Affinage

DISC1

Disrupted in schizophrenia 1 protein · UniProt Q9NRI5

Length
854 aa
Mass
93.6 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DISC1 is a multifunctional scaffold protein that organizes signaling complexes across multiple subcellular compartments—centrosome, synapse, mitochondria, endoplasmic reticulum, and nucleus—to coordinate neuronal development, migration, synaptic plasticity, and bioenergetics. At the centrosome, DISC1 maintains the dynein motor complex and scaffolds PDE4 isoforms to regulate local cAMP-PKA signaling, which controls phosphorylation of NDE1/NDEL1/LIS1 and thereby microtubule dynamics, neurite outgrowth, and cortical neuronal migration (PMID:16299498, PMID:17728464, PMID:21677187); at the synapse, it anchors Kalirin-7 to gate Rac1 activation and spine morphology (PMID:20139976), competitively inhibits ErbB4–PSD95 interaction to tune NRG1 signaling in interneurons (PMID:26656849), stabilizes serine racemase to sustain D-serine-dependent NMDA receptor co-agonism (PMID:22801410), and complexes with the dopamine D2 receptor to regulate GSK-3 signaling and receptor internalization (PMID:25433637). Within mitochondria, DISC1 is a constituent of the MICOS complex where it stabilizes Mitofilin and supports cristae organization, oxidative phosphorylation, and ATP production (PMID:20880836, PMID:27466199), and it interacts with TRAK1/Miro1 to promote anterograde axonal mitochondrial transport (PMID:24092329, PMID:36103832). DISC1 also modulates Wnt-GSK3β/β-catenin signaling through interaction with DIXDC1 and direct GSK3β binding to regulate neural progenitor proliferation (PMID:20624590, PMID:22099458), sequesters ATF4 from the nucleus to restrain CRE-mediated transcription (PMID:31444471), and is itself targeted for proteasomal degradation by the FBXW7 E3 ligase via a structurally characterized phosphodegron (PMID:28727686).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2005 High

    Establishing that DISC1 is a centrosomal dynein complex component resolved how it influences microtubule-based transport and neurite outgrowth, with truncated DISC1 acting dominant-negatively by displacing the complex from the centrosome.

    Evidence Co-immunoprecipitation, dominant-negative expression, in vivo RNAi in developing mouse cortex

    PMID:16299498

    Open questions at the time
    • No atomic-resolution structure of the DISC1–dynein interface
    • Mechanism by which truncated DISC1 sequesters wild-type DISC1 not fully defined
  2. 2005 Medium

    Domain mapping showed that the N-terminal head domain mediates mitochondrial and nuclear targeting while C-terminal sequences direct centrosomal association, providing the first framework for how DISC1 partitions among compartments.

    Evidence Truncation constructs expressed in COS-7 cells with subcellular fractionation and immunofluorescence

    PMID:16209927

    Open questions at the time
    • No identification of specific targeting signals or import machinery
    • Overexpression artifacts possible
  3. 2006 High

    Mapping the NDEL1-binding site to DISC1 exon 13 (aa 802–835) and showing its requirement for neurite outgrowth established a specific C-terminal interaction essential for cytoskeletal remodeling.

    Evidence Deletion mapping, Co-IP, PC12 neurite outgrowth assay, variant analysis

    PMID:17035248

    Open questions at the time
    • No structural detail of the DISC1–NDEL1 interface
    • Contribution of other DISC1 domains to NDEL1 function not tested
  4. 2007 High

    Demonstrating that DISC1 directly scaffolds all four PDE4 families and that cAMP-PKA activation selectively releases PDE4D/C but not PDE4B defined DISC1 as a compartment-specific cAMP signaling organizer, with ENU mutations linking PDE4B binding loss to psychiatric-relevant behaviors.

    Evidence Co-IP, peptide array, PDE4 activity assays, ENU mouse behavioral pharmacology

    PMID:17481393 PMID:17728464

    Open questions at the time
    • Structural basis for isoform-selective PDE4 retention not resolved
    • Whether DISC1-PDE4 dynamics differ across subcellular compartments in vivo unknown
  5. 2008 Medium

    Identifying the DISC1–PDE4–NDE1–NDEL1–LIS1–dynein centrosomal super-complex and showing that nuclear DISC1 modulates CRE-mediated transcription via ATF4/N-CoR expanded DISC1 from a single-complex scaffold to a multi-compartment signaling hub.

