Affinage

HTT

Sodium-dependent serotonin transporter · UniProt P31645

Length
630 aa
Mass
70.3 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTT encodes a large (~350 kDa) cytoplasmic scaffolding protein concentrated in neuronal nerve terminals and largely excluded from nuclei and mitochondria, with roles spanning vesicular trafficking, organelle quality control, chromatin regulation, and neural development (PMID:7748554, PMID:21994396). As a trafficking scaffold, HTT supports dynein/dynactin-dependent transport: its HAP1-interaction and dynein-interaction domains are required to rescue Golgi reformation and BDNF vesicle trafficking in neurons (PMID:20515468), and it associates with RAB7/LAMP1 late endosomes during retrograde axonal injury signaling (PMID:36048753). HTT also organizes mitochondrial quality control, recruiting mitophagy receptors and promoting contact between damaged mitochondria and nascent autophagosomes (PMID:32093570). In the nucleus, wild-type HTT is required for proper PRC2-dependent H3K27me3 deposition at bivalent loci, linking it to chromatin regulation (PMID:25574027). HTT is developmentally essential: its loss in neuroepithelium disrupts neuronal migration, proliferation, and survival via caspase-9-dependent apoptosis (PMID:21994396). Subcellular distribution is governed by an N-terminal 17-residue (Nt17) nuclear export sequence that depends on exportin 1; phosphorylation at Ser-13/Ser-16 disrupts its amphipathic α-helix, inhibits membrane binding and aggregation, and redirects HTT to the nucleus (PMID:23319588, PMID:30185623). Pathogenic CAG/polyQ expansion confers dominant gain-of-function effects, including elevated stress and apoptotic markers (PMID:11092756), enhanced PRC2 activity in neurons and oligodendroglia (PMID:25574027, PMID:31015293), disrupted mitophagy complex assembly with oxidative stress (PMID:32093570), and altered arginine methylation by PRMT4/PRMT6 that drives liquid-to-solid phase transition and toxicity (PMID:34888656). Aggregation is seeded by an exon 1 HTT species generated by incomplete splicing of HTT pre-mRNA, whose levels scale with CAG length and correlate with disease severity (PMID:28465506, PMID:35793238), and is suppressed by a trimeric Hsc70–Hsp110–DNAJB1 chaperone complex in which DNAJB1 engages the polyQ-adjacent proline-rich domain through a specific HTT-binding motif (PMID:29212816, PMID:35948542). HTT protein levels are further controlled by FKBP5, GPR52, HIPK3, and pre-mRNA splicing, nodes exploited for allele- and dose-lowering therapeutic strategies (PMID:31666698, PMID:34024231, PMID:34911927, PMID:29608652, PMID:29130397).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 Medium

    Establishing where the IT15/HTT product resides was the first step toward function; the work showed HTT is a broadly neuronal ~350 kDa cytoplasmic protein concentrated at nerve terminals rather than enriched in the striatum it most affects.

    Evidence Western blot, immunohistochemistry, and subcellular fractionation with two independent antisera

    PMID:7748554

    Open questions at the time
    • No molecular activity assigned
    • Does not explain striatal selectivity of disease
    • Membrane/cytoskeleton association only loosely defined
  2. 1998 Medium

    Whether polyQ expansion causes aggregation in patients was answered by showing intranuclear neuronal inclusions whose density scales with CAG repeat length, tying expansion directly to nuclear aggregate formation.

    Evidence Immunohistochemistry of 20 post-mortem HD brains with N-terminal HTT and anti-ubiquitin antibodies

    PMID:9666478

    Open questions at the time
    • Correlation, not causation, of inclusions with toxicity
    • Does not identify the aggregating species
    • No functional reconstitution
  3. 2000 Medium

    To distinguish loss- from gain-of-function, knock-in striatal cells showed mutant HTT produces dominant phenotypes (elevated p53, ER stress, hypoxia markers) distinct from HTT deficiency or excess.

    Evidence Comparative analysis of Hdh(Q111) knock-in vs wild-type striatal cell lines with multiple readouts

    PMID:11092756

    Open questions at the time
    • Molecular trigger of stress responses not defined
    • Single cell-line model
    • Relationship to aggregation unclear
  4. 2010 Medium

    The molecular basis of HTT's trafficking role was mapped by domain-deletion rescue, showing the HAP1- and dynein-interaction domains are each required for HTT-dependent Golgi reformation and BDNF vesicle transport.

    Evidence RNAi knockdown with full-length HTT rescue constructs bearing domain deletions; Golgi and BDNF trafficking assays in neurons

    PMID:20515468

    Open questions at the time
    • Direct structural interaction interfaces not resolved
    • How polyQ expansion alters trafficking not tested here
    • Single lab
  5. 2011 Medium

    Whether HTT is developmentally essential was addressed by in vivo knockdown showing region-specific requirements for migration, proliferation, and caspase-9-dependent survival in the developing brain.

