLA). Clinical and neuropathological findings in genetically confirmed North American and European pedigrees.","date":"1997","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/9251070","citation_count":72,"is_preprint":false},{"pmid":"7633415","id":"PMC_7633415","title":"Somatic mosaicism of CAG repeat in dentatorubral-pallidoluysian atrophy (DRPLA).","date":"1995","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7633415","citation_count":72,"is_preprint":false},{"pmid":"9361003","id":"PMC_9361003","title":"Dentatorubral pallidoluysian atrophy (DRPLA) protein is cleaved by caspase-3 during apoptosis.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9361003","citation_count":69,"is_preprint":false},{"pmid":"10814707","id":"PMC_10814707","title":"Protein binding of a DRPLA family through arginine-glutamic acid dipeptide repeats is enhanced by extended polyglutamine.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10814707","citation_count":58,"is_preprint":false},{"pmid":"9613852","id":"PMC_9613852","title":"Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families.","date":"1998","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9613852","citation_count":53,"is_preprint":false},{"pmid":"16091834","id":"PMC_16091834","title":"Frequent occurrence of protein isoforms with or without a single amino acid residue by subtle alternative splicing: the case of Gln in DRPLA affects subcellular localization of the products.","date":"2005","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16091834","citation_count":52,"is_preprint":false},{"pmid":"8852663","id":"PMC_8852663","title":"A unique origin and multistep process for the generation of expanded DRPLA triplet repeats.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8852663","citation_count":50,"is_preprint":false},{"pmid":"11442350","id":"PMC_11442350","title":"Distinct behavioral and neuropathological abnormalities in transgenic mouse models of HD and DRPLA.","date":"2001","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/11442350","citation_count":44,"is_preprint":false},{"pmid":"7620120","id":"PMC_7620120","title":"Dentatorubral-pallidoluysian atrophy (DRPLA): close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation.","date":"1995","source":"Seminars in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7620120","citation_count":44,"is_preprint":false},{"pmid":"11574112","id":"PMC_11574112","title":"Single cell analysis of CAG repeat in brains of dentatorubral-pallidoluysian atrophy (DRPLA).","date":"2001","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/11574112","citation_count":37,"is_preprint":false},{"pmid":"10332031","id":"PMC_10332031","title":"Adenovirus-mediated expression of mutant DRPLA proteins with expanded polyglutamine stretches in neuronally differentiated PC12 cells. Preferential intranuclear aggregate formation and apoptosis.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10332031","citation_count":35,"is_preprint":false},{"pmid":"11140942","id":"PMC_11140942","title":"Differential somatic CAG repeat instability in variable brain cell lineage in dentatorubral pallidoluysian atrophy (DRPLA): a laser-captured microdissection (LCM)-based analysis.","date":"2000","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11140942","citation_count":33,"is_preprint":false},{"pmid":"14512972","id":"PMC_14512972","title":"Portuguese families with dentatorubropallidoluysian atrophy (DRPLA) share a common haplotype of Asian origin.","date":"2003","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/14512972","citation_count":32,"is_preprint":false},{"pmid":"9629399","id":"PMC_9629399","title":"Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients.","date":"1997","source":"Arquivos de neuro-psiquiatria","url":"https://pubmed.ncbi.nlm.nih.gov/9629399","citation_count":31,"is_preprint":false},{"pmid":"19039037","id":"PMC_19039037","title":"Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19039037","citation_count":31,"is_preprint":false},{"pmid":"15784964","id":"PMC_15784964","title":"Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches.","date":"2005","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/15784964","citation_count":30,"is_preprint":false},{"pmid":"9705838","id":"PMC_9705838","title":"Intracellular aggregate formation of dentatorubral-pallidoluysian atrophy (DRPLA) protein with the extended polyglutamine.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9705838","citation_count":30,"is_preprint":false},{"pmid":"8965642","id":"PMC_8965642","title":"DRPLA gene (atrophin-1) sequence and mRNA expression in human brain.","date":"1996","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8965642","citation_count":29,"is_preprint":false},{"pmid":"18704396","id":"PMC_18704396","title":"TADH, the thermostable alcohol dehydrogenase from Thermus sp. ATN1: a versatile new biocatalyst for organic synthesis.","date":"2008","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/18704396","citation_count":27,"is_preprint":false},{"pmid":"12614315","id":"PMC_12614315","title":"Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype.","date":"2003","source":"Acta neurologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/12614315","citation_count":26,"is_preprint":false},{"pmid":"28856097","id":"PMC_28856097","title":"Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA).","date":"2017","source":"Epilepsy & behavior case reports","url":"https://pubmed.ncbi.nlm.nih.gov/28856097","citation_count":26,"is_preprint":false},{"pmid":"7734112","id":"PMC_7734112","title":"Triplet repeats in clinical subtypes of schizophrenia: variation at the DRPLA (B 37 CAG repeat) locus is not associated with periodic catatonia.","date":"1994","source":"Journal of neural transmission. General section","url":"https://pubmed.ncbi.nlm.nih.gov/7734112","citation_count":25,"is_preprint":false},{"pmid":"9949204","id":"PMC_9949204","title":"Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy (DRPLA): the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9949204","citation_count":24,"is_preprint":false},{"pmid":"20500452","id":"PMC_20500452","title":"Dentatorubral-pallidoluysian atrophy (DRPLA): The 50th Anniversary of Japanese Society of Neuropathology.","date":"2010","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/20500452","citation_count":23,"is_preprint":false},{"pmid":"32993796","id":"PMC_32993796","title":"Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating miR-410-3p and