    Evidence Co-IP and colocalization in neurons (centrosome); Co-IP with ATF4/N-CoR, CRE-reporter, Drosophila sleep model (nucleus)

    PMID:18762802 PMID:18983980

    Open questions at the time
    • Nuclear function replicated only in one lab at this time
    • Stoichiometry and assembly order of the centrosomal super-complex undefined
  6. 2010 High

    Discovery that DISC1 anchors Kalirin-7 to control Rac1 activation at synapses, interacts with Dixdc1 to regulate Wnt-GSK3β signaling in progenitors, localizes within mitochondria to stabilize Mitofilin and support oxidative phosphorylation, and interacts with TNIK at post-synaptic densities expanded its functional repertoire to spine remodeling, progenitor proliferation, and bioenergetics.

    Evidence Co-IP/Rac1 assays/spine morphology (Kal-7); in vivo electroporation/β-catenin reporter (Dixdc1-Wnt); mitochondrial fractionation/NADH/ATP/Ca²⁺ assays (mitofilin); synaptic fractionation (TNIK)

    PMID:20139976 PMID:20624590 PMID:20838393 PMID:20880836

    Open questions at the time
    • Whether DISC1-Kal7 and DISC1-TNIK operate in the same or distinct synaptic signaling paths unclear
    • Mechanistic link between Mitofilin stabilization and cristae morphology not yet shown
  7. 2011 High

    A series of studies established that DISC1 directly binds GSK3β to inhibit its activity in Wnt signaling, scaffolds PDE4 to control PKA-dependent NDE1 T131 phosphorylation affecting neurite outgrowth, and cooperates with FEZ1 for dendritic growth distinct from the NDEL1 migration pathway, revealing branching downstream effector pathways.

    Evidence Co-IP/GSK-3 inhibitor rescue in Disc1-L100P mice; phosphosite mutagenesis/neurite assay (NDE1-T131); retroviral in vivo KD/epistasis (FEZ1); zebrafish Wnt epistasis

    PMID:20687110 PMID:21677187 PMID:21859895 PMID:22099459

    Open questions at the time
    • How DISC1 coordinates GSK3β inhibition with PDE4-cAMP signaling at the same locus unknown
    • Whether FEZ1 and NDEL1 pathways converge downstream not tested
  8. 2011 High

    Common DISC1 polymorphisms (A83V, R264Q, L607F) were shown to be loss-of-function for Wnt signaling across mouse, zebrafish, and human cells, and DISC1 was localized near the Golgi with full-length knockout mice showing elevated LTP threshold, connecting DISC1 to synaptic plasticity regulation.

    Evidence Wnt reporter assays across species, human lymphoblast lines; Disc1 exon 2–3 KO mouse LTP electrophysiology and immunohistochemistry

    PMID:21903668 PMID:22099458

    Open questions at the time
    • Whether LTP threshold change is mediated through Wnt or other DISC1 pathways not determined
    • Golgi-associated function not characterized
  9. 2012 High

    DISC1 was shown to stabilize serine racemase by blocking its ubiquitination, sustaining D-serine levels for NMDA receptor signaling, and separately DISC1-dependent adult hippocampal neurogenesis was found to require GABA/NKCC1 depolarization converging on AKT-mTOR, adding metabolic and neurotransmitter-level mechanisms.

    Evidence Co-IP/ubiquitination assay/D-serine measurement/behavioral rescue (SR); in vivo retroviral KD/pharmacological GABA manipulation/mTOR assays (neurogenesis)

    PMID:22385968 PMID:22801410

    Open questions at the time
    • Whether DISC1-SR and DISC1-AKT-mTOR pathways interact not tested
    • Identity of the E3 ligase targeting SR in the absence of DISC1 unknown
  10. 2013 High

    Identification of DISC1–TRAK1–Miro1 as a complex mediating specifically anterograde axonal mitochondrial transport, with rare variant 37W impairing this transport, revealed a discrete transport-adaptor function for DISC1.

    Evidence Co-IP, live axonal mitochondrial tracking, rare variant functional analysis

    PMID:24092329

    Open questions at the time
    • Whether DISC1 binds kinesin directly or solely via TRAK1 not resolved
    • Contribution of retrograde transport regulation unclear
  11. 2014 High

    DISC1 was found to form a complex with D2 receptors facilitating GSK-3 signaling and suppressing agonist-driven D2R internalization, and separately to regulate APP trafficking and Aβ processing, broadening its signaling scope to dopaminergic and amyloidogenic pathways.

    Evidence Co-IP/D2R internalization/interfering peptide in vivo (D2R); RNAi/surface biotinylation/APP fragment quantification (APP)

    PMID:25224257 PMID:25433637

    Open questions at the time
    • Whether DISC1–D2R and DISC1–GSK3β interactions are the same or distinct complexes unclear
    • In vivo relevance of DISC1-APP interaction not established
  12. 2015 High

    DISC1 disruption in human iPSC-derived neural progenitors elevated Wnt signaling and altered fate markers (rescued by Wnt antagonism), while in interneurons DISC1 was shown to competitively inhibit ErbB4–PSD95 interaction to tune NRG1 signaling and E/I balance, confirming cell-type-specific signaling roles.