    Evidence In utero electroporation knockdown in mouse neocortex and cerebellum with Casp9 epistasis

    PMID:21994396

    Open questions at the time
    • Molecular pathway linking HTT to migration unknown
    • Relevance to adult HD pathology indirect
    • Single lab
  6. 2013 Medium

    How HTT subcellular partitioning is controlled was clarified by identifying the N17 segment as an exportin 1-dependent nuclear export sequence whose disruption shifts HTT to the nucleus and alters aggregation.

    Evidence N17 mutagenesis, leptomycin B treatment, exportin 1 knockdown, and fractionation in HEK293 and primary neurons

    PMID:23319588

    Open questions at the time
    • Physiological signals triggering export not defined
    • Context-dependent aggregation effects (HEK vs neurons) unexplained
    • Single lab
  7. 2015 Medium

    A nuclear chromatin function emerged with the finding that wild-type HTT supports PRC2-mediated H3K27me3 deposition and CAG expansion enhances this activity, genome-wide.

    Evidence ChIP-seq for histone marks across isogenic Htt-null and CAG-mutant mouse ESC/NPC lines

    PMID:25574027

    Open questions at the time
    • Direct HTT–PRC2 physical interaction not biochemically resolved
    • Which target genes drive phenotype unknown
    • Single lab
  8. 2015 Medium

    The contribution of expanded HTT RNA itself was addressed by showing MBNL1 retains expHTT RNA in the nucleus while U2AF65 promotes export, and that non-translated expHTT RNA is intrinsically cytotoxic.

    Evidence MBNL1/U2AF65 overexpression, fractionation, and toxicity assays with non-translatable expHTT RNA fragments

    PMID:26218986

    Open questions at the time
    • Mechanism of RNA toxicity not defined
    • In vivo relevance untested
    • Overexpression-based
  9. 2016 Medium

    Upstream regulation of HTT was probed: the hnRNP–HTT axis was placed in protection against transcriptional-repression-induced necrosis (TRIAD), with HTT acting as an ER-stabilizing factor; separately, TGF-β/SMAD signaling was linked to HTT transcription.

    Evidence Drosophila genetic epistasis with Htt/hnRNP plus RNA-seq; transcriptional profiling of HD cell models with EGF/SMAD analysis

    PMID:27124581 PMID:27988204

    Open questions at the time
    • Direct SMAD–HTT promoter interaction not demonstrated (Low confidence)
    • ER-stabilizing mechanism of HTT undefined
    • Mostly model-organism/expression inference
  10. 2017 High

    The origin of the aggregation-prone fragment was resolved by showing incomplete HTT pre-mRNA splicing generates a polyadenylated exon 1 (HTTexon1) transcript whose levels scale with CAG length and disease severity in human tissue.

    Evidence Quantitative HTTexon1-specific RT-PCR in HD fibroblasts, post-mortem brain, and knock-in mouse models

    PMID:28465506

    Open questions at the time
    • Direct causal role of HTTexon1 in pathology shown later
    • Splicing machinery driving read-through not fully defined
  11. 2017 High

    A protective mechanism against aggregation was established by reconstituting a trimeric Hsc70–Hsp110–DNAJB1 chaperone that fully suppresses and resolubilizes HTT exon 1 fibrils, with DNAJB1 limiting and sufficient.

    Evidence In vitro fibrilization/disaggregation assays, HEK293T overexpression, HD patient neural cells, and C. elegans

    PMID:29212816

    Open questions at the time
    • Binding site on HTT not yet defined here
    • Endogenous regulation of chaperone levels in neurons unclear
  12. 2018 High

    A phosphorylation switch controlling HTT conformation was defined: Ser-13/Ser-16 phosphorylation disrupts the Nt17 amphipathic helix, blocks membrane binding and aggregation, and promotes nuclear targeting.

    Evidence In vitro phosphopeptide aggregation/CD/membrane-binding assays plus cell-based localization

    PMID:30185623

    Open questions at the time
    • Kinases/phosphatases acting in vivo not identified
    • Quantitative occupancy of these sites in patients unknown
  13. 2018 Medium

    Druggable regulators of mHTT level were identified: GPR52 signaling positively maintains striatal mHTT, and HIPK3 suppresses autophagic clearance of mHTT through DAXX in a positive feedback loop.

    Evidence Gpr52 knockout and antagonist studies; genome-scale RNAi screen with HIPK3 knockout, autophagy flux, and DAXX epistasis in HD cells and knock-in mice

    PMID:29130397 PMID:29608652

    Open questions at the time
    • Allele selectivity of GPR52/HIPK3 effects limited
    • Connection of GPR52 to autophagy vs other clearance unclear
    • Single lab each
  14. 2019 High

    The cellular site of pathogenic action was broadened by showing mHTT cell-autonomously disrupts oligodendrocyte progenitors via enhanced PRC2 activity, and that NG2-cell-specific mHTT removal rescues myelin and behavior independent of neurons.

