{"gene":"DISC1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2005,"finding":"DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining this complex at the centrosome. C-terminally truncated mutant DISC1 acts 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 cerebral cortex development in vivo.","method":"Co-immunoprecipitation, dominant-negative overexpression, RNA interference knockdown in PC12 cells and in vivo mouse cortical electroporation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi loss-of-function, in vivo cortical phenotype, multiple orthogonal methods in single rigorous study","pmids":["16299498"],"is_preprint":false},{"year":2006,"finding":"A specific interaction between DISC1 and NDEL1 (mapped to amino acids 802–835 of DISC1, corresponding to exon 13) is required for neurite outgrowth in differentiating PC12 cells. Genetic variants of DISC1 proximal to this binding site alter the DISC1–NDEL1 interaction.","method":"Co-immunoprecipitation, deletion mapping, PC12 cell neurite outgrowth assay, analysis of disease-associated DISC1 variants","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-mapping with deletion constructs, functional neurite outgrowth assay, replicated across labs","pmids":["17035248"],"is_preprint":false},{"year":2007,"finding":"DISC1 missense mutations Q31L and L100P both exhibit reduced binding to PDE4B. Q31L mutants show lower PDE4B activity consistent with reduced PDE4 engagement. The DISC1–PDE4B interaction is thus required for normal cAMP signaling relevant to mood and psychosis-related behaviors.","method":"ENU mutagenesis in mice, co-immunoprecipitation, PDE4 enzymatic activity assay, behavioral pharmacology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical binding assay, enzymatic activity measurement, and behavioral rescue combined in one study","pmids":["17481393"],"is_preprint":false},{"year":2004,"finding":"DISC1 localizes to the centrosome by binding to kendrin/pericentrin-B. The interaction domain was mapped to residues 446–533 of DISC1. Kendrin anchors gamma-tubulin to the centrosome, implicating DISC1 in centrosomal microtubule nucleation.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunocytochemistry colocalization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-IP and colocalization, replicated in later studies, but no direct functional mutagenesis","pmids":["15094396"],"is_preprint":false},{"year":2008,"finding":"DISC1 acts as a scaffold assembling a complex containing NDE1, NDEL1, LIS1, dynein, PDE4B, and PDE4D at the centrosome and synapse. NDE1 is phosphorylated by PKA, whose activity is regulated by PDE4; DISC1 scaffolds both PDE4 and NDE1/NDEL1/LIS1/dynein at the centrosome and synapse.","method":"Co-immunoprecipitation, immunofluorescence in cultured neurons, subcellular fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple Co-IPs and colocalization, single lab, several orthogonal approaches","pmids":["18983980"],"is_preprint":false},{"year":2008,"finding":"DISC1 in the nucleus co-localizes with PML bodies and interacts with ATF4/CREB2 and the co-repressor N-CoR, modulating CRE-mediated gene transcription. Three functional cis-elements regulating nuclear localization of DISC1 were identified. In Drosophila, nuclear DISC1 accumulation disturbs sleep homeostasis linked to CRE-mediated transcription.","method":"Drosophila transgenic model, mammalian cell immunofluorescence, co-immunoprecipitation, luciferase CRE reporter assay, deletion mapping of nuclear localization signals","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila model plus Co-IP and reporter assay, single lab","pmids":["18762802"],"is_preprint":false},{"year":2007,"finding":"DISC1 interacts with Grb2 and forms a ternary complex with Grb2 and kinesin heavy chain KIF5A. DISC1 is required for NT-3-induced axon elongation by recruiting Grb2 to axonal tips, enabling ERK-1/2 phosphorylation at the distal axon. Knockdown of DISC1 or kinesin light chains inhibits Grb2 accumulation at axon tips and NT-3-induced ERK activation.","method":"Co-immunoprecipitation, RNA interference in hippocampal neurons, immunofluorescence, ERK