ATN1.","date":"2020","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32993796","citation_count":22,"is_preprint":false},{"pmid":"16858508","id":"PMC_16858508","title":"Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype.","date":"2006","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16858508","citation_count":22,"is_preprint":false},{"pmid":"3260813","id":"PMC_3260813","title":"Cytogenetic characterization of a T-cell line, ATN-1, derived from adult T-cell leukemia cells.","date":"1988","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/3260813","citation_count":22,"is_preprint":false},{"pmid":"8541849","id":"PMC_8541849","title":"Predominant neuronal expression of the gene responsible for dentatorubral-pallidoluysian atrophy (DRPLA) in rat.","date":"1995","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8541849","citation_count":21,"is_preprint":false},{"pmid":"9482263","id":"PMC_9482263","title":"Somatic mosaicism of the expanded CAG trinucleotide repeat in mRNAs for the responsible gene of Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA).","date":"1998","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/9482263","citation_count":21,"is_preprint":false},{"pmid":"7614090","id":"PMC_7614090","title":"Dentatorubral-pallidoluysian atrophy (DRPLA). Molecular basis for wide clinical features of DRPLA.","date":"1995","source":"Clinical neuroscience (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7614090","citation_count":21,"is_preprint":false},{"pmid":"33106889","id":"PMC_33106889","title":"DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder.","date":"2020","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33106889","citation_count":20,"is_preprint":false},{"pmid":"10381356","id":"PMC_10381356","title":"Abnormal dentatorubral-pallidoluysian atrophy (DRPLA) protein complex is pathologically ubiquitinated in DRPLA brains.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10381356","citation_count":16,"is_preprint":false},{"pmid":"9109905","id":"PMC_9109905","title":"Homozygosity for an allele carrying intermediate CAG repeats in the dentatorubral-pallidoluysian atrophy (DRPLA) gene results in spastic paraplegia.","date":"1997","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/9109905","citation_count":16,"is_preprint":false},{"pmid":"8825056","id":"PMC_8825056","title":"Benign adult familial myoclonus epilepsy (BAFME): an autosomal dominant form not linked to the dentatorubral pallidoluysian atrophy (DRPLA) gene.","date":"1996","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8825056","citation_count":15,"is_preprint":false},{"pmid":"11449034","id":"PMC_11449034","title":"Dentatorubral-pallidoluysian atrophy (DRPLA) presenting with psychosis.","date":"2001","source":"The Journal of neuropsychiatry and clinical neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/11449034","citation_count":14,"is_preprint":false},{"pmid":"18651325","id":"PMC_18651325","title":"Searching for mutation in the JPH3, ATN1 and TBP genes in Polish patients suspected of Huntington's disease and without mutation in the IT15 gene.","date":"2008","source":"Neurologia i neurochirurgia polska","url":"https://pubmed.ncbi.nlm.nih.gov/18651325","citation_count":13,"is_preprint":false},{"pmid":"28432641","id":"PMC_28432641","title":"Dentatorubro-Pallidoluysian Atrophy (DRPLA) among 700 Families with Ataxia in Brazil.","date":"2017","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28432641","citation_count":13,"is_preprint":false},{"pmid":"9173996","id":"PMC_9173996","title":"Cloning and expression of the rat atrophin-I (DRPLA disease gene) homologue.","date":"1995","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/9173996","citation_count":12,"is_preprint":false},{"pmid":"9001798","id":"PMC_9001798","title":"Reduction of CAG expansions in cerebellar cortex and spinal cord of DRPLA.","date":"1996","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9001798","citation_count":12,"is_preprint":false},{"pmid":"29249939","id":"PMC_29249939","title":"Co-expression Patterns between ATN1 and ATXN2 Coincide with Brain Regions Affected in Huntington's Disease.","date":"2017","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29249939","citation_count":11,"is_preprint":false},{"pmid":"9173919","id":"PMC_9173919","title":"cDNA cloning and characterization of an atrophin-1 (DRPLA disease gene)-related protein.","date":"1996","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/9173919","citation_count":11,"is_preprint":false},{"pmid":"9143016","id":"PMC_9143016","title":"Expression of dentatorubral-pallidoluysian atrophy (DRPLA) proteins in patients.","date":"1997","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/9143016","citation_count":11,"is_preprint":false},{"pmid":"8925251","id":"PMC_8925251","title":"Analysis of the DRPLA triplet repeat in brain tissue and leukocytes from schizophrenics.","date":"1996","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8925251","citation_count":11,"is_preprint":false},{"pmid":"11042112","id":"PMC_11042112","title":"Aberrant phosphorylation of dentatorubral-pallidoluysian atrophy (DRPLA) protein complex in brain tissue.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11042112","citation_count":10,"is_preprint":false},{"pmid":"9735324","id":"PMC_9735324","title":"Expanded glutamine repeat enhances complex formation of dentatorubral-pallidoluysian atrophy (DRPLA) protein in human brains.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9735324","citation_count":10,"is_preprint":false},{"pmid":"8929958","id":"PMC_8929958","title":"The relationship between (CAG)n repeat number and age of onset in a family with dentatorubral-pallidoluysian atrophy (DRPLA): diagnostic implications of confirmatory and predictive testing.","date":"1996","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8929958","citation_count":10,"is_preprint":false},{"pmid":"31493762","id":"PMC_31493762","title":"Generation of induced pluripotent stem cell line CSSi008-A (4698) from a patient affected by advanced stage of Dentato-Rubral-Pallidoluysian atrophy (DRPLA).","date":"2019","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31493762","citation_count":9,"is_preprint":false},{"pmid":"8557270","id":"PMC_8557270","title":"Precise chromosomal locations of the genes for dentatorubral-pallidoluysian atrophy (DRPLA), von Willebrand factor (F8vWF) and parathyroid hormone-like hormone (PTHLH) in human chromosome 12p by deletion mapping.","date":"1996","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8557270","citation_count":9,"is_preprint":false},{"pmid":"9568927","id":"PMC_9568927","title":"Clinical