{"gene":"HTT","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1995,"finding":"The HTT gene product is a ~350 kDa protein widely expressed in neurons throughout the brain, with no enrichment in the striatum (the site of greatest pathology). Within neurons, huntingtin is present in the soluble cytoplasm and loosely associated with membranes or cytoskeleton, and is concentrated in nerve terminals including those in the caudate and putamen, suggesting a role in nerve terminal function.","method":"Immunohistochemistry and subcellular fractionation using antibodies against N-terminal and internal epitopes of the HTT protein","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — direct protein localization by fractionation and IHC with two independent antibodies, replicated by similar study (PMID:8240819)","pmids":["7748554","8240819"],"is_preprint":false},{"year":1995,"finding":"In HD patients, both alleles of the IT15/HTT protein are expressed at similar levels in relatively spared brain regions. In severely affected regions (cortex and caudate), the expanded-repeat allele is present at lower levels and shows a smear of more slowly migrating reactivity, suggesting altered structure, abnormal processing, or abnormal protein-protein interactions of the polyglutamine-expanded HTT.","method":"Quantitative Western blot analysis on 4% polyacrylamide gels of HD patient post-mortem brain tissue and lymphoblastoid cell lines","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative Western blot in patient tissue, single lab","pmids":["7581375"],"is_preprint":false},{"year":1998,"finding":"The HD gene promoter contains two tandemly repeated Sp1 sites that act synergistically as a key positive-acting regulatory element. This region is polymorphic, and a single Sp1 site variant is associated with reduced transcription. Differential control of HTT expression exists between neuronal and non-neuronal cell lines.","method":"Reporter gene assays in neuronal (SK-N-SH) and non-neuronal (JEG3) cell lines with deletion and mutagenesis analysis of the 5' upstream region","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional promoter dissection with mutagenesis, single lab","pmids":["9536082"],"is_preprint":false},{"year":2000,"finding":"Full-length huntingtin, in alternate forms distinguished by epitope accessibility, localizes to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. Mutant STHdh(Q111) cells exhibit dominant phenotypes distinct from those caused by huntingtin deficiency or excess, including elevated p53, endoplasmic reticulum stress response, and hypoxia pathway activation, indicating the mutant protein disrupts striatal homeostasis via a mechanism separate from its normal activity.","method":"Immunofluorescence and subcellular localization in striatal cell lines from wild-type and Hdh(Q111) knock-in embryos; comparison of phenotypes between wild-type and mutant cell lines","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and comparative phenotypic analysis in knock-in cell lines","pmids":["11092756"],"is_preprint":false},{"year":2000,"finding":"Neurotrophic factors FGF-2 and NGF regulate huntingtin protein levels in striatal neuronal cultures in a dose-dependent, factor-specific manner: FGF-2 increases huntingtin levels while NGF decreases them.","method":"Western blotting of striatal cell cultures treated with growth factors","journal":"Cell transplantation","confidence":"Low","confidence_rationale":"Tier 3 — single lab, Western blot only, no mechanistic pathway defined","pmids":["11144959"],"is_preprint":false},{"year":2011,"finding":"Huntingtin is required for neuronal migration, proliferation, and survival in neocortex during early brain development. Knockdown of Htt in neuroepithelial cells causes disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, Htt knockdown causes cell death but not migration defects. The cortical cell death phenotype is partially reversed by co-knockdown of Caspase-9, implicating mitochondria-mediated apoptotic processes.","method":"In utero electroporation-mediated RNAi knockdown of Htt in mouse neocortex and cerebellum; rescue experiments with Casp9 co-knockdown","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic knockdown with specific phenotypic readout and epistasis rescue experiment","pmids":["21994396"],"is_preprint":false},{"year":2013,"finding":"The first 17 amino acids (N17) of huntingtin function as a nuclear export sequence (NES). Mutation of conserved residues within N17 increases nuclear accumulation of Htt exon 1, and nuclear export is sensitive to leptomycin B and reduced by knockdown of exportin 1 (CRM1). In HEK293 cells, NES mutations decrease overall Htt aggregation but increase the fraction of cells with nuclear inclusions; in primary neurons, NES mutations increase nuclear accumulation and increase overall aggregation.","method":"Site-directed mutagenesis of N17 residues, leptomycin B treatment, exportin 1 siRNA knockdown, fluorescence microscopy in HEK293 cells and primary neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mutagenesis, pharmacological inhibition, siRNA knockdown) in two cell types","pmids":["23319588"],"is_preprint":false},{"year":2014,"finding":"Mutant huntingtin directly interacts with IKKγ (NEMO), leading to increased IκB degradation and subsequent nuclear translocation of RelA (NF-κB p65), causing excessive inflammatory cytokine production in human HD myeloid cells. Lowering HTT with siRNA reverses these NFκB-pathway-related immune dysfunction phenotypes.","method":"Co-immunoprecipitation of mutant HTT with IKKγ; measurement of IκB degradation and RelA nuclear translocation; siRNA-mediated HTT knockdown via glucan-encapsulated particles in primary human HD monocytes/macrophages","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP identifying binding partner, functional rescue by HTT lowering in primary human cells","pmids":["24459107"],"is_preprint":false},{"year":2015,"finding":"Full-length expanded HTT (expHTT) RNA is retained in the nucleus. The splicing factor MBNL1 increases nuclear retention of expHTT and decreases cytosolic expHTT protein expression, while the splicing/export factor U2AF65 has the opposite effect, decreasing nuclear retention and increasing cytoplasmic expHTT protein. An expHTT RNA fragment is cytotoxic in the absence of translation.","method":"Overexpression of MBNL1 and U2AF65 in cells expressing expHTT; nuclear/cytoplasmic fractionation and Western blot; cytotoxicity assays with translation-incompetent constructs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct fractionation with functional consequence, two opposing regulators tested","pmids":["26218986"],"is_preprint":false},{"year":2017,"finding":"Incomplete splicing of the huntingtin pre-mRNA between exon 1 and exon 2 produces a small polyadenylated transcript (HTTexon1) encoding the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length. HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and in post-mortem brain tissue from HD individuals.","method":"Quantitative RT-PCR protocols specific for HTTexon1 transcript in human fibroblast lines and post-mortem brain samples; comparison across adult-onset and juvenile-onset HD patients","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — direct quantitative detection of specific aberrant transcript in human patient tissue, replicated across multiple sample types","pmids":["28465506"],"is_preprint":false},{"year":2017,"finding":"A trimeric chaperone complex composed of Hsc70, Hsp110, and a J-protein (DNAJB1) completely suppresses fibrilization of HttExon1Q48 and can also resolubilize pre-formed Htt fibrils. Among the three components, the J-protein is the concentration-limiting factor; overexpression of DNAJB1 alone in HEK293T cells is sufficient to profoundly reduce HttExon1Q97 aggregation.","method":"In vitro fibrilization assays with purified chaperone components; disaggregation assays; overexpression in HEK293T cells; validation in HD patient-derived neural cells and C. elegans","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified components, validated in multiple cellular and in vivo systems","pmids":["29212816"],"is_preprint":false},{"year":2018,"finding":"Phosphorylation of huntingtin exon 1 at Ser-13 and/or Ser-16 inhibits aggregation of mutant Httex1 and strongly disrupts the amphipathic α-helix of the N-terminal 17-residue (Nt17) domain, impairing membrane binding. Only bona fide phosphorylation (not phosphomimetic substitution) prompts internalization and nuclear targeting of preformed Httex1 aggregates. A phosphorylation-dependent switch involving cross-talk between Thr-3 and Ser-13/Ser-16 regulates Httex1 structure.","method":"In vitro phosphorylation of synthetic Httex1 peptides; circular dichroism and NMR analysis of α-helix disruption; membrane-binding assays; live-cell imaging of aggregate internalization and nuclear targeting; comparison of phosphorylated vs. phosphomimetic variants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation with structural validation (CD, NMR), functional cell-based assays, multiple orthogonal methods","pmids":["30185623"],"is_preprint":false},{"year":2018,"finding":"Mutant huntingtin causes intrinsic oligodendroglial dysfunction and myelination deficits through enhancement of polycomb repressive complex 2 (PRC2) activity in NG2+ oligodendrocyte progenitor cells. Selective inactivation of mHTT in the NG2+ population prevents myelin abnormalities and certain behavioral deficits, demonstrating cell-autonomous pathology in oligodendroglia independent of neuronal mHTT expression.","method":"Conditional knockout of mHTT in NG2+ oligodendrocyte progenitors in HD mice; RNA-seq and ChIP-seq to identify PRC2 pathway as a mechanism; behavioral and histological analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with defined molecular mechanism (ChIP-seq for PRC2) and behavioral phenotype rescue","pmids":["31015293"],"is_preprint":false},{"year":2019,"finding":"Compounds that interact with both LC3 (autophagosome protein) and mutant HTT (via its expanded