phosphorylation assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined molecular readout, Co-IP, single lab","pmids":["17202467"],"is_preprint":false},{"year":2005,"finding":"The N-terminal head domain of DISC1 is sufficient for mitochondrial and nuclear targeting, while C-terminal sequence facilitates centrosomal association. DISC1 overexpression produces striking mitochondrial ring-like reorganization, indicating a role in mitochondrial fusion and/or fission.","method":"Truncation construct expression in COS-7 cells, immunofluorescence, live-cell imaging of mitochondria","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain truncation mapping with fluorescence microscopy, single lab, two orthogonal approaches","pmids":["16209927"],"is_preprint":false},{"year":2010,"finding":"Dixdc1 interacts with DISC1 to regulate neural progenitor proliferation via Wnt–GSK3β/β-catenin signaling, and regulates neuronal migration through a distinct pathway requiring Cdk5-mediated phosphorylation of Dixdc1, which then facilitates interaction with the DISC1-binding partner Ndel1. DISC1 and Dixdc1 thus integrate Wnt-dependent and -independent signaling during cortical development.","method":"Co-immunoprecipitation, in utero electroporation (mouse cortex), phosphorylation-defective/mimetic Dixdc1 mutants, Wnt reporter assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vivo electroporation, phospho-mutants, reporter assay) in a single rigorous study","pmids":["20624590"],"is_preprint":false},{"year":2011,"finding":"DISC1 binds directly to GSK3α/β via its N-terminal region (aa 1–220). The L100P mutation reduces DISC1–GSK3 interaction, leading to dysregulated GSK3 activity. Pharmacological or genetic inactivation of GSK3 reverses schizophrenia-related behavioral deficits in Disc1-L100P mice.","method":"Co-immunoprecipitation, genetic GSK3 inactivation, pharmacological GSK3 inhibition, prepulse/latent inhibition behavioral assays","journal":"Synapse","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic and pharmacological rescue, single lab","pmids":["20687110"],"is_preprint":false},{"year":2011,"finding":"DISC1 and PDE4 modulate phosphorylation of NDE1 by PKA at a novel substrate site threonine-131 (T131). Phosphorylation at T131 modulates NDE1–LIS1 and NDE1–NDEL1 interactions; mimicking PKA phosphorylation at T131 inhibits neurite outgrowth. Thus DISC1–PDE4 interaction regulates organization of the NDE1/NDEL1/LIS1 complex.","method":"In vitro PKA phosphorylation assay, phospho-specific antibody, homology modeling, Co-immunoprecipitation, neurite outgrowth assay with phospho-mutants","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay plus mutagenesis plus Co-IP plus functional neurite assay, multiple orthogonal methods","pmids":["21677187"],"is_preprint":false},{"year":2011,"finding":"DISC1 regulates synaptic vesicle transport along microtubules via FEZ1. Knockdown or dominant-negative DISC1 disrupts assembly of the kinesin-1 adaptor FEZ1 with the cargo protein Synaptotagmin-1 (Syt-1), attenuating vesicle transport. Lithium restores FEZ1–Syt-1 assembly and normalizes defective transport.","method":"RNAi knockdown, dominant-negative DISC1 expression, live vesicle transport imaging in cortical neurons, co-immunoprecipitation","journal":"Neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus RNAi plus Co-IP, single lab","pmids":["21664390"],"is_preprint":false},{"year":2011,"finding":"DISC1 interacts with FEZ1 to regulate dendritic growth of newborn neurons in the adult hippocampus, functioning in a pathway parallel to and distinct from the DISC1–NDEL1 interaction that regulates cell positioning and morphogenesis.","method":"RNAi in adult mouse hippocampus (retroviral), co-immunoprecipitation, genetic epistasis analysis in schizophrenia cohorts","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo RNAi, Co-IP, genetic epistasis, single lab","pmids":["22099459"],"is_preprint":false},{"year":2011,"finding":"DISC1 regulates neural progenitor proliferation through Wnt–GSK3β/β-catenin signaling. Common DISC1 variants A83V, R264Q, and L607F are loss-of-function for