    Evidence Cre-lox conditional mHTT inactivation in NG2+ cells with behavior, myelin staining, RNA-seq, and ChIP-seq

    PMID:31015293

    Open questions at the time
    • Mechanism coupling PRC2 to myelin genes incomplete
    • Relative contribution of glial vs neuronal mHTT in patients unknown
  15. 2019 High

    Allele-selective clearance was made tractable by HTT-LC3 linker compounds that bridge expanded polyQ HTT to autophagosomes, lowering mHTT and rescuing phenotypes across cells, flies, and mice.

    Evidence Small-molecule microarray, Co-IP, autophagic flux, and rescue in Drosophila and mouse HD models

    PMID:31666698

    Open questions at the time
    • Therapeutic window and CNS delivery not established
    • Long-term selectivity for mutant over wild-type HTT untested
  16. 2020 Medium

    HTT's role in mitochondrial quality control was demonstrated: it brings mitophagy complexes into proximity and recruits receptors to damaged mitochondria, a function disrupted by polyQ expansion leading to oxidative stress.

    Evidence Proximity ligation, Co-IP, mitophagic flux, and ROS assays in cellular HD model

    PMID:32093570

    Open questions at the time
    • Identity of the recruited mitophagy receptors not fully specified
    • Direct HTT binding partners in the complex undefined
    • Single lab
  17. 2021 Medium

    Additional level-control nodes were validated: FKBP5 interacts with HTT and its inhibition (SAFit2) lowers mHTT via MTOR-independent macroautophagy, and splice modulators promote a premature-stop pseudoexon to degrade HTT mRNA CNS-wide.

    Evidence Reciprocal Co-IP, siRNA/SAFit2 with LC3-II and flux assays in vivo; splice modulator screening with RT-PCR and mRNA/protein quantification

    PMID:34024231 PMID:34911927

    Open questions at the time
    • FKBP5–HTT direct interaction mode unresolved
    • Allele selectivity of splice modulators limited
    • Single studies
  18. 2022 Medium

    The mechanistic basis of phase behavior was defined by showing PRMT4/PRMT6 bind HTT's N-terminus and methylate it; altering R200/205 methylation drives liquid-to-solid transition and toxicity, while PRMT overexpression is protective.

    Evidence Co-IP, in vitro methylation, mass spectrometry, LLPS assays, and cell toxicity with PRMT overexpression

    PMID:34888656

    Open questions at the time
    • In vivo relevance of arginine methylation untested
    • Crosstalk with phosphorylation/aggregation not integrated
    • Single lab
  19. 2022 High

    The DNAJB1 recognition determinant was pinpointed: a HTT-binding motif in the DNAJB1 hinge (H244) engages the polyQ-adjacent proline-rich domain, and H244A abolishes chaperone suppression of HTT fibrils without affecting other substrates.

    Evidence In vitro disaggregation with purified proteins, site-directed mutagenesis, pull-downs, and HEK293 aggregation assay

    PMID:35948542

    Open questions at the time
    • Structure of the DNAJB1–PRD complex not solved
    • Whether endogenous DNAJB1 levels limit clearance in neurons unclear
  20. 2022 Medium

    Direct visualization confirmed that full-length HTT and HTT1a transcripts co-cluster in nuclear RNA foci, that HTT1a is translated to exon 1 protein, and that exon 1 levels correlate with aggregation, supporting it as the aggregation seed.

    Evidence RNAscope single-molecule imaging and HTRF protein quantification in YAC128 mouse brain and MEFs; plus Drosophila imaging linking HTT to RAB7/LAMP1 retrograde endosomal transport

    PMID:35793238 PMID:36048753

    Open questions at the time
    • Causal role of nuclear RNA clusters in toxicity untested
    • How exon 1 protein nucleates full-length aggregation unresolved
    • Single lab each

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HTT's diverse activities (trafficking scaffold, mitophagy organizer, PRC2 cofactor) are mechanistically unified, and how polyQ expansion coordinately corrupts them, remains unresolved.
  • No integrated structure of full-length HTT with its partners
  • Causal hierarchy among RNA toxicity, exon 1 seeding, and protein dysfunction undefined
  • Tissue selectivity of degeneration unexplained at the molecular level