polyQ tract) selectively target mHTT to autophagosomes for autophagic clearance, reducing mHTT levels in an allele-selective manner. These autophagosome-tethering compounds do not interact with wild-type HTT, and also lower mutant ataxin-3, demonstrating that the polyQ expansion is the binding determinant.","method":"Small-molecule microarray screening; co-immunoprecipitation of compounds with LC3 and mHTT; measurement of mHTT levels in cells, Drosophila, and mouse HD models; allele-selective quantification by HTT protein assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with functional validation in multiple model systems (cells, flies, mice), allele-selectivity demonstrated","pmids":["31666698"],"is_preprint":false},{"year":2019,"finding":"FAN1 (FANCD2/FANCI-associated nuclease 1) binds directly to the expanded HTT CAG repeat DNA and stabilizes it against somatic expansion. FAN1 overexpression reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1; FAN1 knockdown increases CAG repeat expansion in patient-derived stem cells and medium spiny neurons. The protective effect is FAN1 concentration- and CAG repeat length-dependent, and does not require FAN1's nuclease activity.","method":"FAN1 overexpression and knockdown in human cells and patient-derived stem cells/neurons; MiSeq-based CAG repeat length quantification; DNA-binding assay of FAN1 with expanded HTT CAG repeat DNA; nuclease-dead mutant experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — direct DNA binding demonstrated, genetic manipulation in patient-derived neurons with quantitative readout, nuclease-dead mutant defines mechanism","pmids":["30358836"],"is_preprint":false},{"year":2019,"finding":"Gpr52, an orphan G protein-coupled receptor, regulates mutant HTT protein levels in the striatum. Knockout of Gpr52 significantly reduces mHTT levels and rescues HD-associated behavioral phenotypes in a knock-in HD mouse model. A Gpr52 antagonist (E7) similarly reduces mHTT levels and rescues phenotypes in cellular and mouse models.","method":"Gpr52 knockout in zQ175 knock-in HD mice; pharmacological inhibition with Gpr52 antagonist E7; mHTT level quantification by HTRF; behavioral testing","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout plus pharmacological inhibition with consistent phenotype, but downstream mechanism linking Gpr52 to HTT levels not fully elucidated","pmids":["29608652"],"is_preprint":false},{"year":2019,"finding":"FKBP5 interacts and colocalizes with HTT in the striatum and cortex. Decreasing FKBP5 levels by siRNA or pharmacological inhibition (SAFit2) reduces mutant HTT levels and increases LC3-II levels and autophagic flux, indicating that FKBP5 modulates mHTT clearance through autophagy in an MTOR-independent manner.","method":"Co-immunoprecipitation and colocalization of FKBP5 and HTT in mouse brain; siRNA knockdown and SAFit2 inhibitor treatment in HD iPSC-derived neurons and mouse models; LC3-II Western blot for autophagic flux","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional autophagy measurement with genetic and pharmacological perturbations","pmids":["34024231"],"is_preprint":false},{"year":2019,"finding":"The polyproline (polyP) region of huntingtin can interact with the N-terminal 17-residue (Nt17) α-helical region, inhibiting nucleation and fibril formation of mutant Htt. Ion mobility spectrometry and gas-phase hydrogen-deuterium exchange coupled with MS and molecular dynamics simulations suggest the C-terminal portion of Nt17 is the primary contact point, and polyP may induce a random coil in this region to reduce the propensity for amyloid-competent amphipathic α-helix formation.","method":"Atomic force microscopy time-course aggregation assays; ion mobility spectrometry-mass spectrometry; gas-phase H/D exchange MS; molecular dynamics simulations","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 — multiple biophysical methods including structural MS; single lab but orthogonal approaches","pmids":["31814404"],"is_preprint":false},{"year":2020,"finding":"HTT is present with Rab4-containing vesicles within axons in vivo and is required for the bidirectional motility of Rab4. HTT and Rab4 move together on a putative vesicle that may also contain synaptotagmin, synaptobrevin, and Rab11. The moving HTT-Rab4 vesicle uses kinesin-1 and dynein motors and the accessory protein HIP1 for bidirectional axonal transport. Pathogenic HTT disrupts HTT-Rab4 vesicle motility, causing synaptic accumulations, aberrant synaptic morphology, and decreased lifespan—phenotypes rescued by excess Rab4.","method":"In vivo dual-color live imaging in Drosophila axons; genetic reduction of HTT; HIP1 accessory protein analysis; Rab4 overexpression rescue; iNeuron studies from human HD patients","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 2 — direct live imaging of co-moving vesicles in vivo, genetic rescue, validated in human HD iNeurons","pmids":["32611447"],"is_preprint":false},{"year":2021,"finding":"Small molecules can lower HTT expression by promoting inclusion of a pseudoexon containing a premature termination codon in HTT pre-mRNA (stop-codon psiExon), leading to mRNA degradation. These orally bioavailable splicing modulators achieve broad CNS distribution and reduce HTT levels consistently throughout CNS and periphery.","method":"Identification of splicing modulators by cell-based screening; RT-PCR characterization of induced pseudoexon inclusion; HTT protein measurement in cells and in vivo mouse brain after oral dosing","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — mechanism of pseudoexon induction defined by RT-PCR, in vivo validation, but single lab","pmids":["34911927"],"is_preprint":false},{"year":2022,"finding":"HTT interacts with several type I protein arginine methyltransferases (PRMTs) via its N-terminal domain. PRMT4 (CARM1) and PRMT6 are the major enzymes methylating HTT at specific arginine residues. Mass spectrometry identified ~24 arginine methylation/dimethylation sites on endogenous HTT from human and mouse brain. Alterations at R200/205 methylation sites render HTT less soluble, promote liquid-to-solid phase transition of HTT assemblies in vitro, and increase neuronal toxicity; overexpression of PRMT4/6 is beneficial for neuronal survival.","method":"Mass spectrometry (data-dependent and targeted quantitative) of endogenous HTT; in vitro methylation assays with purified PRMTs; Co-IP of HTT with PRMTs; cell-based solubility assays; liquid-liquid phase separation assays in vitro; neuronal toxicity assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro methylation reconstitution, Co-IP, structural phase-transition assays, and neuronal toxicity with multiple orthogonal methods","pmids":["34888656"],"is_preprint":false},{"year":2022,"finding":"DNAJB1 contains a HTT-binding motif (HBM) in the hinge region between its C-terminal domains I and II that specifically binds to the polyQ-adjacent proline-rich domain (PRD) of both soluble and aggregated HTT. Mutation of the conserved H244 in the HBM completely abrogates the ability of the trimeric chaperone complex (Hsc70/DNAJB1/Apg2) to suppress and disaggregate HTT fibrils, without affecting DNAJB1's activity on other substrates. Overexpression of wild-type but not H244A DNAJB1 prevents HTTExon1Q97 aggregation in HEK293 cells.","method":"Mutational analysis of DNAJB1 HBM; in vitro fibril suppression and disaggregation assays; pulldown/binding assays between DNAJB1 variants and HTT PRD; overexpression in HEK293 cells; molecular dynamics simulations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of chaperone activity with mutagenesis defining specific interaction interface, validated in cells","pmids":["35948542"],"is_preprint":false},{"year":2022,"finding":"Branaplam, a splicing modulator, promotes inclusion of a novel 115-bp frameshift-inducing exon in the HTT transcript, leading to profound reduction of HTT RNA and protein levels. Branaplam lowers both total HTT and mutant HTT in patient-derived fibroblasts, iPSC, cortical progenitors, and neurons with an IC50 consistently below 10 nM, and ameliorates aberrant alternative splicing patterns in HD patient cells.","method":"RT-PCR and RNA-seq identification of Branaplam-induced novel exon in HTT; HTT protein quantification by MSD assay in multiple patient-derived cell types; dose-response analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — mechanism defined by RNA-seq, validated in multiple patient-derived cell types","pmids":["36357392"],"is_preprint":false},{"year":2022,"finding":"HTT co-migrates retrogradely with RAB7 on signaling LAMP1-containing late endosomes during axonal injury in Drosophila neurons, as demonstrated by in vivo dual-color imaging. This positions HTT on a late endosomal compartment during the injury response.","method":"In vivo dual-color live imaging of HTT and RAB7/LAMP1 in injured Drosophila axons; immunoprecipitation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — direct live co-imaging in vivo, but functional consequence not fully established","pmids":["36048753"],"is_preprint":false},{"year":2016,"finding":"In Drosophila, huntingtin (Htt) participates in a cell death pathway triggered by transcriptional repression. The hnRNP-Htt axis regulates necrotic cell death: transcriptional repression by RNA polymerase II inhibition impairs splicing and expression of Htt (an ER-stabilizing molecule), and hnRNP overexpression rescues both RNA splicing and cell survival. Genetic suppression of Htt worsened, while expression of Htt ameliorated, the decreased survival phenotype.","method":"Genetic screen of knockdown fly library; RNA-seq; fly genetics with Htt suppressors and expressers; α-amanitin (RNA Pol II inhibitor) treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila model with RNA-seq mechanistic support","pmids":["27124581"],"is_preprint":false},{"year":2024,"finding":"AAV5-delivered miHTT (an engineered microRNA targeting HTT exon 1) reduces levels of both full-length HTT mRNA and the aberrantly spliced HTT1a transcript, as well as the pathogenic exon 1 HTT protein, in