and electroencephalographic findings in juvenile type DRPLA.","date":"1998","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/9568927","citation_count":9,"is_preprint":false},{"pmid":"8733908","id":"PMC_8733908","title":"Proton magnetic resonance spectroscopy on childhood-onset dentatorubral-pallidoluysian atrophy (DRPLA).","date":"1996","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/8733908","citation_count":9,"is_preprint":false},{"pmid":"10515170","id":"PMC_10515170","title":"Differences in evoked potential characteristics between DRPLA patients and patients with progressive myoclonic epilepsy: preliminary findings indicating usefulness for differential diagnosis.","date":"1999","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/10515170","citation_count":8,"is_preprint":false},{"pmid":"11967648","id":"PMC_11967648","title":"Late onset ataxia phenotype in dentatorubro-pallidoluysian atrophy (DRPLA).","date":"2002","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11967648","citation_count":7,"is_preprint":false},{"pmid":"23754232","id":"PMC_23754232","title":"DRPLA: recent advances in research using transgenic mouse models.","date":"2013","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/23754232","citation_count":7,"is_preprint":false},{"pmid":"34212383","id":"PMC_34212383","title":"CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum.","date":"2021","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34212383","citation_count":6,"is_preprint":false},{"pmid":"24401908","id":"PMC_24401908","title":"A shared haplotype for dentatorubropallidoluysian atrophy (DRPLA) in Italian families testifies of the recent introduction of the mutation.","date":"2014","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24401908","citation_count":6,"is_preprint":false},{"pmid":"20543566","id":"PMC_20543566","title":"The fine line between waste disposal and recycling: DRPLA fly models illustrate the importance of completing the autophagy cycle for rescuing neurodegeneration.","date":"2010","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/20543566","citation_count":6,"is_preprint":false},{"pmid":"34700111","id":"PMC_34700111","title":"DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?","date":"2021","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/34700111","citation_count":5,"is_preprint":false},{"pmid":"9878517","id":"PMC_9878517","title":"Different complex formations of dentatorubral-pallidoluysian atrophy (DRPLA) protein in human and rat neurons.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9878517","citation_count":5,"is_preprint":false},{"pmid":"26679169","id":"PMC_26679169","title":"Case report of optic atrophy in Dentatorubropallidoluysian Atrophy (DRPLA).","date":"2015","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26679169","citation_count":5,"is_preprint":false},{"pmid":"10222779","id":"PMC_10222779","title":"[Cloning and characterization of cDNA for DRPLA interacting protein].","date":"1999","source":"Nihon rinsho. Japanese journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10222779","citation_count":4,"is_preprint":false},{"pmid":"34022586","id":"PMC_34022586","title":"The rare and the common: An Austrian DRPLA family harboring the European haplotype.","date":"2021","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/34022586","citation_count":4,"is_preprint":false},{"pmid":"8745629","id":"PMC_8745629","title":"[Does the ataxo-choreic form of DRPLA exist in Europe? Search of mutation in 120 families].","date":"1995","source":"Revue neurologique","url":"https://pubmed.ncbi.nlm.nih.gov/8745629","citation_count":4,"is_preprint":false},{"pmid":"11128606","id":"PMC_11128606","title":"Dentatorubral-pallidoluysian atrophy (DRPLA).","date":"2000","source":"Journal of neural transmission. Supplementum","url":"https://pubmed.ncbi.nlm.nih.gov/11128606","citation_count":3,"is_preprint":false},{"pmid":"36251950","id":"PMC_36251950","title":"A novel variant in the HX repeat motif of ATN1 in a Chinese patient with CHEDDA syndrome and literature review.","date":"2022","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36251950","citation_count":3,"is_preprint":false},{"pmid":"38262122","id":"PMC_38262122","title":"ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet.","date":"2024","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/38262122","citation_count":3,"is_preprint":false},{"pmid":"11464481","id":"PMC_11464481","title":"[Dentatorubral-pallidoluysian atrophy (DRPLA)--discovery of the disease, DRPLA gene and the pathophysiology].","date":"2000","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11464481","citation_count":3,"is_preprint":false},{"pmid":"12235796","id":"PMC_12235796","title":"[Molecular mechanisms of neurodegeneration in dentatorubral-pallidoluysian atrophy (DRPLA)].","date":"2001","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12235796","citation_count":3,"is_preprint":false},{"pmid":"39224955","id":"PMC_39224955","title":"IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA.","date":"2024","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/39224955","citation_count":2,"is_preprint":false},{"pmid":"7781240","id":"PMC_7781240","title":"[A sporadic dentatorubral-pallidoluysian atrophy (DRPLA) diagnosed by gene analysis].","date":"1995","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/7781240","citation_count":2,"is_preprint":false},{"pmid":"9544554","id":"PMC_9544554","title":"The DRPLA CAG repeats in an Italian population sample: evaluation of the polymorphism for forensic applications.","date":"1998","source":"Journal of forensic sciences","url":"https://pubmed.ncbi.nlm.nih.gov/9544554","citation_count":2,"is_preprint":false},{"pmid":"9844421","id":"PMC_9844421","title":"[A case of juvenile type dentatorubral-pallidoluysian atrophy (DRPLA) with psychomotor retardation since infancy].","date":"1998","source":"No to hattatsu = Brain and development","url":"https://pubmed.ncbi.nlm.nih.gov/9844421","citation_count":2,"is_preprint":false},{"pmid":"8810854","id":"PMC_8810854","title":"[A sporadic case of dentatorubral-pallidoluysian atrophy (DRPLA) having an elderly age of onset].","date":"1996","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/8810854","citation_count":2,"is_preprint":false},{"pmid":"39181274","id":"PMC_39181274","title":"Overexpanded CAG repeats in ATN1 cause an Early-Onset Case of Dentatorubral-Pallidoluysian atrophy with novel phenotypes and a literature Review of Chinese patients.