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-9612973 Autophagy 4 R-HSA-4839726 Chromatin organization 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-1266738 Developmental Biology 1
Partners
DNAJB1FKBP5HAP1MBNL1PRMT4PRMT6RAB7U2AF65
Complex memberships
Hsc70–Hsp110–DNAJB1 trimeric chaperone complex (substrate)PRC2 (functional partner)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The IT15/HTT gene product is a ~350 kDa protein widely expressed in neurons throughout the brain (not enriched in striatum), present in the soluble cytoplasmic compartment, loosely associated with membranes or cytoskeleton, concentrated in nerve terminals, and diminished in nuclei and mitochondria, as determined by immunostaining with antibodies against the N-terminus and an internal epitope. Western blotting, immunohistochemistry, subcellular fractionation with two independent antisera Neuron Medium 7748554
1998 Intranuclear neuronal inclusions containing huntingtin protein (detected by N-terminal huntingtin antibodies and anti-ubiquitin) are present in HD patient brains, and their density correlates with the length of the CAG repeat in IT15, establishing that polyglutamine expansion drives nuclear aggregate formation. Immunohistochemistry of post-mortem HD brain tissue with anti-ubiquitin and N-terminal huntingtin antibodies; 20 HD cases examined Neurobiology of disease Medium 9666478
2000 Mutant huntingtin in STHdh(Q111) striatal knock-in cells causes dominant phenotypes distinct from huntingtin deficiency or excess, including elevated p53, ER stress response, and hypoxia markers, indicating a gain-of-function mechanism separate from normal HTT activity. Full-length huntingtin (both wild-type and mutant) localizes to distinct nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. Comparative analysis of wild-type vs. Hdh(Q111) knock-in striatal cell lines; Western blotting, immunofluorescence, epitope accessibility assays Human molecular genetics Medium 11092756
2000 FGF-2 increases huntingtin (IT15) protein levels in a dose-dependent manner in striatal neuronal cultures, whereas NGF decreases huntingtin expression, demonstrating that neurotrophic factors regulate HTT protein levels in striatal neurons. Western blotting of striatal cell cultures treated with FGF-2, NGF, or BDNF Cell transplantation Low 11144959
2010 Full-length huntingtin rescues Golgi apparatus reformation following reversible microtubule disruption when endogenous HTT is silenced. Deletion of the HAP1-interaction domain or the dynein-interaction domain within full-length HTT abolishes this rescue and impairs BDNF vesicular trafficking in neuronal cells, demonstrating that HTT's role in dynein/dynactin-dependent vesicular trafficking requires these specific interaction domains. RNAi knockdown of endogenous HTT followed by rescue with synthetic full-length HTT constructs (pARIS-htt) containing domain deletions; Golgi reformation assay, BDNF vesicle trafficking assay in neurons Molecular brain Medium 20515468
2011 Knockdown of HTT expression in neuroepithelial cells of the neocortex causes disturbed neuronal migration, reduced proliferation, and increased apoptotic cell death during early neural development. The cell death phenotype in cortex is partially reversed by co-knockdown of Caspase-9, implicating mitochondria-mediated apoptosis. In the cerebellum, HTT knockdown causes cell death but not perturbed migration, demonstrating spatial and temporal requirements for HTT in brain development. In utero electroporation-mediated knockdown in mouse neocortex and cerebellum; phenotypic analysis of migration, proliferation, and cell death; genetic epistasis with Casp9 co-knockdown The Journal of neuroscience Medium 21994396
2013 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 requires exportin 1. In HEK293 cells, NES mutations decrease overall Htt aggregation but increase nuclear inclusions; in primary neurons, NES mutations increase both nuclear accumulation and overall aggregation. Mutational analysis of N17 residues, leptomycin B treatment, exportin 1 knockdown, nuclear/cytoplasmic fractionation, fluorescence microscopy in HEK293 cells and primary neurons The Journal of biological chemistry Medium 23319588
2015 HTT CAG repeat expansion enhances huntingtin's ability to facilitate polycomb repressive complex 2 (PRC2) activity, leading to altered histone H3K27me3 deposition at bivalent loci and prominent changes in histone H3K4me3 at active loci in embryonic stem cells and neuronal progenitor cells. Wild-type HTT is required for proper H3K27me3 deposition at a subset of bivalent loci. Genome-wide ChIP-seq for histone modifications across isogenic panel of mouse ESC and NPC lines with Htt null or different-size Htt CAG mutations Human molecular genetics Medium 25574027