the striatum and cortex of HD mouse models (zQ175 and humanized Hu128/21 mice). The exon 1 HTT protein, translated from HTT1a, is detectable in knock-in HD mice and is significantly reduced by miHTT treatment.","method":"Intrastriatal AAV5-miHTT injection; QuantiGene multiplex assay for HTT and HTT1a mRNA; HTRF assay for mutant HTT and HTTexon1 protein; dose-response analysis in mouse brain regions","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 — dual targeting of FL HTT and HTTexon1 validated in two mouse models with multiple quantitative assays","pmids":["39155061"],"is_preprint":false}],"current_model":"Huntingtin (HTT) is a large scaffold protein (~350 kDa) that in its wild-type form functions in axonal transport of Rab4- and Rab7-containing vesicles via kinesin-1/dynein motors, supports neuronal migration and survival during brain development through mitochondria-dependent pathways, and is regulated by phosphorylation (at Ser-13/Ser-16 by unidentified kinases) and arginine methylation (by PRMT4/PRMT6), which control its α-helical conformation, membrane binding, nuclear export via CRM1, and phase transition behavior; the CAG repeat expansion in HTT produces a mutant protein that aberrantly interacts with IKKγ to activate NFκB-driven neuroinflammation, disrupts oligodendroglial function via PRC2 enhancement, generates a pathogenic exon 1 HTT protein through incomplete pre-mRNA splicing (producing the HTTexon1/HTT1a transcript in proportion to repeat length), and forms amyloid aggregates that can be suppressed by the trimeric chaperone complex Hsc70/DNAJB1/Hsp110 via a specific HTT-binding motif in DNAJB1's proline-rich domain interface."},"narrative":{"teleology":[],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"Insufficient on-target evidence to synthesize a narrative — discovery timeline does not match the canonical HTT protein."},"prefetch_data":{"uniprot":{"accession":"P42858","full_name":"Huntingtin","aliases":["Huntington disease protein","HD protein"],"length_aa":3142,"mass_kda":347.6,"function":"May play a role in microtubule-mediated transport or vesicle function Promotes the formation of autophagic vesicles","subcellular_location":"Cytoplasmic vesicle, autophagosome","url":"https://www.uniprot.org/uniprotkb/P42858/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HTT","classification":"Not Classified","n_dependent_lines":108,"n_total_lines":1208,"dependency_fraction":0.08940397350993377},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HTT","total_profiled":1310},"omim":[{"mim_id":"619200","title":"SORTING NEXIN FAMILY, MEMBER 21; SNX21","url":"https://www.omim.org/entry/619200"},{"mim_id":"617485","title":"WD REPEAT- AND FYVE DOMAIN-CONTAINING PROTEIN 3; WDFY3","url":"https://www.omim.org/entry/617485"},{"mim_id":"617435","title":"LOPES-MACIEL-RODAN SYNDROME; LOMARS","url":"https://www.omim.org/entry/617435"},{"mim_id":"616417","title":"ADHESION G PROTEIN-COUPLED RECEPTOR L3; ADGRL3","url":"https://www.omim.org/entry/616417"},{"mim_id":"615684","title":"HELICASE FOR MEIOSIS 1; HFM1","url":"https://www.omim.org/entry/615684"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HTT"},"hgnc":{"alias_symbol":["IT15"],"prev_symbol":["HD"]},"alphafold":{"accession":"P31645","domains":[{"cath_id":"1.20.1740,1.20.1730","chopping":"104-214_222-620","consensus_level":"medium","plddt":94.1674,"start":104,"end":620}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31645","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31645-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31645-F1-predicted_aligned_error_v6.png","plddt_mean":84.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HTT","jax_strain_url":"https://www.jax.org/strain/search?query=HTT"},"sequence":{"accession":"P31645","fasta_url":"https://rest.uniprot.org/uniprotkb/P31645.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31645/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31645"}},"corpus_meta":[{"pmid":"12869766","id":"PMC_12869766","title":"Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12869766","citation_count":4885,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11092756","id":"PMC_11092756","title":"Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11092756","citation_count":540,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17698401","id":"PMC_17698401","title":"The true story of the HD-Zip family.","date":"2007","source":"Trends in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/17698401","citation_count":448,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7748554","id":"PMC_7748554","title":"Widespread expression of Huntington's disease gene (IT15) protein product.","date":"1995","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/7748554","citation_count":420,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31666698","id":"PMC_31666698","title":"Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31666698","citation_count":383,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19015103","id":"PMC_19015103","title":"Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting.","date":"2008","source":"Social cognitive and affective neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19015103","citation_count":337,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9771716","id":"PMC_9771716","title":"Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA.","date":"1998","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9771716","citation_count":313,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8240819","id":"PMC_8240819","title":"Huntington's disease gene (IT15) is widely expressed in human and rat tissues.","date":"1993","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/8240819","citation_count":286,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19548255","id":"PMC_19548255","title":"CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches.","date":"2010","source":"American journal of medical genetics. 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The expanded allele is expressed, consistent with a gain-of-function mechanism.\",\n      \"method\": \"Immunostaining and subcellular fractionation using antibodies against N-terminus and internal epitopes; Western blot\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization by fractionation and immunostaining, replicated with two independent antisera\",\n      \"pmids\": [\"7748554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Both alleles of the HTT (IT15) protein are expressed at similar levels in HD lymphoblastoid lines and post-mortem hippocampus/cerebellum; in severely affected cortex and caudate the expanded allele protein is present at lower levels with a smear of more slowly migrating species, suggesting altered structure, abnormal processing, or abnormal protein-protein interactions of the expanded polyglutamine protein.\",\n      \"method\": \"Quantitative Western blot on 4% polyacrylamide gels of HD patient and control tissue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative Western blot, single lab but systematic across multiple tissues\",\n      \"pmids\": [\"7581375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The HTT gene promoter contains two Sp1 sites in a tandem repeat that act synergistically as a key positive-acting transcriptional element; a polymorphic single Sp1 site variant is associated with reduced transcription; differential transcriptional control exists between neuronal and non-neuronal cell lines.\",\n      \"method\": \"Reporter gene assays in neuronal (SK-N-SH) and non-neuronal (JEG3) cell lines; mutational analysis of Sp1 sites\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter dissection with mutagenesis in two cell lines, single lab\",\n      \"pmids\": [\"9536082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In striatal knock-in STHdh(Q111) cells, full-length mutant huntingtin localizes to different nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking compared to wild-type; mutant HTT produces dominant phenotypes including elevated p53, endoplasmic reticulum stress response, and hypoxia stress responses that are distinct from huntingtin deficiency or excess phenotypes.\",\n      \"method\": \"Comparative analysis of wild-type and Hdh(Q111) knock-in striatal cell lines; epitope accessibility assays, immunolocalization, stress pathway readouts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and functional phenotyping in isogenic knock-in lines, single lab\",\n      \"pmids\": [\"11092756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FGF-2 increases huntingtin protein levels in striatal neuronal cell cultures in a dose-dependent manner, whereas NGF decreases huntingtin expression, demonstrating neurotrophic factor-specific regulation of HTT protein levels.\",\n      \"method\": \"Western blotting of striatal cell cultures treated with FGF-2, NGF, or BDNF\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Western blot readout, single lab, no mechanistic pathway identified\",\n      \"pmids\": [\"11144959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HTT is required for neocortical neuronal migration and survival during early brain development; knockdown of Htt in neuroepithelial cells disrupts cell migration, reduces proliferation, and increases apoptotic cell death that can be partially rescued by co-knockdown of Casp9, implicating mitochondria-mediated apoptosis.\",\n      \"method\": \"In utero electroporation-based Htt knockdown in mouse neocortex; Casp9 co-knockdown epistasis; BrdU labeling, immunohistochemistry\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific migration/proliferation/death phenotypes and epistasis with Casp9, single lab\",\n      \"pmids\": [\"21994396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The first 17 amino acids (N17) of huntingtin exon 1 function as a bona fide nuclear export sequence (NES) via exportin 1 (CRM1); mutation of conserved residues within N17 increases nuclear accumulation of Htt exon 1, and NES mutations decrease overall aggregation in HEK293 cells but increase nuclear inclusions, while in primary neurons NES mutations increase both nuclear accumulation and aggregation.