    Evidence CRISPR/TALEN isogenic iPSC-derived progenitors/Wnt reporter/pharmacological rescue; cell-type-specific KD/OE, competitive binding, electrophysiology

    PMID:26299970 PMID:26656849

    Open questions at the time
    • Whether DISC1-ErbB4 inhibition operates in all interneuron subtypes unknown
    • Mechanism by which DISC1 loss elevates rather than decreases Wnt signaling not fully reconciled with earlier GSK3β inhibition model
  13. 2016 High

    DISC1 was identified as a MICOS complex constituent whose loss causes cristae disorganization, OXPHOS failure, and mtDNA depletion, establishing it as an integral mitochondrial architectural component beyond a transport adaptor, and separately TLR3-MYD88 was found to negatively regulate DISC1 expression to impair dendrite growth.

    Evidence MICOS Co-IP, electron microscopy, O₂ consumption/ATP assays, rescue with full-length vs. truncated DISC1; TLR3 agonist/MYD88 KO/DISC1 OE rescue in neurons

    PMID:27466199 PMID:27979975

    Open questions at the time
    • How DISC1 is imported into MICOS versus its other mitochondrial roles unclear
    • Whether TLR3-mediated DISC1 downregulation occurs in vivo during neuroinflammation not shown
  14. 2017 High

    Structural determination of FBXW7 bound to a DISC1 phosphodegron defined the proteasomal degradation mechanism for DISC1, and separately a DISC1–HTT–PDE4 ternary complex was identified where polyQ-HTT cross-seeds DISC1 aggregation to aberrantly elevate PDE4 activity.

    Evidence Crystal structure/ubiquitination assay/iPSC rescue (FBXW7); Co-IP/PDE4 activity/R6/2 mouse rescue (HTT)

    PMID:28263187 PMID:28727686

    Open questions at the time
    • Kinase(s) responsible for DISC1 phosphodegron phosphorylation not identified
    • Whether DISC1 aggregation is a general feature of proteinopathies beyond HD not tested
  15. 2019 High

    Crystal structure of the DISC1–ATF4 complex and demonstration that a rare DISC1 frameshift disrupts ATF4 sequestration, causing aberrant nuclear ATF4 transcription rescued by heterozygous ATF4 knockout, established the structural and functional basis for DISC1's nuclear transcriptional regulatory role.

    Evidence Crystal structure, ChIP-seq, RNA-seq, CRISPR ATF4 KO rescue in iPSC-derived neurons

    PMID:31444471

    Open questions at the time
    • Full repertoire of ATF4 target genes dysregulated by DISC1 loss not mapped in vivo
    • Whether DISC1–ATF4 interaction is dynamically regulated by signaling unknown
  16. 2021 High

    A rare DISC1 frameshift mutation was shown to elevate PDE4 levels in patient iPSC-derived neurons, with knock-in mice recapitulating synaptic and behavioral deficits rescued by PDE4 inhibition, validating the DISC1–PDE4–cAMP axis as a therapeutic target.

    Evidence Isogenic iPSC-derived cortical neurons, knock-in mouse, PDE4 activity, pharmacological rescue, behavioral readouts

    PMID:33658519

    Open questions at the time
    • Whether PDE4 inhibition rescues non-cAMP-related DISC1 functions (mitochondrial, Wnt) not tested
    • Long-term efficacy and specificity of PDE4 inhibition unknown
  17. 2022 High

    In vivo demonstration that DISC1 gene delivery rescues anterograde mitochondrial transport, axonal ATP, neuronal survival, and visual responses in ocular hypertension confirmed DISC1's mitochondrial transport adaptor function as a neuroprotective mechanism in disease.

    Evidence Multiphoton live imaging, genetically encoded ATP sensor, AAV-DISC1 delivery in retinal ganglion neurons, longitudinal in vivo imaging, electrophysiology