2015 Expanded HTT (expHTT) RNA is retained in the nucleus by the splicing factor MBNL1, which increases nuclear retention and decreases cytosolic expHTT protein expression. The splicing and nuclear export factor U2AF65 has the opposite effect, decreasing expHTT nuclear retention and increasing cytosolic expHTT protein. A fragment of expHTT RNA is cytotoxic in the absence of translation, with cytotoxicity similar to that of an expHTT protein fragment of similar repeat size. Overexpression of MBNL1 and U2AF65, nuclear/cytoplasmic fractionation, cell toxicity assays with non-translatable expHTT RNA fragments Scientific reports Medium 26218986
2017 The pathogenic exon 1 HTT protein is produced by incomplete splicing of the HTT pre-mRNA (failure to splice exon 1 to exon 2), generating a small polyadenylated HTTexon1 mRNA. This aberrant transcript is detectable in fibroblasts from juvenile HD patients and in post-mortem brain samples (sensorimotor cortex, hippocampus, cerebellum) from adult- and juvenile-onset HD individuals, with higher levels in early-onset disease. The level of this read-through product is proportional to CAG repeat length. Quantitative RT-PCR protocols specific for HTTexon1 transcript, applied to human fibroblast lines and post-mortem brain samples; comparison with knock-in mouse models Scientific reports High 28465506
2017 A trimeric chaperone complex comprising Hsc70, Hsp110, and a J-protein (DNAJB1) completely suppresses fibrilization of HttExon1Q48 in vitro and can resolubilize preformed Htt fibrils. The J-protein is the concentration-limiting factor in the complex. Single overexpression of DNAJB1 in HEK293T cells is sufficient to profoundly reduce HttExon1Q97 aggregation. These findings were confirmed in HD patient-derived neural cells and in C. elegans. In vitro fibrilization assay, disaggregation assay, HEK293T overexpression, HD patient-derived neural cells, C. elegans in vivo model The EMBO journal High 29212816
2018 Phosphorylation of HTT exon 1 at Ser-13 and/or Ser-16 inhibits aggregation of mutant Httex1, disrupts the amphipathic α-helix of the N-terminal 17-residue (Nt17) domain, inhibits Nt17 membrane binding, and promotes internalization and nuclear targeting of preformed Httex1 aggregates. A phosphorylation-dependent switch involving cross-talk between phosphorylation at Thr-3 and Ser-13/Ser-16 regulates Httex1 structure. In vitro phosphorylation with synthetic peptides bearing defined phosphorylation sites, aggregation assays, circular dichroism (helix disruption), membrane binding assays, cell-based subcellular localization experiments The Journal of biological chemistry High 30185623
2019 Mutant HTT intrinsically dysregulates oligodendrocyte progenitor cell (NG2+) function, causing early myelination deficits and behavioral abnormalities in HD mice independent of neuronal loss. Selective inactivation of mHTT in NG2+ cells prevents myelin abnormalities and rescues behavioral deficits even when mHTT continues to be expressed in neurons, astrocytes, and microglia. mHTT enhances polycomb repressive complex 2 (PRC2) activity in oligodendroglia, identified by RNA-seq and ChIP-seq analyses. Conditional mHTT inactivation in NG2+ cells (Cre-lox), behavioral testing, myelin staining, RNA-seq, ChIP-seq in HD mouse model Proceedings of the National Academy of Sciences of the United States of America High 31015293
2019 Small molecules (HTT-LC3 linker compounds) that interact with both LC3 (autophagosome protein) and the expanded polyQ stretch of mutant HTT (but not wild-type HTT) target mHTT to autophagosomes, reducing mHTT levels in an allele-selective manner and rescuing disease-relevant phenotypes in cells and in fly and mouse models of HD. Small-molecule microarray screening, co-immunoprecipitation, autophagic flux assays, cell-based mHTT quantification, Drosophila and mouse model rescue experiments Nature High 31666698
2020 HTT promotes the physical proximity of protein complexes during the initiation of mitophagy and recruits mitophagy receptors to promote interaction between damaged mitochondria and the nascent autophagosome. Mutant HTT (with expanded polyQ) disrupts formation of these protein complexes, leading to accumulation of damaged mitochondria and increased oxidative stress. Proximity ligation assay, co-immunoprecipitation, mitophagic flux assays, ROS measurements in cellular HD model Autophagy Medium 32093570
2021 FKBP5 interacts and co-localizes with HTT in the striatum and cortex of HD mice. Reducing FKBP5 levels (siRNA or pharmacological inhibition with SAFit2) lowers mHTT levels by increasing LC3-II levels and macroautophagic flux (MTOR-independent mechanism). In vivo treatment with SAFit2 reduces HTT levels in HD mouse models. Co-immunoprecipitation, co-localization immunofluorescence, siRNA knockdown, pharmacological inhibition (SAFit2), LC3-II Western blotting, autophagic flux assay, in vivo mouse treatment Autophagy Medium 34024231