\",\n      \"method\": \"Leptomycin B treatment, exportin 1 knockdown, NES mutation constructs, live fluorescence imaging of YFP-tagged Htt exon 1 in HEK293 cells and primary neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — pharmacological inhibition, genetic knockdown, and mutagenesis converge on the same conclusion in multiple cell types\",\n      \"pmids\": [\"23319588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutant huntingtin interacts with IKKγ (NEMO) in myeloid cells, leading to increased IκB degradation and subsequent nuclear translocation of RelA (NF-κB subunit), causing excessive inflammatory cytokine production; siRNA-mediated lowering of HTT reverses this NF-κB pathway dysregulation and normalizes cytokine production in primary human HD monocytes/macrophages.\",\n      \"method\": \"Co-immunoprecipitation of mHTT with IKKγ; siRNA HTT lowering via glucan-encapsulated particles; cytokine measurements; NF-κB pathway analysis in primary human HD myeloid cells\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional siRNA rescue in primary human cells with defined molecular readouts\",\n      \"pmids\": [\"24459107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Full-length expanded HTT (expHTT) RNA is retained in the nucleus; the splicing factor MBNL1 increases nuclear retention of expHTT and decreases cytosolic expHTT protein expression, while U2AF65 has the opposite effect, decreasing nuclear retention and increasing cytosolic expHTT protein. A fragment of expHTT RNA is cytotoxic in the absence of translation.\",\n      \"method\": \"Overexpression and knockdown of MBNL1 and U2AF65 in cell lines; nuclear/cytoplasmic fractionation; reporter constructs without ATG (to test RNA toxicity); Western blot and qPCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function of two splicing factors with opposing effects, single lab\",\n      \"pmids\": [\"26218986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HTT exon 1 does not always splice to exon 2, producing a small polyadenylated HTTexon1 mRNA that encodes the highly pathogenic exon 1 HTT protein; the level of this aberrant transcript is proportional to CAG repeat length and is detectable in post-mortem brain tissue from HD patients, particularly those with early onset disease.\",\n      \"method\": \"Quantitative RT-PCR protocols specific for HTTexon1 transcript in patient fibroblasts and post-mortem brain; comparison across CAG repeat lengths\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative transcript analysis across multiple human tissues and cell lines with repeat-length correlation; replicated in multiple mouse models\",\n      \"pmids\": [\"28465506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A trimeric chaperone complex of Hsc70, Hsp110, and a J-protein (DNAJB1) completely suppresses fibrilization of HttExon1Q48 in vitro and can also resolubilize pre-formed Htt fibrils; the J-protein is the concentration-limiting factor, and single overexpression of DNAJB1 in HEK293T cells is sufficient to profoundly reduce HttExon1Q97 aggregation.\",\n      \"method\": \"In vitro fibrilization assay with purified chaperone components; disaggregation assay of pre-formed fibrils; overexpression in HEK293T cells; validation in HD patient-derived neural cells and C. elegans\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified components, validated in cells and in vivo model\",\n      \"pmids\": [\"29212816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Phosphorylation of huntingtin exon 1 at Ser-13 and/or Ser-16 inhibits aggregation of mutant Httex1, strongly disrupts the amphipathic α-helix of the N-terminal 17 residues (Nt17), inhibits Nt17 membrane binding, and prompts internalization and nuclear targeting of preformed Httex1 aggregates; a phosphorylation-dependent switch involves cross-talk between Thr-3 and Ser-13/Ser-16 phosphorylation.\",\n      \"method\": \"In vitro phosphorylation by kinases on synthetic peptides and Httex1 protein; aggregation assays; circular dichroism and structural analysis of Nt17 helix; membrane binding assays; subcellular localization by fluorescence microscopy; comparison of bona fide phosphorylation vs. phosphomimetic substitutions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation with structural validation, aggregation assays, and membrane/nuclear trafficking readouts in single comprehensive study\",\n      \"pmids\": [\"30185623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HTT interacts with FKBP5 (FKBP51) in the striatum and cortex; reducing FKBP5 levels by siRNA or pharmacological inhibition (SAFit2) lowers mutant HTT levels through increased autophagic flux (LC3-II elevation) in an MTOR-independent manner, in human HD iPSC-derived cells and in HD mouse models.\",\n      \"method\": \"Co-immunoprecipitation and colocalization of FKBP5 and HTT in mouse brain; siRNA knockdown and SAFit2 pharmacological inhibition; LC3-II Western blot (autophagic flux); mHTT HTRF quantification; in vivo treatment in R6/2 and zQ175 mice\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction plus genetic and pharmacological loss-of-function with autophagy flux readout in multiple models, single lab\",\n      \"pmids\": [\"34024231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Small molecules (HTT-LC3 linker compounds) identified by small-molecule microarray screening bind both LC3 and mutant HTT (via the expanded polyQ stretch) but not wild-type HTT, targeting mHTT to autophagosomes for autophagic clearance in an allele-selective manner; these compounds also lower mutant ataxin-3.\",\n      \"method\": \"Small-molecule microarray screening; direct binding assays to LC3 and mHTT; autophagosome co-localization; mHTT level quantification in cells; rescue in fly and mouse HD models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — binding mechanism established by screening plus direct binding assays, functional rescue in multiple in vivo models\",\n      \"pmids\": [\"31666698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAN1 (a DNA repair nuclease) binds directly to expanded HTT CAG repeat DNA and stabilizes it against somatic expansion; FAN1 overexpression reduces CAG repeat expansion in cells expressing mutant HTT exon 1, and FAN1 knockdown increases expansion in patient-derived stem cells and differentiated medium spiny neurons; this protective effect is nuclease-independent.\",\n      \"method\": \"DNA binding assays; FAN1 overexpression and knockdown in human cells and patient iPSC-derived neurons; CAG repeat length measurement by sequencing; nuclease-dead mutant experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct DNA binding demonstrated, gain- and loss-of-function with nuclease-dead mutation distinguishing mechanism, validated in patient-derived neurons\",\n      \"pmids\": [\"30358836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knocking out GPR52, an orphan G protein-coupled receptor enriched in striatum, significantly reduces mutant HTT levels in the striatum and rescues HD-associated behavioral phenotypes in knock-in mice; a GPR52 antagonist (compound E7) similarly reduces mutant HTT levels and rescues phenotypes in cellular and mouse models.\",\n      \"method\": \"Gpr52 knockout in knock-in HD mice; pharmacological antagonism with E7; mHTT quantification; behavioral assays\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological loss-of-function with defined molecular and behavioral phenotypes, single lab\",\n      \"pmids\": [\"29608652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mutant huntingtin (mHTT) interacts with HTT via its N-terminal domain with several type I protein arginine methyltransferases (PRMT4/CARM1 and PRMT6); these enzymes methylate HTT at specific arginine sites; alterations at R200/205 methylation sites reduce HTT solubility, promote phase transition from liquid-like to solid-like assemblies, and increase neuronal toxicity, while PRMT4/6 overexpression is beneficial for neuronal survival.\",\n      \"method\": \"Mass spectrometry (data-dependent and targeted quantitative) identification of arginine methylation sites on endogenous HTT from human and mouse brain; in vitro methylation assays; Co-IP of HTT with PRMTs; cell-based solubility assays; liquid-liquid phase separation assays; neuronal toxicity assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — endogenous site identification by MS, in vitro methylation, Co-IP, phase separation, and toxicity assays in single comprehensive study\",\n      \"pmids\": [\"34888656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Selective inactivation of mHTT in NG2+ oligodendrocyte progenitor cells prevents myelin abnormalities and certain behavioral deficits in HD mice, despite continued mHTT expression in neurons, astrocytes, and microglia; mHTT enhances polycomb repressive complex 2 (PRC2) activity in oligodendroglia, causing intrinsic oligodendroglial dysfunction.\",\n      \"method\": \"Conditional Cre-mediated mHTT knockout in NG2+ cells in HD mice; MRI, behavioral testing; RNA-seq and ChIP-seq analysis of PRC2 targets in oligodendroglia\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with defined molecular mechanism (PRC2 ChIP-seq) and behavioral rescue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31015293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HTT is present with Rab4-containing vesicles within axons in vivo; reduction of HTT perturbs bi-directional motility of Rab4 vesicles, causing axonal and synaptic accumulations; the HTT-Rab4 vesicle also contains synaptotagmin, synaptobrevin, and Rab11, and its movement requires kinesin-1 and dynein motors as well as the accessory protein HIP1 (HTT-interacting protein 1); pathogenic HTT disrupts this motility causing locomotion defects, aberrant synaptic morphology, and decreased lifespan rescued by excess Rab4.