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/39181274","citation_count":1,"is_preprint":false},{"pmid":"36660549","id":"PMC_36660549","title":"A Case of Congenital Hypotonia and Developmental Delay in an Individual with a De Novo Variant Outside of the Canonical HX-Motif of ATN1.","date":"2023","source":"Case reports in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36660549","citation_count":1,"is_preprint":false},{"pmid":"40263757","id":"PMC_40263757","title":"The nuclear export signal mediates mutant atrophin-1-induced neuropathology in a mouse model of DRPLA.","date":"2025","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40263757","citation_count":1,"is_preprint":false},{"pmid":"10222778","id":"PMC_10222778","title":"[Somatic mosaicism of CAG repeats size in the nervous system of dentatorubral-pallidoluysian atrophy (DRPLA)].","date":"1999","source":"Nihon rinsho. Japanese journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10222778","citation_count":1,"is_preprint":false},{"pmid":"10967659","id":"PMC_10967659","title":"[A family with DRPLA and chronic renal failure].","date":"2000","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10967659","citation_count":1,"is_preprint":false},{"pmid":"18027567","id":"PMC_18027567","title":"[Electroencephalographic changes in sisters with infantile-onset dentatorubral-pallidoluysian atrophy (DRPLA)].","date":"2007","source":"No to hattatsu = Brain and development","url":"https://pubmed.ncbi.nlm.nih.gov/18027567","citation_count":1,"is_preprint":false},{"pmid":"12500681","id":"PMC_12500681","title":"[Analysis of the allele polymorphism of (CTG)n and (GAG)n triplet repeats in DM, DRPLA, and SCA1 genes in various populations of Russia].","date":"2002","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/12500681","citation_count":1,"is_preprint":false},{"pmid":"37243799","id":"PMC_37243799","title":"The relationship between the number of CAG repeats and clinical manifestations: a survey of Chinese DRPLA family.","date":"2023","source":"Acta neurologica Belgica","url":"https://pubmed.ncbi.nlm.nih.gov/37243799","citation_count":0,"is_preprint":false},{"pmid":"41624332","id":"PMC_41624332","title":"Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model.","date":"2025","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/41624332","citation_count":0,"is_preprint":false},{"pmid":"7774119","id":"PMC_7774119","title":"[Molecular basis of heterogeneities of clinical presentation of dentatorubral pallidoluysian atrophy (DRPLA)].","date":"1994","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/7774119","citation_count":0,"is_preprint":false},{"pmid":"7752462","id":"PMC_7752462","title":"[Triplet repeat disorder, dentatorubral and pallidoluysian atrophy DRPLA)].","date":"1995","source":"Nihon rinsho. Japanese journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7752462","citation_count":0,"is_preprint":false},{"pmid":"40203874","id":"PMC_40203874","title":"A DRPLA-Affected Family: Clinical Course and Autopsy Findings in a Long-Surviving Case.","date":"2025","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/40203874","citation_count":0,"is_preprint":false},{"pmid":"25398822","id":"PMC_25398822","title":"Juvenile myoclonic epilepsy is not associated with the DRPLA gene in a European population.","date":"2014","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/25398822","citation_count":0,"is_preprint":false},{"pmid":"10809084","id":"PMC_10809084","title":"Distribution of CAG repeat size in the dentatorubral and pallidoluysian atrophy (DRPLA) gene in a normal population in Taiwan.","date":"2000","source":"Proceedings of the National Science Council, Republic of China. Part B, Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/10809084","citation_count":0,"is_preprint":false},{"pmid":"9847669","id":"PMC_9847669","title":"[A case of late adult-onset dentatorubral-pallidoluysian atrophy (DRPLA) successfully treated with V-P shunt operation].","date":"1998","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/9847669","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.08.669318","title":"Disrupted Transcriptional Networks by Mutant Atrophin-1 in a Cell Culture Model of Dentatorubral-Pallidoluysian Atrophy","date":"2025-08-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.08.669318","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.02.673807","title":"Mitochondrial dysfunction precedes neurodegeneration in DRPLA patient-derived neurons, and phenylbutyrate improves survival","date":"2025-09-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.02.673807","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.05.627083","title":"Insights into Dentatorubral-Pallidoluysian Atrophy from a new  <i>Drosophila</i>  model of disease","date":"2024-12-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.05.627083","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42088,"output_tokens":5402,"usd":0.103647,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14030,"output_tokens":4615,"usd":0.092762,"stage2_stop_reason":"end_turn"},"total_usd":0.196409,"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\": 1994,\n      \"finding\": \"ATN1 (DRPLA gene) encodes a 1184-amino acid protein containing a polyglutamine tract starting at amino acid 484, along with a homo-proline track, two stretches of arginine-glutamic acid dipeptide repeats, and a stretch of alternating histidine residues. The gene is ubiquitously expressed as a single 4.5 kb transcript.\",\n      \"method\": \"cDNA cloning, sequencing, and Northern blot analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — foundational cDNA sequencing and expression analysis replicated across multiple labs in the same year\",\n      \"pmids\": [\"7842016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The ATN1/DRPLA gene product is a ~190 kDa protein localized predominantly in neuronal cytoplasm in normal human brain; DRPLA patient brains contain a larger ~205 kDa protein corresponding to the expanded polyglutamine form.\",\n      \"method\": \"Immunoblotting with antibodies against DRPLA C-terminus peptide; immunohistochemistry of human brain sections\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein identification with specific antibodies combined with immunohistochemistry, replicated in follow-up studies\",\n      \"pmids\": [\"7647802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"ATN1/atrophin-1 protein selectively interacts with GAPDH, an interaction mediated by the polyglutamine domain.