    PMID:36103832

    Open questions at the time
    • Whether DISC1 gene therapy efficacy extends to CNS neurodegeneration beyond retinal neurons unknown
    • Mechanism coupling restored transport to improved survival not molecularly dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive characterization, an integrated structural model of full-length DISC1 explaining how it simultaneously engages its many partners in a compartment-specific manner, and the signaling logic that allocates DISC1 among centrosome, synapse, mitochondria, ER, and nucleus, remains unresolved.
  • No full-length DISC1 structure exists
  • Regulatory signals governing DISC1 partitioning among compartments unknown
  • How DISC1 stoichiometry is coordinated across its many complexes is not understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 3 GO:0005815 microtubule organizing center 3 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 5 R-HSA-112316 Neuronal System 4 R-HSA-1430728 Metabolism 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 2
Partners
ATF4DIXDC1FBXW7GSK3BKALRNNDEL1PDE4BTRAK1
Complex memberships
DISC1-PDE4 signaling complexMICOS complexTRAK1/Miro1 mitochondrial transport complexdynein motor complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining this complex at the centrosome. Carboxy-terminal-truncated mutant DISC1 functions in a dominant-negative manner by redistributing wild-type DISC1 through self-association and dissociating the DISC1-dynein complex from the centrosome, impairing neurite outgrowth in vitro and cortical development in vivo. Co-immunoprecipitation, dominant-negative expression, in vivo RNAi knockdown in developing mouse cortex, neurite outgrowth assay Nature cell biology High 16299498
2007 DISC1 directly binds PDE4B, and missense mutations Q31L and L100P in mouse Disc1 reduce PDE4B binding. Q31L mutants show reduced PDE4B activity consistent with depression-like behavior, while L100P mutants show schizophrenia-like phenotypes reversed by antipsychotics, placing DISC1 upstream of PDE4B-cAMP signaling. ENU mutagenesis mouse models, binding assays, behavioral pharmacology (forced swim, PPI, latent inhibition), PDE4 activity assays Neuron High 17481393
2007 The full-length 100 kDa DISC1 isoform binds members of all four PDE4 gene families. Elevation of intracellular cAMP activates PKA and selectively releases PDE4D3 and PDE4C2 from DISC1 while PDE4B1 and PDE4A5 remain bound, due to additional PDE4B-specific binding sites on DISC1 identified by peptide array. Co-immunoprecipitation, peptide array interaction mapping, cAMP elevation experiments, isoform-specific binding assays The Journal of neuroscience High 17728464
2006 DISC1 interaction with NDEL1 (NUDEL) is specifically required for neurite outgrowth in differentiating PC12 cells. The NDEL1-binding site on DISC1 was mapped to amino acids 802–835 (exon 13), and genetic variants of DISC1 proximal to this site affect the DISC1-NDEL1 interaction. Co-immunoprecipitation, deletion mapping, PC12 neurite outgrowth assay, analysis of DISC1 genetic variants Human molecular genetics High 17035248
2010 DISC1 anchors Kalirin-7 (Kal-7) at synapses, regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor stimulation, thereby regulating dendritic spine morphology in cortical cultures and rat brain in vivo. Co-immunoprecipitation, in vivo rat brain studies, Rac1 activation assays, DISC1 knockdown with spine morphology readout Nature neuroscience High 20139976
2010 DISC1 interacts with Dixdc1 to regulate neural progenitor proliferation via Wnt-GSK3β/β-catenin signaling, and during neuronal migration, Cdk5-phosphorylated Dixdc1 interacts with the DISC1 binding partner Ndel1, with this phosphorylation-dependent interaction required for proper neuronal migration. Co-immunoprecipitation, in vivo cortical electroporation, epistasis analysis, Cdk5 phosphorylation assays, β-catenin pathway reporter assays Neuron High 20624590
2010 A fraction of DISC1 localizes inside mitochondria and directly interacts with Mitofilin (an inner mitochondrial membrane protein). DISC1 deficiency causes decreased mitochondrial NADH dehydrogenase activity, reduced cellular ATP, perturbed mitochondrial Ca2+ dynamics, and reduced monoamine oxidase-A activity; DISC1 also stabilizes Mitofilin by preventing its ubiquitination. Co-immunoprecipitation, subcellular fractionation, mitochondrial functional assays (NADH dehydrogenase, ATP, Ca2+ dynamics, MAO-A), ubiquitination assay Proceedings of the National Academy of Sciences of the United States of America High 20880836