\",\n      \"method\": \"In vivo dual-color live imaging in Drosophila axons; HTT knockdown; genetic rescue with excess Rab4; iNeurons from human HD patients; Co-localization and motility quantification\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo live imaging in Drosophila with genetic rescue, validated in human HD patient-derived neurons; multiple orthogonal approaches\",\n      \"pmids\": [\"32611447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Small molecule splicing modulators promote inclusion of a pseudoexon containing a premature termination codon in the HTT pre-mRNA, leading to HTT mRNA degradation via nonsense-mediated decay and systemic reduction of HTT protein throughout the CNS and periphery after oral administration.\",\n      \"method\": \"Splicing assay; RT-PCR identification of pseudoexon; mRNA and protein quantification in multiple CNS regions after oral dosing in animals\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanism (pseudoexon inclusion leading to NMD) demonstrated by RNA analysis, replicated in multiple tissues in vivo\",\n      \"pmids\": [\"34911927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNAJB1 has a specific HTT-binding motif (HBM) in the hinge region between CTD I and II that binds to the polyQ-adjacent proline-rich domain (PRD) of soluble and aggregated HTT; mutation of the conserved H244 in this HBM completely abrogates suppression and disaggregation of HTT fibrils by the trimeric chaperone complex (Hsc70/DNAJB1/Apg2) without affecting any other substrate, establishing the HBM as a HTT-specific interaction site.\",\n      \"method\": \"Mutagenesis of DNAJB1 HBM (H244A); in vitro fibrilization and disaggregation assays with purified components; pulldown/binding assays with HTT PRD; HEK293 cell aggregation rescue with wt vs. mutant DNAJB1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis identifying specific binding interface, confirmed in cells; substrate specificity established by testing other substrates\",\n      \"pmids\": [\"35948542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HTT and RAB7 co-migrate retrogradely together on LAMP1-containing late endosomes during axonal injury in Drosophila neurons; this co-migration represents a signaling endosome response to axonal damage.\",\n      \"method\": \"In vivo dual-color live axonal imaging in Drosophila; co-localization of HTT, RAB7, and LAMP1 on moving vesicles following axonal injury; immunoprecipitation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo live imaging with co-localization and IP, single lab but direct observation of co-migration\",\n      \"pmids\": [\"36048753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Alternative splicing of HTT pre-mRNA generates the HTT1a transcript (exon 1 only) in YAC128 mice expressing human HTT; HTT1a and full-length HTT transcripts are retained together in large nuclear RNA clusters as well as present as single transcripts in the cytoplasm; HTT1a is translated to produce the exon 1 HTT protein whose levels correlate with HTT aggregation.\",\n      \"method\": \"RNAscope single-molecule RNA FISH; HTRF protein quantification; RT-PCR; QuantiGene multiplex assay in YAC128 mice and MEF lines\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — single-molecule visualization of nuclear RNA clusters with protein-level confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"35793238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila, the hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression: transcriptional repression by RNA Pol II inhibitor impairs RNA splicing of Htt (an ER-stabilizing molecule), and this impairment is rescued by hnRNP overexpression; genetic suppression or expression of Htt and hnRNP respectively worsens or ameliorates transcriptional repression-induced necrosis.\",\n      \"method\": \"Genetic screen of knockdown fly library; RNA sequencing; fly epistasis with Htt suppressors/expressors and hnRNP overexpression; measurement of pupa-to-larva transformation ratio\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila model with RNA-seq mechanistic support; ortholog context consistent with mammalian HTT\",\n      \"pmids\": [\"27124581\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Huntingtin (HTT) is a large scaffold protein concentrated at nerve terminals and on vesicles involved in axonal transport (including Rab4- and Rab7-positive endosomes), whose N-terminal domain undergoes phosphorylation (Ser-13/16 by kinases) and arginine methylation (by PRMT4/6) that regulate its aggregation propensity, nuclear trafficking, and phase-separation behavior; the expanded polyglutamine in mutant HTT confers toxic gain-of-function via interactions with IKKγ to dysregulate NF-κB signaling in immune cells, enhancement of PRC2 activity in oligodendroglia causing myelination defects, disruption of Rab4-vesicle axonal motility, and formation of amyloid fibrils that are suppressed and reversed by a trimeric chaperone complex (Hsc70/DNAJB1/Hsp110) acting through a specific HTT-binding motif in DNAJB1; aberrant incomplete splicing of the expanded HTT pre-mRNA produces a pathogenic exon 1 HTT protein and nuclear RNA clusters, and HTT levels are regulated by autophagy (modulated via FKBP5 and autophagosome-tethering compounds) and by pre-mRNA splicing modulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nPapers about HTT (huntingtin gene/protein) → KEEP:\n- Papers 2, 4, 5, 7, 8, 11, 12, 13, 14, 19, 20, 22, 23, 24, 25, 26, 28, 29, 36, 38, 39, 43, 48, 51, 52, 54, 56, 58, 63, 66, 72, 75, 77, 86, 91, 93, 94, 95, 100 from main corpus\n\nPapers about 5-HTT/SLC6A4 (serotonin transporter) → EXCLUDE (alias collision):\n- Papers 1, 6, 10, 15, 30, 33, 34, 44, 59, 62, 65, 81, 85 and all gene2pubmed papers (virtually all are about SLC6A4)\n\nPapers about HD-Zip plant transcription factors → EXCLUDE (symbol collision):\n- Papers 3, 17, 40, 41, 42, 46, 53, 55, 57, 60, 73, 82, 90, 97\n\nPapers about HD-GYP bacterial proteins → EXCLUDE (symbol collision):\n- Papers 21, 70\n\nPapers about HD-PTP/PTPN23 → EXCLUDE (symbol collision):\n- Papers 45, 74\n\nPapers about SAMHD1 (HD domain) → EXCLUDE:\n- Paper 16\n\nPapers about AD/HD (ADHD) → EXCLUDE:\n- Paper 67\n\nUnrelated (CAG repeat epidemiology, genetic counseling, etc., no mechanism) → EXCLUDE:\n- Papers 9, 18, 27, 28 (clinical only), 37, 49, 50, 64, 84, 87, 98\n\nOther non-mechanistic (reviews/epidemiology) → skip\n\nNow extracting discoveries from KEEP papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"The HTT gene product is a ~350 kDa protein widely expressed in neurons throughout the brain, with no enrichment in the striatum (the site of greatest pathology). Within neurons, huntingtin is present in the soluble cytoplasm and loosely associated with membranes or cytoskeleton, and is concentrated in nerve terminals including those in the caudate and putamen, suggesting a role in nerve terminal function.\",\n      \"method\": \"Immunohistochemistry and subcellular fractionation using antibodies against N-terminal and internal epitopes of the HTT protein\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization by fractionation and IHC with two independent antibodies, replicated by similar study (PMID:8240819)\",\n      \"pmids\": [\"7748554\", \"8240819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In HD patients, both alleles of the IT15/HTT protein are expressed at similar levels in relatively spared brain regions. In severely affected regions (cortex and caudate), the expanded-repeat allele is present at lower levels and shows a smear of more slowly migrating reactivity, suggesting altered structure, abnormal processing, or abnormal protein-protein interactions of the polyglutamine-expanded HTT.\",\n      \"method\": \"Quantitative Western blot analysis on 4% polyacrylamide gels of HD patient post-mortem brain tissue and lymphoblastoid cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative Western blot in patient tissue, single lab\",\n      \"pmids\": [\"7581375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The HD gene promoter contains two tandemly repeated Sp1 sites that act synergistically as a key positive-acting regulatory element. This region is polymorphic, and a single Sp1 site variant is associated with reduced transcription. Differential control of HTT expression exists between neuronal and non-neuronal cell lines.\",\n      \"method\": \"Reporter gene assays in neuronal (SK-N-SH) and non-neuronal (JEG3) cell lines with deletion and mutagenesis analysis of the 5' upstream region\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter dissection with mutagenesis, single lab\",\n      \"pmids\": [\"9536082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Full-length huntingtin, in alternate forms distinguished by epitope accessibility, localizes to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. Mutant STHdh(Q111) cells exhibit dominant phenotypes distinct from those caused by huntingtin deficiency or excess, including elevated p53, endoplasmic reticulum stress response, and hypoxia pathway activation, indicating the mutant protein disrupts striatal homeostasis via a mechanism separate from its normal activity.\",\n      \"method\": \"Immunofluorescence and subcellular localization in striatal cell lines from wild-type and Hdh(Q111) knock-in embryos; comparison of phenotypes between wild-type and mutant cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and comparative phenotypic analysis in knock-in cell lines\",\n      \"pmids\": [\"11092756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Neurotrophic factors FGF-2 and NGF regulate huntingtin protein levels in striatal neuronal cultures in a dose-dependent, factor-specific manner: FGF-2 increases huntingtin levels while NGF decreases them.\",\n      \"method\": \"Western blotting of striatal cell cultures treated with growth factors\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Western blot only, no mechanistic pathway defined\",\n      \"pmids\": [\"11144959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Huntingtin is required for neuronal migration, proliferation, and survival in neocortex during early brain development. Knockdown of Htt in neuroepithelial cells causes disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, Htt knockdown causes cell death but not migration defects. The cortical cell death phenotype is partially reversed by co-knockdown of Caspase-9, implicating mitochondria-mediated apoptotic processes.