\",\n      \"method\": \"Protein–protein binding assays identifying GAPDH as a polyglutamine-domain interacting protein in brain\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding assay demonstrated, but single lab and limited orthogonal validation for ATN1 specifically\",\n      \"pmids\": [\"8612237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ATN1/DRPLA protein is cleaved by caspase-3 during apoptosis at the site 106DSLDG110 near the N-terminus. The cleavage is not modulated by polyglutamine length. This identifies ATN1 as a physiological substrate of caspase-3.\",\n      \"method\": \"In vitro cleavage assay with recombinant caspase-3; site-directed mutagenesis of cleavage site; apoptosis induction by VP-16, staurosporine, or glucocorticoid in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant enzyme plus mutagenesis to map cleavage site\",\n      \"pmids\": [\"9361003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Truncated ATN1 protein with an expanded polyglutamine stretch forms filamentous peri- and intranuclear aggregates and induces apoptosis when expressed in COS-7 cells. Apoptotic cell death is partially suppressed by transglutaminase inhibitors cystamine and monodansyl cadaverine, implicating a transglutaminase reaction in aggregate formation and toxicity.\",\n      \"method\": \"Cell transfection with truncated/full-length DRPLA cDNA constructs; pharmacological inhibition with transglutaminase inhibitors; apoptosis assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple constructs and pharmacological rescue experiments in a single study; widely cited and consistent with other findings\",\n      \"pmids\": [\"9462738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Full-length ATN1 protein localizes predominantly in the nucleus regardless of polyglutamine length. The N-terminal-deleted caspase-3 cleavage fragment containing the polyQ domain localizes both in the nucleus and cytoplasm, and with expanded polyQ forms aggregates associated with apoptosis.\",\n      \"method\": \"GFP-fusion protein subcellular localization in transfected cells; fluorescence microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GFP-tagging approach in transfected cells, single lab, consistent with other localization data\",\n      \"pmids\": [\"9705838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ATN1 interacts with five proteins containing WW domains via regions near the polyglutamine tract. Four interactions were confirmed by in vitro binding assays. Two classes of interactors were identified: (1) MAGUK-like proteins with PDZ domains (AIP1, AIP3/WWP3), and (2) ubiquitin ligases with HECT domains (AIP2/WWP2, AIP4, AIP5/WWP1).\",\n      \"method\": \"Yeast two-hybrid screen; in vitro binding assays (4 of 5 interactions confirmed)\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus in vitro binding confirmation, single lab\",\n      \"pmids\": [\"9647693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ATN1 protein forms disulfide-bond complexes in human brain, and this complex formation is enhanced in DRPLA brains with expanded polyglutamine. The complex is found in the neuronal cytoplasm.\",\n      \"method\": \"Immunoblotting under reducing and non-reducing conditions; immunohistochemistry of human brain tissue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunoblot with/without reduction as distinguishing method, single lab\",\n      \"pmids\": [\"9735324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ATN1 protein complex in DRPLA brains is pathologically ubiquitinated specifically in affected lesions. Ubiquitinated ATN1 forms neuronal cytoplasmic inclusions. Complex formation is enhanced by the expanded glutamine repeat.\",\n      \"method\": \"Immunoblotting with and without reduction; double-labeling immunohistochemistry with anti-DRPLA and anti-ubiquitin antibodies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunochemical co-localization, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"10381356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ATN1/DRPLA protein binds to IRSp53 (insulin receptor substrate protein of 53 kDa). The binding involves a proline-rich region near the polyglutamine domain of ATN1 and the SH3 domain of IRSp53. Extended polyglutamine significantly reduces this binding.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation; co-localization studies\",\n      \"journal\": \"Nihon rinsho. Japanese journal of clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-IP confirmation, but published as a short review/summary; single lab\",\n      \"pmids\": [\"10222779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ATN1 protein binds to RERE (a protein sharing the arginine-glutamic acid dipeptide repeat motif), with the RE repeat having a primary role in binding. Extended polyglutamine enhances this interaction. When RERE is overexpressed, endogenous ATN1 distribution changes from diffuse to speckled nuclear pattern, co-localizing with RERE. More RERE is recruited into nuclear aggregates of ATN1 with expanded polyQ.\",\n      \"method\": \"Immunoprecipitation; in vitro binding assays; transfection and co-localization microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation plus in vitro binding and cellular co-localization, single lab\",\n      \"pmids\": [\"10814707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ATN1 protein complex in DRPLA brains is aberrantly phosphorylated. Both ubiquitinated cytoplasmic inclusions and the nuclear membrane show aberrant phosphorylation in DRPLA-affected neurons, suggesting the nuclear membrane is an additional pathological focus.\",\n      \"method\": \"Immunochemical methods; enzymatic dephosphorylation; immunohistochemistry\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunochemical and enzymatic dephosphorylation methods, single lab\",\n      \"pmids\": [\"11042112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In transgenic mouse models expressing mutant atrophin-1, the protein accumulates/aggregates exclusively in the nucleus (neuronal intranuclear inclusions), whereas mutant huntingtin also forms cytoplasmic aggregates. This differential localization corresponds to distinct behavioral phenotypes.