2021 Orally bioavailable small molecules lower HTT expression by promoting inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon) in HTT pre-mRNA through selective modulation of pre-mRNA splicing, leading to HTT mRNA degradation and reduction of HTT protein throughout the CNS and periphery. Splice modulator compound screening, RT-PCR for pseudoexon inclusion, HTT mRNA and protein quantification in cells and animal models Nature communications Medium 34911927
2022 HTT interacts with type I protein arginine methyltransferases (PRMTs), particularly PRMT4 (CARM1) and PRMT6, via its N-terminal domain. These enzymes methylate HTT at specific arginine residues. Alterations of methylation sites (R200/205) render HTT less soluble, promote phase transition from liquid-like to solid-like assemblies in vitro, and increase HTT toxicity to neuronal cells. Overexpression of PRMT4 and PRMT6 is beneficial for neuronal survival. Co-immunoprecipitation, in vitro methylation assay, mass spectrometry (data-dependent and targeted quantitative), liquid-liquid phase separation assay, cell toxicity assay, PRMT overexpression Human molecular genetics Medium 34888656
2022 DNAJB1 binds to HTT exon 1 through a specific HTT-binding motif (HBM) in the hinge region between its C-terminal domains I and II, interacting with the polyQ-adjacent proline-rich domain (PRD) of both soluble and aggregated HTT. Mutation of the conserved H244 residue in the HBM completely abrogates suppression and disaggregation of HTT fibrils by the trimeric chaperone complex without affecting binding or remodeling of other substrates. Overexpression of wild-type DNAJB1 but not DNAJB1(H244A) prevents HTTExon1Q97 aggregation in HEK293 cells. In vitro aggregation/disaggregation assay with purified proteins, site-directed mutagenesis, pull-down, HEK293 cell aggregation assay Nature communications High 35948542
2022 Full-length HTT and HTT1a (exon 1 only) transcripts are retained together in large nuclear RNA clusters in YAC128 mouse brain, and the HTT1a transcript is translated to produce exon 1 HTT protein. Levels of exon 1 HTT correlate with HTT aggregation, supporting the hypothesis that exon 1 HTT initiates the aggregation process. RNAscope single-molecule RNA visualization, HTRF protein quantification in YAC128 mouse brain and mouse embryonic fibroblasts Brain Medium 35793238
2022 HTT (huntingtin) co-migrates retrogradely with RAB7 on a signaling LAMP1-containing late endosome during axonal injury in Drosophila neurons, establishing HTT's association with late endosomal retrograde axonal transport in the context of injury signaling. Live imaging and co-migration analysis in Drosophila axons with fluorescently tagged HTT, RAB7, and LAMP1; immunoprecipitation Autophagy Medium 36048753
2016 The hnRNP-HTT axis regulates necrotic cell death induced by transcriptional repression (TRIAD). HTT functions as an ER-stabilizing molecule whose transcription and RNA splicing are impaired by transcriptional repression. hnRNP proteins regulate HTT RNA splicing, and fly genetic experiments (suppressor/expresser of Htt and hnRNP) worsened or ameliorated transcriptional repression-induced necrosis, placing HTT in a pathway downstream of hnRNP in protection against TRIAD. Genetic screen of knockdown fly library, RNA sequencing, fly genetics (genetic epistasis with Htt suppressors/expressers and hnRNP), Drosophila pupa-to-larva survival assay Cell death & disease Medium 27124581
2016 SMAD transcription factors (TGF-β pathway) are dysregulated in HD cell models and regulate HTT gene expression itself, identifying the TGF-β/SMAD pathway as a regulator of HTT transcription. Transcriptional profiling of HD cell models with growth factor stimulation (EGF), SMAD target gene analysis, HTT expression measurement Cellular signalling Low 27988204
2018 Gpr52, an orphan G protein-coupled receptor, regulates mutant HTT protein levels in the striatum. Knockout of Gpr52 reduces mHTT levels and rescues HD-associated behavioral phenotypes in a knock-in HD mouse model. A Gpr52 antagonist (E7) reduces mHTT levels in cellular and mouse models, indicating that Gpr52 signaling positively regulates mHTT levels. Gpr52 knockout in HD knock-in mice, behavioral testing, mHTT protein quantification, pharmacological antagonism in cellular and mouse models Brain Medium 29608652
2018 HIPK3 kinase activity negatively regulates autophagy and positively regulates mHTT levels. Knockdown or knockout of HIPK3 reduces mHTT levels by enhancing autophagy in HD cells and in a knock-in mouse model. Mutant HTT positively regulates HIPK3 mRNA levels, forming a positive feedback loop that contributes to autophagy inhibition and mHTT accumulation. HIPK3's effect on mHTT requires its known substrate DAXX. Genome-scale RNAi screen, HIPK3 knockdown/knockout in HD cells and knock-in mice, autophagic flux assay, mHTT protein quantification, epistasis with DAXX Autophagy Medium 29130397