\",\n      \"method\": \"In utero electroporation-mediated RNAi knockdown of Htt in mouse neocortex and cerebellum; rescue experiments with Casp9 co-knockdown\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with specific phenotypic readout and epistasis rescue experiment\",\n      \"pmids\": [\"21994396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The first 17 amino acids (N17) of huntingtin function as a nuclear export sequence (NES). Mutation of conserved residues within N17 increases nuclear accumulation of Htt exon 1, and nuclear export is sensitive to leptomycin B and reduced by knockdown of exportin 1 (CRM1). In HEK293 cells, NES mutations decrease overall Htt aggregation but increase the fraction of cells with nuclear inclusions; in primary neurons, NES mutations increase nuclear accumulation and increase overall aggregation.\",\n      \"method\": \"Site-directed mutagenesis of N17 residues, leptomycin B treatment, exportin 1 siRNA knockdown, fluorescence microscopy in HEK293 cells and primary neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mutagenesis, pharmacological inhibition, siRNA knockdown) in two cell types\",\n      \"pmids\": [\"23319588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutant huntingtin directly interacts with IKKγ (NEMO), leading to increased IκB degradation and subsequent nuclear translocation of RelA (NF-κB p65), causing excessive inflammatory cytokine production in human HD myeloid cells. Lowering HTT with siRNA reverses these NFκB-pathway-related immune dysfunction phenotypes.\",\n      \"method\": \"Co-immunoprecipitation of mutant HTT with IKKγ; measurement of IκB degradation and RelA nuclear translocation; siRNA-mediated HTT knockdown via glucan-encapsulated particles in primary human HD monocytes/macrophages\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying binding partner, functional rescue by HTT lowering in primary human cells\",\n      \"pmids\": [\"24459107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Full-length expanded HTT (expHTT) RNA is retained in the nucleus. The splicing factor MBNL1 increases nuclear retention of expHTT and decreases cytosolic expHTT protein expression, while the splicing/export factor U2AF65 has the opposite effect, decreasing nuclear retention and increasing cytoplasmic expHTT protein. An expHTT RNA fragment is cytotoxic in the absence of translation.\",\n      \"method\": \"Overexpression of MBNL1 and U2AF65 in cells expressing expHTT; nuclear/cytoplasmic fractionation and Western blot; cytotoxicity assays with translation-incompetent constructs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation with functional consequence, two opposing regulators tested\",\n      \"pmids\": [\"26218986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Incomplete splicing of the huntingtin pre-mRNA between exon 1 and exon 2 produces a small polyadenylated transcript (HTTexon1) encoding the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length. HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and in post-mortem brain tissue from HD individuals.\",\n      \"method\": \"Quantitative RT-PCR protocols specific for HTTexon1 transcript in human fibroblast lines and post-mortem brain samples; comparison across adult-onset and juvenile-onset HD patients\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct quantitative detection of specific aberrant transcript in human patient tissue, replicated across multiple sample types\",\n      \"pmids\": [\"28465506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A trimeric chaperone complex composed of Hsc70, Hsp110, and a J-protein (DNAJB1) completely suppresses fibrilization of HttExon1Q48 and can also resolubilize pre-formed Htt fibrils. Among the three components, the J-protein is the concentration-limiting factor; overexpression of DNAJB1 alone in HEK293T cells is sufficient to profoundly reduce HttExon1Q97 aggregation.\",\n      \"method\": \"In vitro fibrilization assays with purified chaperone components; disaggregation assays; overexpression in HEK293T cells; validation in HD patient-derived neural cells and C. elegans\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified components, validated in multiple cellular and in vivo systems\",\n      \"pmids\": [\"29212816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Phosphorylation of huntingtin exon 1 at Ser-13 and/or Ser-16 inhibits aggregation of mutant Httex1 and strongly disrupts the amphipathic α-helix of the N-terminal 17-residue (Nt17) domain, impairing membrane binding. Only bona fide phosphorylation (not phosphomimetic substitution) prompts internalization and nuclear targeting of preformed Httex1 aggregates. A phosphorylation-dependent switch involving cross-talk between Thr-3 and Ser-13/Ser-16 regulates Httex1 structure.\",\n      \"method\": \"In vitro phosphorylation of synthetic Httex1 peptides; circular dichroism and NMR analysis of α-helix disruption; membrane-binding assays; live-cell imaging of aggregate internalization and nuclear targeting; comparison of phosphorylated vs. phosphomimetic variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation with structural validation (CD, NMR), functional cell-based assays, multiple orthogonal methods\",\n      \"pmids\": [\"30185623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutant huntingtin causes intrinsic oligodendroglial dysfunction and myelination deficits through enhancement of polycomb repressive complex 2 (PRC2) activity in NG2+ oligodendrocyte progenitor cells. Selective inactivation of mHTT in the NG2+ population prevents myelin abnormalities and certain behavioral deficits, demonstrating cell-autonomous pathology in oligodendroglia independent of neuronal mHTT expression.\",\n      \"method\": \"Conditional knockout of mHTT in NG2+ oligodendrocyte progenitors in HD mice; RNA-seq and ChIP-seq to identify PRC2 pathway as a mechanism; behavioral and histological analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with defined molecular mechanism (ChIP-seq for PRC2) and behavioral phenotype rescue\",\n      \"pmids\": [\"31015293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Compounds that interact with both LC3 (autophagosome protein) and mutant HTT (via its expanded polyQ tract) selectively target mHTT to autophagosomes for autophagic clearance, reducing mHTT levels in an allele-selective manner. These autophagosome-tethering compounds do not interact with wild-type HTT, and also lower mutant ataxin-3, demonstrating that the polyQ expansion is the binding determinant.\",\n      \"method\": \"Small-molecule microarray screening; co-immunoprecipitation of compounds with LC3 and mHTT; measurement of mHTT levels in cells, Drosophila, and mouse HD models; allele-selective quantification by HTT protein assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional validation in multiple model systems (cells, flies, mice), allele-selectivity demonstrated\",\n      \"pmids\": [\"31666698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAN1 (FANCD2/FANCI-associated nuclease 1) binds directly to the expanded HTT CAG repeat DNA and stabilizes it against somatic expansion. FAN1 overexpression reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1; FAN1 knockdown increases CAG repeat expansion in patient-derived stem cells and medium spiny neurons. The protective effect is FAN1 concentration- and CAG repeat length-dependent, and does not require FAN1's nuclease activity.\",\n      \"method\": \"FAN1 overexpression and knockdown in human cells and patient-derived stem cells/neurons; MiSeq-based CAG repeat length quantification; DNA-binding assay of FAN1 with expanded HTT CAG repeat DNA; nuclease-dead mutant experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct DNA binding demonstrated, genetic manipulation in patient-derived neurons with quantitative readout, nuclease-dead mutant defines mechanism\",\n      \"pmids\": [\"30358836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Gpr52, an orphan G protein-coupled receptor, regulates mutant HTT protein levels in the striatum. Knockout of Gpr52 significantly reduces mHTT levels and rescues HD-associated behavioral phenotypes in a knock-in HD mouse model. A Gpr52 antagonist (E7) similarly reduces mHTT levels and rescues phenotypes in cellular and mouse models.\",\n      \"method\": \"Gpr52 knockout in zQ175 knock-in HD mice; pharmacological inhibition with Gpr52 antagonist E7; mHTT level quantification by HTRF; behavioral testing\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout plus pharmacological inhibition with consistent phenotype, but downstream mechanism linking Gpr52 to HTT levels not fully elucidated\",\n      \"pmids\": [\"29608652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FKBP5 interacts and colocalizes with HTT in the striatum and cortex. Decreasing FKBP5 levels by siRNA or pharmacological inhibition (SAFit2) reduces mutant HTT levels and increases LC3-II levels and autophagic flux, indicating that FKBP5 modulates mHTT clearance through autophagy in an MTOR-independent manner.\",\n      \"method\": \"Co-immunoprecipitation and colocalization of FKBP5 and HTT in mouse brain; siRNA knockdown and SAFit2 inhibitor treatment in HD iPSC-derived neurons and mouse models; LC3-II Western blot for autophagic flux\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional autophagy measurement with genetic and pharmacological perturbations\",\n      \"pmids\": [\"34024231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The polyproline (polyP) region of huntingtin can interact with the N-terminal 17-residue (Nt17) α-helical region, inhibiting nucleation and fibril formation of mutant Htt. Ion mobility spectrometry and gas-phase hydrogen-deuterium exchange coupled with MS and molecular dynamics simulations suggest the C-terminal portion of Nt17 is the primary contact point, and polyP may induce a random coil in this region to reduce the propensity for amyloid-competent amphipathic α-helix formation.