Wnt signaling and reduce neural progenitor proliferation, whereas S704C inhibits neuronal migration. These variants fail to rescue DISC1 knockdown-mediated brain development defects in zebrafish.","method":"Wnt reporter assay, zebrafish knockdown rescue, mouse cortical progenitor proliferation assay, human lymphoblast Wnt signaling, TALEN/CRISPR mutants","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple model systems (mouse, zebrafish, human cells), multiple orthogonal methods, variant-specific functional dissection","pmids":["22099458"],"is_preprint":false},{"year":2012,"finding":"DISC1 regulation of dendritic development of newborn neurons during adult hippocampal neurogenesis requires GABA-induced, NKCC1-dependent depolarization converging on the AKT–mTOR pathway. Genetic epistasis between DISC1 and NKCC1 (SLC12A2) affects schizophrenia risk.","method":"Retroviral RNAi in adult mouse hippocampus, pharmacological NKCC1 inhibition, mTOR pathway inhibitor/activator, genetic epistasis in two human case-control cohorts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo RNAi, pharmacological dissection of pathway, human genetic epistasis replication in two cohorts","pmids":["22385968"],"is_preprint":false},{"year":2012,"finding":"DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine. Mutant DISC1 fails to bind SR, facilitating its ubiquitination and proteasomal degradation, decreasing D-serine production and impairing NMDA receptor signaling.","method":"Co-immunoprecipitation, dominant-negative DISC1 mouse model (astrocyte-selective), ubiquitination assay, D-serine measurement, NMDA antagonist behavioral tests","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, in vivo mouse model, pharmacological rescue with D-serine, multiple orthogonal methods","pmids":["22801410"],"is_preprint":false},{"year":2010,"finding":"DISC1 interacts with TNIK (Traf2 and Nck-interacting kinase) at synapses. The DISC1–TNIK interaction stabilizes key postsynaptic density proteins, regulating synaptic composition and activity.","method":"Co-immunoprecipitation, synaptic fractionation, RNAi knockdown, electrophysiology","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional synaptic readout, single lab","pmids":["20838393"],"is_preprint":false},{"year":2010,"finding":"DISC1 localizes near the base of primary cilia and is required for primary cilia formation/maintenance. RNAi-mediated knockdown of DISC1 markedly reduces the number of cells bearing primary cilia in NIH3T3 cells and striatal neurons. Specific dopamine receptor subtypes (D1, D2, D5 but not D3/D4) are concentrated on the ciliary surface.","method":"GFP-DISC1 localization imaging, RNAi knockdown, immunofluorescence for primary cilia markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNAi loss-of-function plus localization imaging, single lab","pmids":["20531939"],"is_preprint":false},{"year":2013,"finding":"DISC1 associates with TRAK1 (trafficking-protein kinesin-binding 1) and Miro1, forming a functional mitochondrial transport complex. In neuronal axons, DISC1 specifically promotes anterograde mitochondrial transport. A rare human DISC1 sequence variant (37W) impairs this anterograde transport function.","method":"Co-immunoprecipitation, live axonal mitochondria transport imaging, variant-specific functional analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus live transport imaging plus human variant functional test, single lab","pmids":["24092329"],"is_preprint":false},{"year":2015,"finding":"DISC1 couples to mitochondrial transport and fusion machinery via interactions with Miro1, Miro2, TRAK1, TRAK2, and mitofusins. Disruption of the DISC1–Miro–TRAK complex inhibits mitochondrial transport in neurons. DISC1–Boymaw fusion protein localizes to mitochondria, disrupts mitochondrial dynamics, decreases ER–mitochondria contact area (shown by super-resolution microscopy), and impairs neuronal dendritic development.","method":"Co-immunoprecipitation, live-cell mitochondria transport imaging, super-resolution microscopy, dominant-negative expression, dendritic morphology analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs, live