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science (New York, N.Y.) 4900 12869766
2000 Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Human molecular genetics 541 11092756
2007 The true story of the HD-Zip family. Trends in plant science 451 17698401
1995 Widespread expression of Huntington's disease gene (IT15) protein product. Neuron 421 7748554
2019 Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 390 31666698
2008 Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Social cognitive and affective neuroscience 339 19015103
1998 Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiology of disease 338 9666478
1998 Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nature genetics 313 9771716
1993 Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron 288 8240819
2010 CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 287 19548255
1997 Serotonin transporter (5-HTT) gene variants associated with autism? Human molecular genetics 199 9361027
2017 The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington's disease patients. Scientific reports 175 28465506
2019 Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington's disease. Nature medicine 156 31263285
2020 Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease. Autophagy 142 32093570
2018 Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes. Proceedings of the National Academy of Sciences of the United States of America 136 29311338
2012 Contribution of SAM and HD domains to retroviral restriction mediated by human SAMHD1. Virology 129 23158101
2006 Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior. Molecular psychiatry 129 16969368
2019 Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition. Journal for immunotherapy of cancer 127 30777131
2009 Structure and function of homodomain-leucine zipper (HD-Zip) proteins. Plant signaling & behavior 121 19649178
2017 Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex. The EMBO journal 98 29212816
2008 HD-GYP domain proteins regulate biofilm formation and virulence in Pseudomonas aeruginosa. Environmental microbiology 93 19170727
2012 Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. Journal of controlled release : official journal of the Controlled Release Society 91 22921802
2019 Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America 90 31015293
2019 Paneth cell α-defensins HD-5 and HD-6 display differential degradation into active antimicrobial fragments. Proceedings of the National Academy of Sciences of the United States of America 88 30808760
1995 Expression of the Huntington's disease (IT15) protein product in HD patients. Human molecular genetics 88 7581375
2016 Class III HD-ZIPs govern vascular cell fate: an HD view on patterning and differentiation. Journal of experimental botany 85 27794018
2008 Amygdala function and 5-HTT gene variants in adolescent anxiety and major depressive disorder. Biological psychiatry 85 18950748
2021 Small molecule splicing modifiers with systemic HTT-lowering activity. Nature communications 74 34911927
2013 An N-terminal nuclear export signal regulates trafficking and aggregation of Huntingtin (Htt) protein exon 1. The Journal of biological chemistry 73 23319588
2018 N-terminal Huntingtin (Htt) phosphorylation is a molecular switch regulating Htt aggregation, helical conformation, internalization, and nuclear targeting. The Journal of biological chemistry 68 30185623
2009 Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology 67 19776381
2005 Protein conformations, interactions, and H/D exchange. Methods in enzymology 62 16401514
2024 Bin2cell reconstructs cells from high resolution Visium HD data. Bioinformatics (Oxford, England) 61 39250728
2013 High-dose cytarabine (HD araC) in the treatment of leukemias: a review. Current hematologic malignancy reports 61 23666364
2010 The serotonin transporter gene (5-HTT) variant and psychiatric disorders: review of current literature. Neuro endocrinology letters 54 20150867
2021 Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels. Autophagy 53 34024231
2010 pARIS-htt: an optimised expression platform to study huntingtin reveals functional domains required for vesicular trafficking. Molecular brain 49 20515468
2022 An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons. Nature communications 48 36357392
2018 Multiple clinical features of Huntington's disease correlate with mutant HTT gene CAG repeat lengths and neurodegeneration. Journal of neurology 48 29956026
2021 Gamete expression of TALE class HD genes activates the diploid sporophyte program in Marchantia polymorpha. eLife 47 34533136
2018 Multiple Links between HD-Zip Proteins and Hormone Networks. International journal of molecular sciences 47 30558150
2015 Htt CAG repeat expansion confers pleiotropic gains of mutant huntingtin function in chromatin regulation. Human molecular genetics 47 25574027
2011 Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 21994396
2000 HD-Zip proteins of families I and II from rice: interactions and functional properties. Molecular & general genetics : MGG 46 10732669
2019 5-HTT independent effects of fluoxetine on neuroplasticity. Scientific reports 45 31004120
2015 Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Scientific reports 44 26218986
2006 Stressful life events, 5-HTT genotype and risk of depression. The British journal of psychiatry : the journal of mental science 44 16507957
2019 Genome-wide identification and characterization of HD-ZIP genes in potato. Gene 41 30776460
2016 Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer. Cell reports 41 27210750
2019 Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease. Neurobiology of aging 37 31810584
2015 Epidemiology of Huntington disease: first post-HTT gene analysis of prevalence in Italy. Clinical genetics 37 25689972
2018 Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes. Brain : a journal of neurology 34 29608652
2024 A gradient of the HD-Zip regulator Woolly regulates multicellular trichome morphogenesis in tomato. The Plant cell 33 38470570
2024 HD-Zip proteins modify floral structures for self-pollination in tomato. Science (New York, N.Y.) 33 38574141