2010 DISC1 interacts with TNIK (Traf2 and Nck-interacting kinase) at synapses, and this interaction stabilizes key postsynaptic density proteins, regulating synaptic composition and activity. Co-immunoprecipitation, synaptic fractionation, DISC1/TNIK knockdown with PSD protein level readout Molecular psychiatry Medium 20838393
2011 DISC1 and DIXDC1 regulate neural progenitor proliferation by co-modulating Wnt-GSK3β/β-catenin signaling, and DISC1 common polymorphisms (A83V, R264Q, L607F) are loss-of-function in Wnt signaling, failing to activate Wnt signaling and resulting in decreased neural progenitor proliferation in mouse, zebrafish, and human cell systems. Wnt pathway reporter assays, zebrafish rescue experiments, human lymphoblast cell lines, mouse cortical progenitor proliferation assays Neuron High 22099458
2012 DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine. Mutant DISC1 fails to bind SR, facilitating SR ubiquitination and degradation, decreasing D-serine production and thus diminishing NMDA receptor neurotransmission. Co-immunoprecipitation, ubiquitination assay, D-serine measurement, transgenic mouse model with behavioral readouts, pharmacological rescue with D-serine Molecular psychiatry High 22801410
2012 DISC1-dependent regulation of dendritic development of newborn neurons during adult hippocampal neurogenesis requires GABA-induced, NKCC1-dependent depolarization converging on the AKT-mTOR pathway; DISC1 and NKCC1 interact epistatically for schizophrenia risk. In vivo retroviral knockdown, pharmacological manipulation of GABA signaling, mTOR pathway assays, genetic epistasis analysis in human case-control cohorts Cell High 22385968
2011 FEZ1 interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in adult mouse hippocampus via a pathway complementary to but distinct from the DISC1-NDEL1 pathway that controls cell positioning and morphogenesis. Co-immunoprecipitation, retroviral-mediated in vivo knockdown in adult hippocampus, epistasis analysis in human cohorts Neuron High 22099459
2013 DISC1 forms a complex with TRAK1 (trafficking kinesin-binding protein) and Miro1 (outer mitochondrial membrane protein) to promote specifically anterograde axonal mitochondrial transport in neurons. A rare DISC1 variant (37W) impairs this anterograde transport. Co-immunoprecipitation, live imaging of axonal mitochondrial transport in neurons, rare variant functional analysis Human molecular genetics High 24092329
2008 Nuclear DISC1 colocalizes with PML bodies and interacts with ATF4/CREB2 and the corepressor N-CoR to modulate CRE-mediated gene transcription; nuclear DISC1 accumulation in Drosophila causes sleep homeostasis disturbance associated with altered CREB signaling. Immunofluorescence colocalization with PML bodies, co-immunoprecipitation with ATF4/N-CoR, CRE-reporter assays, Drosophila transgenic model with sleep phenotype Molecular psychiatry Medium 18762802
2008 DISC1, PDE4B, PDE4D, NDE1, NDEL1, LIS1, and dynein form a complex at the centrosome; NDE1 is phosphorylated by PKA, whose activity is regulated by PDE4 which is in turn scaffolded by DISC1, placing DISC1 as an assembly scaffold modulating cAMP-PKA signaling at the centrosome and synapse. Co-immunoprecipitation, immunofluorescence colocalization in cultured neurons, subcellular fractionation Biochemical and biophysical research communications Medium 18983980
2011 DISC1-PDE4 interaction modulates PKA-dependent phosphorylation of NDE1 at threonine-131; phosphorylation at T131 alters NDE1 interactions with LIS1 and NDEL1 and inhibits neurite outgrowth. T131-phosphorylated NDE1 localizes to postsynaptic density, proximal axons, nucleus, and centrosome. Phosphosite identification, homology modeling, mutational analysis, Co-immunoprecipitation, neurite outgrowth assay, immunofluorescence The Journal of neuroscience High 21677187
2011 DISC1 regulates synaptic vesicle transport along microtubules via FEZ1; DISC1 knockdown or dominant-negative DISC1 disrupts FEZ1-Synaptotagmin-1 (Syt-1) assembly and attenuates vesicle transport in cortical neurons; lithium restores FEZ1-Syt-1 assembly and normalizes defective transport. Live imaging of vesicle transport in primary neurons, Co-immunoprecipitation, DISC1 knockdown/dominant-negative expression, lithium rescue Neuroscience research Medium 21664390