\",\n      \"method\": \"Atomic force microscopy time-course aggregation assays; ion mobility spectrometry-mass spectrometry; gas-phase H/D exchange MS; molecular dynamics simulations\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods including structural MS; single lab but orthogonal approaches\",\n      \"pmids\": [\"31814404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HTT is present with Rab4-containing vesicles within axons in vivo and is required for the bidirectional motility of Rab4. HTT and Rab4 move together on a putative vesicle that may also contain synaptotagmin, synaptobrevin, and Rab11. The moving HTT-Rab4 vesicle uses kinesin-1 and dynein motors and the accessory protein HIP1 for bidirectional axonal transport. Pathogenic HTT disrupts HTT-Rab4 vesicle motility, causing synaptic accumulations, aberrant synaptic morphology, and decreased lifespan—phenotypes rescued by excess Rab4.\",\n      \"method\": \"In vivo dual-color live imaging in Drosophila axons; genetic reduction of HTT; HIP1 accessory protein analysis; Rab4 overexpression rescue; iNeuron studies from human HD patients\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live imaging of co-moving vesicles in vivo, genetic rescue, validated in human HD iNeurons\",\n      \"pmids\": [\"32611447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Small molecules can lower HTT expression by promoting inclusion of a pseudoexon containing a premature termination codon in HTT pre-mRNA (stop-codon psiExon), leading to mRNA degradation. These orally bioavailable splicing modulators achieve broad CNS distribution and reduce HTT levels consistently throughout CNS and periphery.\",\n      \"method\": \"Identification of splicing modulators by cell-based screening; RT-PCR characterization of induced pseudoexon inclusion; HTT protein measurement in cells and in vivo mouse brain after oral dosing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanism of pseudoexon induction defined by RT-PCR, in vivo validation, but single lab\",\n      \"pmids\": [\"34911927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HTT interacts with several type I protein arginine methyltransferases (PRMTs) via its N-terminal domain. PRMT4 (CARM1) and PRMT6 are the major enzymes methylating HTT at specific arginine residues. Mass spectrometry identified ~24 arginine methylation/dimethylation sites on endogenous HTT from human and mouse brain. Alterations at R200/205 methylation sites render HTT less soluble, promote liquid-to-solid phase transition of HTT assemblies in vitro, and increase neuronal toxicity; overexpression of PRMT4/6 is beneficial for neuronal survival.\",\n      \"method\": \"Mass spectrometry (data-dependent and targeted quantitative) of endogenous HTT; in vitro methylation assays with purified PRMTs; Co-IP of HTT with PRMTs; cell-based solubility assays; liquid-liquid phase separation assays in vitro; neuronal toxicity assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro methylation reconstitution, Co-IP, structural phase-transition assays, and neuronal toxicity with multiple orthogonal methods\",\n      \"pmids\": [\"34888656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNAJB1 contains a HTT-binding motif (HBM) in the hinge region between its C-terminal domains I and II that specifically binds to the polyQ-adjacent proline-rich domain (PRD) of both soluble and aggregated HTT. Mutation of the conserved H244 in the HBM completely abrogates the ability of the trimeric chaperone complex (Hsc70/DNAJB1/Apg2) to suppress and disaggregate HTT fibrils, without affecting DNAJB1's activity on other substrates. Overexpression of wild-type but not H244A DNAJB1 prevents HTTExon1Q97 aggregation in HEK293 cells.\",\n      \"method\": \"Mutational analysis of DNAJB1 HBM; in vitro fibril suppression and disaggregation assays; pulldown/binding assays between DNAJB1 variants and HTT PRD; overexpression in HEK293 cells; molecular dynamics simulations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of chaperone activity with mutagenesis defining specific interaction interface, validated in cells\",\n      \"pmids\": [\"35948542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Branaplam, a splicing modulator, promotes inclusion of a novel 115-bp frameshift-inducing exon in the HTT transcript, leading to profound reduction of HTT RNA and protein levels. Branaplam lowers both total HTT and mutant HTT in patient-derived fibroblasts, iPSC, cortical progenitors, and neurons with an IC50 consistently below 10 nM, and ameliorates aberrant alternative splicing patterns in HD patient cells.\",\n      \"method\": \"RT-PCR and RNA-seq identification of Branaplam-induced novel exon in HTT; HTT protein quantification by MSD assay in multiple patient-derived cell types; dose-response analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanism defined by RNA-seq, validated in multiple patient-derived cell types\",\n      \"pmids\": [\"36357392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HTT co-migrates retrogradely with RAB7 on signaling LAMP1-containing late endosomes during axonal injury in Drosophila neurons, as demonstrated by in vivo dual-color imaging. This positions HTT on a late endosomal compartment during the injury response.\",\n      \"method\": \"In vivo dual-color live imaging of HTT and RAB7/LAMP1 in injured Drosophila axons; immunoprecipitation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct live co-imaging in vivo, but functional consequence not fully established\",\n      \"pmids\": [\"36048753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila, huntingtin (Htt) participates in a cell death pathway triggered by transcriptional repression. The hnRNP-Htt axis regulates necrotic cell death: transcriptional repression by RNA polymerase II inhibition impairs splicing and expression of Htt (an ER-stabilizing molecule), and hnRNP overexpression rescues both RNA splicing and cell survival. Genetic suppression of Htt worsened, while expression of Htt ameliorated, the decreased survival phenotype.\",\n      \"method\": \"Genetic screen of knockdown fly library; RNA-seq; fly genetics with Htt suppressors and expressers; α-amanitin (RNA Pol II inhibitor) treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila model with RNA-seq mechanistic support\",\n      \"pmids\": [\"27124581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AAV5-delivered miHTT (an engineered microRNA targeting HTT exon 1) reduces levels of both full-length HTT mRNA and the aberrantly spliced HTT1a transcript, as well as the pathogenic exon 1 HTT protein, in the striatum and cortex of HD mouse models (zQ175 and humanized Hu128/21 mice). The exon 1 HTT protein, translated from HTT1a, is detectable in knock-in HD mice and is significantly reduced by miHTT treatment.\",\n      \"method\": \"Intrastriatal AAV5-miHTT injection; QuantiGene multiplex assay for HTT and HTT1a mRNA; HTRF assay for mutant HTT and HTTexon1 protein; dose-response analysis in mouse brain regions\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dual targeting of FL HTT and HTTexon1 validated in two mouse models with multiple quantitative assays\",\n      \"pmids\": [\"39155061\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Huntingtin (HTT) is a large scaffold protein (~350 kDa) that in its wild-type form functions in axonal transport of Rab4- and Rab7-containing vesicles via kinesin-1/dynein motors, supports neuronal migration and survival during brain development through mitochondria-dependent pathways, and is regulated by phosphorylation (at Ser-13/Ser-16 by unidentified kinases) and arginine methylation (by PRMT4/PRMT6), which control its α-helical conformation, membrane binding, nuclear export via CRM1, and phase transition behavior; the CAG repeat expansion in HTT produces a mutant protein that aberrantly interacts with IKKγ to activate NFκB-driven neuroinflammation, disrupts oligodendroglial function via PRC2 enhancement, generates a pathogenic exon 1 HTT protein through incomplete pre-mRNA splicing (producing the HTTexon1/HTT1a transcript in proportion to repeat length), and forms amyloid aggregates that can be suppressed by the trimeric chaperone complex Hsc70/DNAJB1/Hsp110 via a specific HTT-binding motif in DNAJB1's proline-rich domain interface.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Huntingtin (HTT) is a large scaffold protein that functions in vesicular trafficking, nuclear-cytoplasmic transport, and transcriptional regulation, with critical roles in neuronal migration, axonal transport, and myelination. HTT localizes to nerve terminals and associates with Rab4- and Rab7-positive endosomes, where it facilitates bidirectional axonal transport via kinesin-1 and dynein motors; disruption of this function by polyglutamine-expanded mutant HTT causes synaptic and axonal defects rescued by excess Rab4 [PMID:32611447, PMID:36048753]. The N-terminal 17 residues serve as a CRM1-dependent nuclear export signal whose activity is modulated by phosphorylation at Ser-13/16 (inhibiting aggregation and membrane binding) and arginine methylation by PRMT4/6 at R200/205 (regulating phase separation from liquid-like to solid-like assemblies) [PMID:23319588, PMID:30185623, PMID:34888656]. Expansion of the CAG repeat in HTT causes Huntington disease through multiple convergent mechanisms: aberrant incomplete splicing produces a pathogenic exon 1 protein and nuclear RNA clusters [PMID:28465506, PMID:35793238], mutant HTT dysregulates NF-κB signaling via interaction with IKKγ in myeloid cells [PMID:24459107], enhances PRC2 activity in oligodendroglia causing myelination defects [PMID:31015293], and forms amyloid fibrils that are suppressed and disaggregated by a trimeric Hsc70/DNAJB1/Hsp110 chaperone complex acting through a HTT-specific binding motif in DNAJB1 [PMID:29212816, PMID:35948542].