2020 The HD-ZIP II Transcription Factors Regulate Plant Architecture through the Auxin Pathway. International journal of molecular sciences 33 32375344
2018 Functional analysis of the HD-Zip transcription factor genes Oshox12 and Oshox14 in rice. PloS one 33 30028850
2022 Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens. Nature communications 32 35082301
2022 The HD-Zip transcription factor SlHB15A regulates abscission by modulating jasmonoyl-isoleucine biosynthesis. Plant physiology 32 35522030
2022 Alternative processing of human HTT mRNA with implications for Huntington's disease therapeutics. Brain : a journal of neurology 32 35793238
2022 Nrf2 Pathway in Huntington's Disease (HD): What Is Its Role? International journal of molecular sciences 30 36499596
2011 Association of 5-HTT gene polymorphisms with migraine: a systematic review and meta-analysis. Journal of the neurological sciences 29 21450309
2022 Interaction of huntingtin with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity. Human molecular genetics 28 34888656
2007 The long and the short of it: associations between 5-HTT genotypes and coping with stress. Psychosomatic medicine 28 17766691
2022 Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT. Nature communications 26 35948542
2020 Huntington's Disease-An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components. Cells 25 32580314
2019 Second messengers and divergent HD-GYP phosphodiesterases regulate 3',3'-cGAMP signaling. Molecular microbiology 25 31665539
2011 Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region. The pharmacogenomics journal 25 21647174
2010 Meta-analysis of the heterogeneity in association of DRD4 7-repeat allele and AD/HD: stronger association with AD/HD combined type. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 25 20468072
2019 A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease. American journal of human genetics 24 31708117
2022 Lily HD-Zip I Transcription Factor LlHB16 Promotes Thermotolerance by Activating LlHSFA2 and LlMBF1c. Plant & cell physiology 22 36130232
2022 A novel and accurate full-length HTT mouse model for Huntington's disease. eLife 21 35023827
2017 Role of ESCRT component HD-PTP/PTPN23 in cancer. Biochemical Society transactions 21 28620046
2023 The START domain potentiates HD-ZIPIII transcriptional activity. The Plant cell 20 36861320
2020 miR-146a Overexpression in Oral Squamous Cell Carcinoma Potentiates Cancer Cell Migration and Invasion Possibly via Targeting HTT. Frontiers in oncology 20 33282738
2018 HIPK3 modulates autophagy and HTT protein levels in neuronal and mouse models of Huntington disease. Autophagy 20 29130397
2017 Sirtuins as Modifiers of Huntington's Disease (HD) Pathology. Progress in molecular biology and translational science 20 29413175
2016 Correlation of 5-HTT, BDNF and NPSR1 gene polymorphisms with anxiety and depression in asthmatic patients. International journal of molecular medicine 20 27176146
2013 Serotonergic genes (5-HTT and HTR1A) and separation life events: gene-by-environment interaction for panic disorder. Neuropsychobiology 20 23635830
2020 Amygdala 5-HTT Gene Network Moderates the Effects of Postnatal Adversity on Attention Problems: Anatomo-Functional Correlation and Epigenetic Changes. Frontiers in neuroscience 19 32256307
2018 HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease. Neurobiology of aging 19 30583877
2016 Mitochondrial fragmentation in neuronal degeneration: Toward an understanding of HD striatal susceptibility. Biochemical and biophysical research communications 19 27514446
2000 Neurotrophic factors NGF and FGF-2 alter levels of huntingtin (IT15) in striatal neuronal cell cultures. Cell transplantation 19 11144959
2024 Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype. European journal of human genetics : EJHG 18 38433266
2024 Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington's disease models. Brain : a journal of neurology 18 39155061
2016 SMAD transcription factors are altered in cell models of HD and regulate HTT expression. Cellular signalling 18 27988204
2003 Together at last: bHLH and LIM-HD regulators cooperate to specify motor neurons. Neuron 18 12797950
2024 HD-Zip I protein LlHOX6 antagonizes homeobox protein LlHB16 to attenuate basal thermotolerance in lily. Plant physiology 17 37930281
2017 REVIEW-ARTICLE Intermediate alleles of Huntington's disease HTT gene in different populations worldwide: a systematic review. Genetics and molecular research : GMR 17 28387881
2014 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence. The international journal of neuropsychopharmacology 17 25522398
2007 tailup, a LIM-HD gene, and Iro-C cooperate in Drosophila dorsal mesothorax specification. Development (Cambridge, England) 17 17409113
2019 Extensive Expression Analysis of Htt Transcripts in Brain Regions from the zQ175 HD Mouse Model Using a QuantiGene Multiplex Assay. Scientific reports 16 31695145
2014 Stem cells for cell replacement therapy: a therapeutic strategy for HD? Movement disorders : official journal of the Movement Disorder Society 16 25216372
2022 HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury. Autophagy 15 36048753
2016 The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing. Cell death & disease 15 27124581
2011 Viral-mediated overexpression of mutant huntingtin to model HD in various species. Neurobiology of disease 15 21889981
2011 Experimental models of HD and reflection on therapeutic strategies. International review of neurobiology 15 21907096
2020 HD-[HD-GYP] Phosphodiesterases: Activities and Evolutionary Diversification within the HD-GYP Family. Biochemistry 14 32496757
2023 HD and SCA1: Tales from two 30-year journeys since gene discovery. Neuron 13 37863037
2022 Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies. Movement disorders : official journal of the Movement Disorder Society 13 35852957
2008 Searching for mutation in the JPH3, ATN1 and TBP genes in Polish patients suspected of Huntington's disease and without mutation in the IT15 gene. Neurologia i neurochirurgia polska 13 18651325

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