\",\n      \"method\": \"Neuropathological analysis of transgenic mice; immunohistochemistry; behavioral testing\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparison in transgenic mouse models, single lab with systematic neuropathological analysis\",\n      \"pmids\": [\"11442350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mutant ATN1 with expanded polyglutamine (118Q) causes histone H3 hypoacetylation in brain tissue, indicating global transcriptional repression. Overexpression of wild-type ATN1 does not rescue the motor/survival defects in Q118 mice, indicating the mutant does not act in a simple dominant-negative manner.\",\n      \"method\": \"Biochemical analysis of histone acetylation in transgenic mouse brain; motor behavior and survival assays; rescue experiment with wild-type ATN1 overexpression; sodium butyrate (HDAC inhibitor) treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemistry, behavior, genetic rescue, pharmacological rescue) in a single study\",\n      \"pmids\": [\"16407196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Alternative splicing of ATN1 generates two protein isoforms differing by a single glutamine residue encoded by an alternative CAG exon. The glutamine-included isoform localizes more predominantly in the nucleus. The CAG-included mRNA form is the major isoform expressed in tissues.\",\n      \"method\": \"RT-PCR confirmation of splice isoforms; transfection and subcellular localization studies\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — experimental splice confirmation plus localization study, single lab\",\n      \"pmids\": [\"16091834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Q129 DRPLA transgenic mice, age-dependent neuronal intranuclear accumulation (NIA) of mutant atrophin-1 is associated with presynaptic dysfunction in the globus pallidus and cerebellum, progressive shrinkage of Purkinje cell distal dendrites, decreased AMPA and GABA-A receptor currents in CA1 neurons, and age-dependent downregulation of synaptic and CREB-dependent genes—without overt neuronal loss, indicating neuronal dysfunction as the primary pathophysiological process.\",\n      \"method\": \"Electrophysiology; neuropathology; immunohistochemistry; expression profiling in transgenic mice\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, morphology, gene expression) in a well-characterized transgenic model\",\n      \"pmids\": [\"19039037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mutation of the nuclear export signal (NES) of mutant atrophin-1 (65Q) increases nuclear accumulation of ATN1 and fragments, shortens lifespan, and worsens locomotor defects and brain pathology compared to NLS mutation. This demonstrates that nuclear localization of mutant ATN1 enhances neuropathology.\",\n      \"method\": \"Site-directed mutagenesis of NLS and NES; transgenic mice; behavioral testing; neuropathological analysis; protein localization\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific signals with in vivo transgenic mouse validation using multiple phenotypic readouts\",\n      \"pmids\": [\"40263757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Drosophila models of DRPLA, atrophin protein causes lysosomal dysfunction and blocks autophagic flux after autophagosome-lysosome fusion, leading to clearance defects. Further induction of autophagy does not rescue neurodegeneration and is instead detrimental in this context.\",\n      \"method\": \"Drosophila genetics; autophagy pathway analysis; lysosomal function assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila model with genetic/cell biological dissection of autophagy pathway, single lab\",\n      \"pmids\": [\"20543566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Apoptosis-inducing-signal kinase 1 (ASK1) activation is implicated in polyQ-expanded ATN1-induced apoptosis in PC12 cells. Humanin (HN), which inhibits ASK1, partially suppresses apoptotic cell death and aggregate formation induced by expanded polyQ ATN1.\",\n      \"method\": \"Tet-Off inducible expression in PC12 cells; humanin peptide treatment; apoptosis and aggregate formation assays\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pharmacological intervention with partial effect, no direct demonstration of ASK1 role specific to ATN1\",\n      \"pmids\": [\"15784964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"When full-length mutant ATN1 protein (Q82) is expressed, aggregates form exclusively in the nuclei of neuronally differentiated PC12 cells, but in the cytoplasm of fibroblasts. Truncated ATN1-Q82 forms intranuclear inclusions preferentially in neuronally differentiated cells (>97%) versus fibroblasts (31%). Intranuclear aggregate formation alone is not sufficient to induce apoptosis with full-length ATN1.\",\n      \"method\": \"Adenovirus-mediated expression of truncated and full-length DRPLA constructs in PC12 cells and fibroblasts; fluorescence microscopy; apoptosis assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic comparison of cell types with controlled expression levels and multiple readouts, single lab\",\n      \"pmids\": [\"10332031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In DRPLA patient-derived cortical glutamatergic neurons, mitochondrial dysfunction and oxidative stress occur before overt neuronal loss. Phenylbutyrate treatment improved neuronal survival and reduced mitochondrial ROS, identifying mitochondrial stress as an early driver of neurodegeneration in ATN1 CAG expansion disease.\",\n      \"method\": \"iPSC differentiation into cortical neurons; mitochondrial function assays; pharmacological treatment; survival assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, patient-derived neurons with functional assays, single lab, not peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.02.673807\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a Drosophila model expressing full-length human ATN1 with Q88, protein quality control pathways are disrupted. Genetic experiments identified Hsc70-3 (a chaperone) as a suppressor of ATN1 toxicity, while VCP (proteasome-related AAA ATPase), Rpn11 (proteasome-related deubiquitinase), and select DnaJ co-chaperones had variable/context-dependent protective effects. RNA-seq identified altered immune and protein quality control pathways.\",\n      \"method\": \"Drosophila transgenic model; RNA-seq; genetic epistasis experiments; behavioral assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, Drosophila model with genetic epistasis, single lab, not peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.12.05.627083\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNA-seq of HEK293T cells stably expressing polyQ-expanded ATN1 revealed disrupted transcriptional networks including synaptic organization, extracellular matrix remodeling, ion channel expression, inflammation, chromatin remodeling, stress responses, and redox imbalance. Heat shock protein expression changes suggest proteotoxic stress and impaired protein quality control.