2014 DISC1 regulates APP trafficking and proteolytic processing: DISC1 knockdown increases APP at the cell surface, decreases APP internalization, increases sAPPα and APP-CTFα, and decreases Aβ42/40; rescue requires DISC1 residues needed for APP interaction. RNAi knockdown, surface biotinylation, APP fragment quantification, rescue with wild-type vs. interaction-deficient mutant DISC1 Molecular psychiatry Medium 25224257
2014 DISC1 forms a protein complex with dopamine D2 receptor (D2R) that facilitates D2R-mediated GSK-3 signaling and inhibits agonist-induced D2R internalization; disrupting this complex with an interfering peptide reverses schizophrenia-relevant behaviors without inducing catalepsy. Co-immunoprecipitation, GSK-3 phosphorylation assays, D2R internalization assay, interfering peptide in vivo administration, postmortem human brain analysis Neuron High 25433637
2015 DISC1 disruption in human iPSC-derived neural progenitor cells increases canonical Wnt signaling, altering expression of fate markers (Foxg1, Tbr2); these changes are rescued by Wnt antagonism during a critical developmental window. TALEN/CRISPR-Cas9 gene editing in hiPSCs, Wnt reporter assays, qPCR for fate markers, pharmacological rescue Cell reports High 26299970
2015 DISC1 in cortical interneurons inhibits NRG1-induced ErbB4 activation by competitively inhibiting ErbB4 binding to PSD95, thereby regulating fast-spiking interneuron-pyramidal neuron excitatory-inhibitory circuit formation. Cell type-specific DISC1 knockdown/overexpression in vitro and in vivo, ErbB4 phosphorylation assay, competitive binding assay, electrophysiology Nature communications High 26656849
2016 DISC1 is a constituent of the mammalian Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex. DISC1 knockdown causes MICOS disassembly, mitochondrial fragmentation, reduced mtDNA content, impaired OXPHOS complexes, and severe bioenergetic deficits; pathogenic truncated DISC1 (Δ597-854) fails to rescue these defects. MICOS complex co-immunoprecipitation, electron microscopy, mtDNA quantification, oxygen consumption and ATP synthesis assays, mitochondrial membrane potential measurement, rescue with full-length vs. truncated DISC1 Human molecular genetics High 27466199
2017 FBXW7 ubiquitinates DISC1 via a phosphodegron motif, mediating proteasomal degradation of DISC1. Crystal structure of FBXW7 bound to the DISC1 phosphodegron was solved; disruption of the FBXW7-DISC1 complex stabilizes DISC1 and counteracts DISC1 deficiency in neural progenitor cells from schizophrenia patient iPSCs. Crystal structure determination, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, iPSC-derived neural progenitor cells Molecular psychiatry High 28727686
2017 HTT (huntingtin) forms a ternary complex with DISC1 and PDE4 to regulate PDE4 activity. In Huntington's disease, polyQ-expanded HTT causes pathological cross-seeding with DISC1, reducing soluble DISC1 and aberrantly increasing PDE4 activity; exogenous DISC1 that binds PDE4 but not mutant HTT normalizes PDE4 activity and ameliorates anhedonia. Co-immunoprecipitation of ternary complex, PDE4 activity assays, postmortem HD brain analysis, R6/2 mouse model, exogenous DISC1 rescue The Journal of clinical investigation High 28263187
2019 DISC1 interacts with ATF4 to sequester it from the nucleus; a rare frameshift DISC1 mutation disrupts this interaction, causing excessive nuclear ATF4 binding to dysregulated gene targets. High-resolution crystal structure of the DISC1-ATF4 complex was solved. Heterozygous ATF4 knockout rescues transcriptional and synaptic deficits in DISC1 mutant neurons. Crystal structure determination, Co-immunoprecipitation, ChIP-seq, RNA-seq, CRISPR ATF4 knockout rescue in iPSC-derived neurons Molecular psychiatry High 31444471
2011 DISC1 N-terminal region (aa 1-220) interacts with GSK-3α and β; the L100P mutation reduces DISC1-GSK3 binding, and pharmacological or genetic inactivation of GSK-3 reverses PPI and latent inhibition deficits as well as hyperactivity in Disc1-L100P mice, placing GSK-3 downstream of DISC1 in schizophrenia-relevant signaling. Co-immunoprecipitation, GSK-3 inhibitor treatment, genetic GSK-3 inactivation, behavioral phenotyping of Disc1-L100P mice Synapse Medium 20687110