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing HTT as a widely expressed neuronal protein concentrated at nerve terminals resolved the question of whether the HD gene product had a neuron-restricted or ubiquitous expression pattern, and showed that the expanded allele is expressed—supporting a gain-of-function disease mechanism rather than haploinsufficiency.\",\n      \"evidence\": \"Immunostaining, subcellular fractionation, and Western blot of human brain tissues and HD lymphoblastoid lines\",\n      \"pmids\": [\"7748554\", \"7581375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No interacting partners or biochemical activity identified\", \"Mechanism by which expanded HTT causes toxicity unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of Sp1-dependent transcriptional control of the HTT promoter established that HTT expression is differentially regulated between neuronal and non-neuronal cells, addressing how tissue-specific HTT levels might arise.\",\n      \"evidence\": \"Reporter gene assays with Sp1 site mutagenesis in neuronal (SK-N-SH) and non-neuronal (JEG3) cell lines\",\n      \"pmids\": [\"9536082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation of promoter regulation\", \"Whether Sp1-site polymorphisms modify HD onset unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Full-length mutant HTT in isogenic knock-in cells was shown to mislocalize to nuclear and perinuclear organelles and to induce dominant stress phenotypes (p53 elevation, ER stress) distinct from HTT loss, establishing that expanded HTT confers gain-of-function at the full-length protein level.\",\n      \"evidence\": \"Epitope accessibility assays, immunolocalization, and stress pathway readouts in STHdh(Q111) knock-in striatal lines\",\n      \"pmids\": [\"11092756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets mediating stress responses not identified\", \"Whether phenotypes recapitulate in vivo pathology not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that HTT is required for cortical neuronal migration and survival during development, with rescue by Casp9 co-knockdown, established a developmental function for normal HTT beyond its role in adult neurodegeneration.\",\n      \"evidence\": \"In utero electroporation of Htt shRNA in mouse neocortex with Casp9 epistasis, BrdU labeling, and immunohistochemistry\",\n      \"pmids\": [\"21994396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking HTT to migration machinery unknown\", \"Whether developmental role is cell-autonomous in all neuron types untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The discovery that the N-terminal 17 residues of HTT function as a CRM1-dependent nuclear export signal resolved how HTT is actively excluded from the nucleus and why pathogenic fragments accumulate there when this sequence is disrupted.\",\n      \"evidence\": \"Leptomycin B treatment, CRM1 knockdown, and NES mutagenesis with live imaging in HEK293 cells and primary neurons\",\n      \"pmids\": [\"23319588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether full-length HTT uses the same NES for nuclear export not directly tested\", \"Regulation of N17-mediated export by post-translational modifications not yet connected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of a direct interaction between mutant HTT and IKKγ/NEMO in myeloid cells, with consequent NF-κB hyperactivation and excessive cytokine production reversible by HTT lowering, established a non-neuronal cell-autonomous disease mechanism in HD.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA HTT lowering, NF-κB pathway and cytokine analysis in primary human HD monocytes/macrophages\",\n      \"pmids\": [\"24459107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IKKγ interaction is polyQ-length dependent not fully resolved\", \"Contribution of peripheral immune activation to CNS disease progression not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two parallel advances established that aberrant incomplete splicing produces a pathogenic HTTexon1 mRNA proportional to CAG length, and that a trimeric Hsc70/DNAJB1/Hsp110 chaperone complex can completely suppress and reverse HTT exon 1 fibrilization, identifying both a key toxic species and an endogenous disaggregation machinery.\",\n      \"evidence\": \"Quantitative RT-PCR for HTTexon1 in patient fibroblasts and brain (splicing); in vitro reconstitution with purified chaperones plus cell and C. elegans validation (disaggregation)\",\n      \"pmids\": [\"28465506\", \"29212816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why incomplete splicing is repeat-length dependent mechanistically unclear\", \"Whether chaperone-mediated disaggregation occurs at relevant rates in vivo unknown\", \"Relative contribution of exon 1 protein vs. full-length mHTT to disease not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Phosphorylation at Ser-13/16 was shown to disrupt the Nt17 amphipathic helix, inhibit membrane binding and aggregation, and redirect preformed aggregates to the nucleus, establishing a post-translational switch that controls multiple HTT behaviors.\",\n      \"evidence\": \"In vitro phosphorylation, circular dichroism, aggregation assays, membrane binding, and subcellular localization in cells\",\n      \"pmids\": [\"30185623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase(s) responsible for Ser-13/16 phosphorylation in vivo not fully established\", \"Cross-talk between Thr-3 and Ser-13/16 not characterized in disease context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple discoveries converged to define HTT's roles in arginine methylation-dependent phase separation, oligodendroglial PRC2 regulation, autophagy-mediated clearance, and CAG repeat stability: PRMT4/6 methylation at R200/205 regulates HTT liquid-to-solid phase transition; mHTT enhances PRC2 activity in oligodendroglia causing myelination defects; FKBP5 interaction modulates autophagic clearance; and FAN1 stabilizes expanded CAG repeats via nuclease-independent DNA binding.\",\n      \"evidence\": \"Mass spectrometry and phase separation assays (methylation); conditional NG2-Cre KO with ChIP-seq (PRC2); Co-IP and pharmacological inhibition with autophagy flux readouts (FKBP5); DNA binding and gain/loss-of-function in iPSC-neurons (FAN1)\",\n      \"pmids\": [\"34888656\", \"31015293\", \"34024231\", \"30358836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether methylation status differs between WT and mHTT in patient brain not established\", \"Molecular basis for mHTT-PRC2 interaction not identified\", \"Whether FKBP5-mediated autophagy is selective for mHTT unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Live imaging demonstrated that HTT co-migrates with Rab4-containing synaptic vesicles in axons, requiring kinesin-1, dynein, and HIP1, and that pathogenic HTT disrupts this motility in a manner rescued by excess Rab4, establishing HTT as an axonal transport scaffold.\",\n      \"evidence\": \"In vivo dual-color live imaging in Drosophila axons; genetic rescue with Rab4; validation in human HD iNeurons\",\n      \"pmids\": [\"32611447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis for HTT–motor protein interaction not resolved\", \"Whether Rab4 rescue is sufficient in mammalian models unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Oral splicing modulators that induce a premature termination codon via pseudoexon inclusion demonstrated that HTT mRNA can be systemically reduced through nonsense-mediated decay, validating pre-mRNA splicing as a therapeutic modality.\",\n      \"evidence\": \"RT-PCR identification of pseudoexon; mRNA and protein quantification across CNS regions after oral dosing in animals\",\n      \"pmids\": [\"34911927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety of systemic HTT lowering not established\", \"Whether WT HTT is equally affected and what functional consequences ensue not fully addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of a specific HTT-binding motif (HBM) in DNAJB1 that contacts the proline-rich domain of HTT, and visualization of HTTexon1/full-length HTT transcripts in nuclear RNA clusters, refined the molecular mechanisms of chaperone-mediated disaggregation and RNA-level pathogenesis.\",\n      \"evidence\": \"DNAJB1 H244A mutagenesis with in vitro fibrilization/disaggregation assays (HBM); RNAscope single-molecule FISH in YAC128 mice (RNA clusters)\",\n      \"pmids\": [\"35948542\", \"35793238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HBM-targeted chaperone activation can be pharmacologically enhanced in vivo unknown\", \"Function and composition of nuclear RNA clusters beyond HTT transcripts not characterized\", \"Whether nuclear RNA clusters are pathogenic or protective is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural model of full-length HTT as a transport scaffold—integrating its interactions with Rab GTPases, motor proteins, chaperones, and signaling complexes—and the relative pathogenic contributions of the exon 1 protein, full-length mHTT, and expanded-repeat RNA remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length HTT in complex with transport or signaling partners\", \"Relative contributions of protein versus RNA toxicity in HD not quantified\", \"How somatic CAG expansion feeds back to affect aberrant splicing and exon 1 protein production is mechanistically undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 15]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 9, 22]}\n    ],\n    \"complexes\": [\n      \"Hsc70/DNAJB1/Hsp110 disaggregase (substrate)\"\n    ],\n    \"partners\": [\n      \"DNAJB1\",\n      \"NEMO\",\n      \"RAB4\",\n      \"RAB7\",\n      \"FKBP5\",\n      \"PRMT4\",\n      \"PRMT6\",\n      \"HIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Insufficient on-target evidence to synthesize a narrative — discovery timeline does not match the canonical HTT protein.\",\n  \"teleology\": [],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}