\",\n      \"method\": \"Stable cell line generation; RNA-seq transcriptomic profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, transcriptomic profiling in non-neuronal cell line, no mechanistic validation experiments\",\n      \"pmids\": [\"bio_10.1101_2025.08.08.669318\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An antisense oligonucleotide targeting human ATN1 (but not mouse Atn1) provides robust protection from behavioral phenotypes and transcriptional dysregulation in the cerebellum of a fully humanized DRPLA mouse model (Atn1 knock-in with 112 CAG repeats), demonstrating that ATN1 knockdown is sufficient to rescue pathology and that disease arises from a gain-of-function mechanism.\",\n      \"method\": \"Humanized knock-in mouse model; ASO treatment; behavioral assays; RNA-seq\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo ASO knockdown with allele-specific rescue in humanized model, behavioral and molecular endpoints, peer-reviewed\",\n      \"pmids\": [\"41624332\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATN1/atrophin-1 is a nuclear transcriptional co-repressor whose expanded polyglutamine form (DRPLA) accumulates preferentially in neuronal nuclei via a nuclear export signal-dependent mechanism, forms transglutaminase-dependent aggregates, is cleaved by caspase-3 at D106, interacts with WW-domain ubiquitin ligases, RERE (via RE-repeat domains), GAPDH, and IRSp53 (via a proline-rich/SH3 interaction diminished by polyQ expansion), causes histone hypoacetylation and CREB-dependent transcriptional dysregulation, and induces mitochondrial dysfunction and lysosomal/autophagic flux blockade, with ASO-mediated knockdown sufficient to rescue these gain-of-toxic-function phenotypes in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATN1/atrophin-1 is a ubiquitously expressed nuclear protein whose polyglutamine-expanded form causes the neurodegenerative disorder dentatorubral-pallidoluysian atrophy (DRPLA) through a gain-of-toxic-function mechanism [#0, #23]. The protein carries a polyglutamine tract beginning at residue 484 flanked by proline-rich and arginine-glutamic acid (RE) dipeptide repeat motifs that organize its protein interactions [#0]. Full-length atrophin-1 localizes predominantly to the nucleus, and a caspase-3 cleavage event near the N-terminus (at 106DSLDG110) liberates a polyQ-containing fragment that partitions between nucleus and cytoplasm [#3, #5]. Nuclear accumulation of the mutant protein is the principal driver of pathology: disrupting its nuclear export signal increases nuclear burden and worsens lifespan, locomotor, and neuropathological phenotypes in vivo [#16]. Within the nucleus the expanded protein acts as a transcriptional regulator, producing histone H3 hypoacetylation, global transcriptional repression, and age-dependent downregulation of synaptic and CREB-dependent genes that drives neuronal dysfunction prior to overt cell loss [#13, #15]. Atrophin-1 engages defined partners through the regions surrounding its repeats — the RE-repeat protein RERE, which is recruited into nuclear aggregates by expanded polyQ [#10]; WW-domain proteins including HECT-domain ubiquitin ligases [#6]; IRSp53 via a proline-rich/SH3 contact diminished by polyQ expansion [#9]; and GAPDH [#2]. Expansion promotes transglutaminase-dependent aggregation, disulfide-linked and ubiquitinated cytoplasmic inclusions, and neuronal intranuclear inclusions [#4, #7, #8]. Downstream, the mutant protein causes lysosomal/autophagic flux blockade and mitochondrial dysfunction with oxidative stress [#17]. ASO-mediated knockdown of human ATN1 rescues behavioral and transcriptional phenotypes in a humanized DRPLA mouse model, confirming that lowering the mutant protein is sufficient to reverse pathology [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Cloning the DRPLA gene defined ATN1 as the molecular cause of the disease and revealed the polyglutamine tract and flanking repeat architecture that would frame all subsequent mechanistic work.\",\n      \"evidence\": \"cDNA cloning, sequencing, and Northern blot of the ubiquitously expressed 4.5 kb transcript\",\n      \"pmids\": [\"7842016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence alone did not establish a molecular function or localization\", \"No interacting partners or enzymatic activity identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying the endogenous ~190 kDa protein and its larger expanded counterpart in patient brain established that the disease form is an enlarged polyQ protein expressed in neurons.\",\n      \"evidence\": \"Immunoblotting and immunohistochemistry of normal and DRPLA human brain with C-terminal antibodies\",\n      \"pmids\": [\"7647802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reported cytoplasmic localization in normal brain conflicted with later nuclear data\", \"Did not address how expansion confers toxicity\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapping a caspase-3 cleavage site at residue 106 showed ATN1 is a physiological protease substrate, providing a mechanism to generate the toxic polyQ-bearing fragment independent of repeat length.\",\n      \"evidence\": \"In vitro cleavage with recombinant caspase-3 and site-directed mutagenesis in apoptotic cells\",\n      \"pmids\": [\"9361003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether cleavage is required for in vivo toxicity\", \"In vivo relevance of the fragment to DRPLA pathology untested at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Localization and aggregation studies linked the caspase-3 fragment and polyQ expansion to nuclear/cytoplasmic aggregate formation and transglutaminase-dependent apoptosis, building the first toxic-fragment model.\",\n      \"evidence\": \"GFP-fusion localization, truncation constructs, and transglutaminase-inhibitor rescue in COS-7 cells\",\n      \"pmids\": [\"9705838\", \"9462738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-line overexpression may not reflect neuronal context\", \"Whether aggregation is causal or a bystander of toxicity unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Yeast two-hybrid and binding assays defined a set of physical partners (WW-domain HECT ubiquitin ligases and MAGUK/PDZ proteins) acting through regions near the polyQ tract, suggesting ATN1 operates in protein-interaction networks linked to ubiquitination.