2011 DISC1 is localized to the Golgi apparatus vicinity in hippocampal neurons and astrocytes; full-length Disc1 deficiency raises the threshold for LTP induction in the dentate gyrus. Immunohistochemistry with specific antibodies, Disc1 exon 2-3 knockout mouse, LTP electrophysiology Human molecular genetics Medium 21903668
2022 DISC1 acts as a mitochondrial transport adaptor promoting anterograde axonal mitochondrial transport; loss of DISC1 in retinal ganglion neurons under ocular hypertension disrupts anterograde mitochondrial transport and causes ATP decline; Disc1 gene delivery rescues anterograde transport, replenishes axonal ATP, promotes neuronal survival, and restores visual responses. Multiphoton live imaging, genetically encoded ATP sensor, Disc1 gene delivery (AAV), longitudinal in vivo imaging, electrophysiology Cell reports High 36103832
2012 The DISC1-Boymaw (DB7) fusion gene generated by the t(1;11) translocation inhibits intracellular NADH oxidoreductase activity and protein translation; humanized DISC1-Boymaw mice show decreased protein translation in hippocampus, reduced GAD67, NMDAR1, and PSD95 protein levels, and prolonged responses to NMDA receptor antagonist ketamine. In vitro NADH oxidoreductase assay, protein translation assay, gene-targeted humanized mice, Western blot, behavioral pharmacology Human molecular genetics Medium 24908665
2005 The N-terminal head domain of DISC1 is sufficient for mitochondrial and nuclear targeting, while C-terminal sequence facilitates centrosomal association. Loss of C-terminal sequence increases nuclear localization, and DISC1 overexpression produces striking mitochondrial ring-like reorganization, suggesting involvement in mitochondrial fusion/fission. Recombinant DISC1 domain expression in COS-7 cells, subcellular fractionation, immunofluorescence microscopy Molecular and cellular neurosciences Medium 16209927
2015 DISC1 localizes to the outer surface of the endoplasmic reticulum and interacts with EXOC1 (exocyst complex subunit), which affects DISC1 recruitment to IP3R1; DISC1 knockdown elicits exaggerated ER calcium release upon IP3R agonist stimulation, reversed by antipsychotic drugs. Co-immunoprecipitation of DISC1-EXOC1-IP3R1, subcellular fractionation, ER calcium imaging in neurons, DISC1 mutant mouse hippocampal neurons Scientific reports Medium 25732993
2012 The DISC1 promoter contains a positive regulatory region (-300 to -177 bp from TSS) and a repressive region (-982 to -301 bp); FOXP2 transcription factor inhibits DISC1 promoter activity and protein expression, an effect diminished by FOXP2 mutations R553H and R328X associated with verbal dyspraxia. Dual luciferase promoter assays, FOXP2 overexpression, site-directed mutagenesis of FOXP2 binding Human molecular genetics Medium 22434823
2021 A rare DISC1 frameshift patient mutation elevates PDE4 transcript levels in iPSC-derived cortical neurons; knock-in mice harboring the same mutation show elevated PDE4 levels and synaptic/behavioral deficits; PDE4 inhibition or cAMP pathway activation rescues synaptic, social, and cognitive deficits. Isogenic iPSC-derived neurons, knock-in mouse model, PDE4 activity measurement, pharmacological rescue, synaptic and behavioral readouts Nature communications High 33658519
2011 Disc1 in zebrafish binds GSK3β and promotes β-catenin-mediated Wnt signaling by inhibiting GSK3β activity during early brain development; Disc1 loss-of-function also disrupts noncanonical Wnt/planar cell polarity signaling via Daam and Rho, causing convergent extension defects. Zebrafish Disc1 morpholino knockdown and rescue, GSK3β binding assay, β-catenin reporter, dominant-negative GSK3β rescue, convergent extension phenotype analysis FASEB journal Medium 21859895
2016 TLR3 acts through MYD88 to negatively regulate Disc1 expression in neurons; TLR3 activation impairs dendrite outgrowth, and this is rescued by MYD88 deficiency or DISC1 overexpression, placing DISC1 downstream of TLR3-MYD88 innate immune signaling in neuronal morphology regulation. TLR3 agonist treatment of cultured neurons and in vivo, MYD88 knockout, DISC1 overexpression rescue, dendritic arborization quantification EMBO reports Medium 27979975