\",\n      \"evidence\": \"Yeast two-hybrid screen with in vitro binding confirmation of 4 of 5 interactors\",\n      \"pmids\": [\"9647693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of each interaction undefined\", \"No demonstration of in vivo ubiquitination through these ligases at this stage\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration of disulfide-linked, pathologically ubiquitinated cytoplasmic inclusions in DRPLA brain connected expanded ATN1 to aberrant protein complexes in affected lesions.\",\n      \"evidence\": \"Reducing/non-reducing immunoblotting and double-label immunohistochemistry with anti-ubiquitin in human brain\",\n      \"pmids\": [\"9735324\", \"10381356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination machinery responsible not identified\", \"Causal link between inclusions and neuronal dysfunction not shown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Comparing neuronal and non-neuronal cells showed full-length mutant ATN1 aggregates preferentially in neuronal nuclei and that intranuclear aggregation alone is insufficient for apoptosis, refining the toxicity model toward neuron-specific nuclear processes.\",\n      \"evidence\": \"Adenoviral expression of full-length and truncated Q82 constructs in PC12 cells versus fibroblasts with apoptosis readouts\",\n      \"pmids\": [\"10332031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of neuron-specific nuclear targeting undefined\", \"Dissociated aggregation from death without identifying the toxic species\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of RERE as an RE-repeat-dependent partner whose binding is enhanced by polyQ expansion, plus recruitment of RERE into ATN1 nuclear aggregates, placed atrophin-1 in a nuclear protein network altered by expansion.\",\n      \"evidence\": \"Reciprocal immunoprecipitation, in vitro binding, and co-localization microscopy\",\n      \"pmids\": [\"10814707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional or functional output of the ATN1-RERE complex not defined\", \"Single lab without orthogonal in vivo validation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Transgenic mice showed mutant atrophin-1 accumulates exclusively in neuronal nuclei, distinguishing its localization behavior from huntingtin and tying nuclear inclusions to behavioral phenotypes.\",\n      \"evidence\": \"Neuropathology, immunohistochemistry, and behavioral testing in transgenic mice\",\n      \"pmids\": [\"11442350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not isolate which nuclear function drives behavior\", \"Correlative association between inclusions and phenotype\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating histone H3 hypoacetylation and failure of wild-type rescue established a chromatin-level transcriptional repression mechanism that is a gain of toxic function rather than simple dominant-negative loss.\",\n      \"evidence\": \"Histone acetylation biochemistry, genetic and HDAC-inhibitor rescue, and behavior/survival assays in Q118 mice\",\n      \"pmids\": [\"16407196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct genomic targets of repression not mapped\", \"Mechanism connecting ATN1 to HDAC activity unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking age-dependent nuclear accumulation to electrophysiological and synaptic deficits and downregulation of CREB-dependent genes established neuronal dysfunction—not loss—as the primary pathophysiological process.\",\n      \"evidence\": \"Electrophysiology, morphology, and expression profiling in Q129 transgenic mice\",\n      \"pmids\": [\"19039037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CREB-pathway mechanism not biochemically dissected\", \"Reversibility of dysfunction not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Drosophila work identified lysosomal dysfunction and a post-fusion autophagic flux block as a clearance defect contributing to neurodegeneration, and showed boosting autophagy is detrimental in this context.\",\n      \"evidence\": \"Drosophila genetics with autophagy pathway and lysosomal function assays\",\n      \"pmids\": [\"20543566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular step at which flux is blocked not defined\", \"Relevance to mammalian neurons untested in this study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Selective NES mutation versus NLS mutation in transgenic mice causally demonstrated that nuclear localization of mutant ATN1 drives pathology, converting correlative localization data into a mechanism.\",\n      \"evidence\": \"Site-directed mutagenesis of NLS/NES in transgenic mice with behavioral and neuropathological readouts\",\n      \"pmids\": [\"40263757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear effector mechanism downstream of accumulation not pinpointed\", \"Contribution of cleavage fragment versus full-length not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Allele-specific ASO knockdown rescue in a fully humanized knock-in model provided definitive evidence that DRPLA is a gain-of-function disease and that lowering mutant ATN1 is therapeutically sufficient.\",\n      \"evidence\": \"Human-specific ASO in Atn1 112-CAG knock-in mice with behavioral and RNA-seq endpoints\",\n      \"pmids\": [\"41624332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and CNS-wide distribution of rescue not fully characterized\", \"Does not identify the molecular toxic species being lowered\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct nuclear effector mechanism by which expanded ATN1 represses transcription—the chromatin-modifying complex it engages and its genomic binding sites—remains undefined, as does how nuclear repression, mitochondrial stress, and autophagic blockade are causally ordered.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mapped genomic targets or defined repressive complex\", \"Causal hierarchy among transcriptional, mitochondrial, and lysosomal phenotypes unresolved\", \"Role of the caspase-3 fragment versus full-length protein in vivo unsettled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 12, 16, 19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 7, 8]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RERE\", \"IRSp53\", \"GAPDH\", \"WWP1\", \"WWP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}