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nature cell biology 447 16299498
2007 Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 415 17481393
2005 Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America 385 15939883
2010 Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nature neuroscience 352 20139976
2011 Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nature reviews. Neuroscience 350 22095064
2007 Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Molecular psychiatry 271 17848917
2005 Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Archives of general psychiatry 263 16275808
2010 Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biological psychiatry 211 21130225
2012 Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia. Cell 174 22385968
2010 DISC1-binding proteins in neural development, signalling and schizophrenia. Neuropharmacology 155 21195721
2009 DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proceedings of the National Academy of Sciences of the United States of America 153 19805229
2006 A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biological psychiatry 151 16797264
2006 DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Human molecular genetics 146 17035248
2007 Association of DISC1 with autism and Asperger syndrome. Molecular psychiatry 143 17579608
2006 The genetics and biology of DISC1--an emerging role in psychosis and cognition. Biological psychiatry 136 16843095
2007 Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. The Journal of neuroscience : the official journal of the Society for Neuroscience 132 17728464
2012 Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. Molecular psychiatry 127 22801410
2010 Dixdc1 is a critical regulator of DISC1 and embryonic cortical development. Neuron 127 20624590
2010 The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function. Molecular psychiatry 124 20838393
2010 Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders. Molecular psychiatry 122 20048751
2010 Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin. Proceedings of the National Academy of Sciences of the United States of America 122 20880836
2011 Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Human molecular genetics 118 21903668
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2017 The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review. Translational psychiatry 93 28140405
2008 Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly. Molecular psychiatry 93 18762802
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2014 A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects. Neuron 89 25433637
2005 Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Molecular and cellular neurosciences 89 16209927
2013 DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking. Human molecular genetics 85 24092329
2011 Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia. Neuron 85 22099459
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2002 Cloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1). Genomics 77 12504857
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2008 DISC1, PDE4B, and NDE1 at the centrosome and synapse. Biochemical and biophysical research communications 74 18983980
2011 PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 21677187
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2010 Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia. Genes, brain, and behavior 69 20618446
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2011 Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse (New York, N.Y.) 68 20687111
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2011 Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction. The Journal of neuroscience : the official journal of the Society for Neuroscience 66 22072671
2004 DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness. Annals of medicine 65 15478311
2011 Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice. Neuropharmacology 63 21376063
2006 Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder. Biological psychiatry 60 16814263
2016 Utility and validity of DISC1 mouse models in biological psychiatry. Neuroscience 59 26768401
2015 Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. Nature communications 59 26656849
2009 Gene models of schizophrenia: DISC1 mouse models. Progress in brain research 58 20302820
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2006 Genetic association between schizophrenia and the DISC1 gene in the Scottish population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 51 16389590
2004 Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia. Neurotoxicity research 49 15184103
2017 DISC1 in Astrocytes Influences Adult Neurogenesis and Hippocampus-Dependent Behaviors in Mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 47 28631721
2014 DISC1 regulates trafficking and processing of APP and Aβ generation. Molecular psychiatry 47 25224257
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2006 Schizophrenia in translation: disrupted in schizophrenia (DISC1): integrating clinical and basic findings. Schizophrenia bulletin 41 17138582
2011 DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway. Neuroscience research 40 21664390
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2017 Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia. Molecular psychiatry 38 28630456
2011 Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model. Neuropharmacology 38 21315744
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2014 Identification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through high-throughput RNA sequencing. Carcinogenesis 37 25239642
2017 Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease. The Journal of clinical investigation 36 28263187
2011 Disc1 regulates both β-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 21859895
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2013 DISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders. Frontiers in behavioral neuroscience 35 24027503
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2012 Comprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice. BMC research notes 32 22348257
2012 The DISC1 promoter: characterization and regulation by FOXP2. Human molecular genetics 32 22434823
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2007 How has DISC1 enabled drug discovery? Molecular and cellular neurosciences 31 18055216
2006 Disrupted-in-schizophrenia-1 (DISC1): a key susceptibility factor for major mental illnesses. Annals of the New York Academy of Sciences 31 17185511
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2017 FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system. Molecular psychiatry 29 28727686
2017 Gene polymorphisms of DISC1 is associated with schizophrenia: Evidence from a meta-analysis. Progress in neuro-psychopharmacology & biological psychiatry 29 29031911
2014 Inhibition of protein translation by the DISC1-Boymaw fusion gene from a Scottish family with major psychiatric disorders. Human molecular genetics 29 24908665
2011 Regulation of the cytoskeleton by Disrupted-in-schizophrenia 1 (DISC1). Molecular and cellular neurosciences 29 21757008
2007 PC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation. Neuroscience research 29 17418909
2008 Immunohistochemical analysis of Disc1 expression in the developing and adult hippocampus. Gene expression patterns : GEP 28 18620078
2007 Dissecting DISC1 function through protein-protein interactions. Biochemical Society transactions 28 17956330
2011 Evidence for association between Disrupted-in-Schizophrenia 1 (DISC1) gene polymorphisms and autism in Chinese Han population: a family-based association study. Behavioral and brain functions : BBF 27 21569632
2016 Disrupted in schizophrenia 1 (DISC1) inhibits glioblastoma development by regulating mitochondria dynamics. Oncotarget 26 27852062
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2007 Molecular mechanism of schizophrenia with reference to disrupted-in-schizophrenia 1 (DISC1). Neurochemistry international 24 17664024
2016 Missense mutation in DISC1 C-terminal coiled-coil has GSK3β signaling and sex-dependent behavioral effects in mice. Scientific reports 23 26728762
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2018 The TRAX, DISC1, and GSK3 complex in mental disorders and therapeutic interventions. Journal of biomedical science 22 30285728
2018 Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression. Translational psychiatry 22 30410030
2014 DBZ, a CNS-specific DISC1 binding protein, positively regulates oligodendrocyte differentiation. Glia 22 24481677
2009 Role of the PACAP-PAC1-DISC1 and PACAP-PAC1-stathmin1 systems in schizophrenia and bipolar disorder: novel treatment mechanisms? Pharmacogenomics 22 19958095
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2017 Role of DISC1 in Neuronal Trafficking and its Implication in Neuropsychiatric Manifestation and Neurotherapeutics. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 21 28664299
2006 Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia. Dialogues in clinical neuroscience 21 17117617