imaging, super-resolution microscopy, functional dendritic phenotype, multiple orthogonal methods in one study","pmids":["26553875"],"is_preprint":false},{"year":2014,"finding":"DISC1 forms a protein complex with the dopamine D2 receptor (D2R), facilitating D2R-mediated GSK-3 signaling and inhibiting agonist-induced D2R internalization. D2R–DISC1 complex levels are increased and GSK-3 phospho-inhibition is decreased in schizophrenia postmortem brain and in Disc1-L100P mice. An interfering peptide disrupting this complex reverses schizophrenia-relevant behaviors without inducing catalepsy.","method":"Co-immunoprecipitation, postmortem brain biochemistry, interfering peptide in vivo, behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, human postmortem validation, in vivo peptide rescue, multiple orthogonal approaches","pmids":["25433637"],"is_preprint":false},{"year":2014,"finding":"DISC1 interaction with APP (amyloid precursor protein) regulates APP proteolytic processing: DISC1 knockdown increases APP-CTFα and sAPPα while decreasing Aβ42 and Aβ40 levels. DISC1 knockdown increases APP at the cell surface and decreases its internalization. Rescue with wild-type but not APP-interaction-deficient DISC1 confirms the interaction is required.","method":"RNAi knockdown in cortical neurons, ELISA for Aβ and sAPP fragments, surface biotinylation, rescue with DISC1 interaction-deficient mutant","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi plus biochemical assays plus mutant rescue, single lab","pmids":["25224257"],"is_preprint":false},{"year":2015,"finding":"DISC1 disruption near the translocation site results in decreased DISC1 protein due to nonsense-mediated decay of long splice variants, causing increased canonical Wnt signaling in neural progenitor cells and altered expression of cortical fate markers (Foxg1, Tbr2). WNT antagonism during a critical developmental window rescues these gene expression changes.","method":"TALEN/CRISPR-Cas9 DISC1 targeting in hiPSCs, Wnt reporter assay, RT-qPCR, pharmacological Wnt antagonism rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic human iPSC models, multiple genome editing strategies, pharmacological rescue, multiple orthogonal methods","pmids":["26299970"],"is_preprint":false},{"year":2015,"finding":"DISC1 inhibits NRG1-induced ErbB4 activation and downstream signaling in mature cortical interneurons. This is likely mediated by competitive inhibition of ErbB4 binding to PSD95. Interneuronal DISC1 thus affects the fast-spiking interneuron–pyramidal neuron excitatory–inhibitory circuit.","method":"Cell type-specific viral gene knockdown/overexpression in vitro and in vivo, mutant DISC1 mouse model, ErbB4 phosphorylation assay, co-immunoprecipitation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type specific in vivo manipulation, biochemical signaling readout, single lab","pmids":["26656849"],"is_preprint":false},{"year":2015,"finding":"DISC1 localizes to the outer surface of the endoplasmic reticulum (ER). EXOC1 (a subunit of the exocyst complex) interacts with DISC1 and affects its recruitment to IP3R1. DISC1 knockdown elicits exaggerated ER calcium responses upon IP3R agonist stimulation, an effect reversed by antipsychotic drugs.","method":"Subcellular fractionation, co-immunoprecipitation, calcium imaging, RNAi knockdown, DISC1-deficient mutant mouse neurons","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, calcium imaging, KO mouse validation, pharmacological rescue, single lab","pmids":["25732993"],"is_preprint":false},{"year":2016,"finding":"DISC1 regulates astrogenesis through direct association with RASSF7, activating the RAS/MEK/ERK signaling pathway. The pERK complex undergoes nuclear translocation and influences expression of astrogenesis-related genes. DISC1 knockdown represses astrogenesis; overexpression enhances it.","method":"Co-immunoprecipitation, in utero electroporation (knockdown and overexpression), in vitro astrogenesis assay, phospho-ERK nuclear translocation analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo and in vitro functional assays, single lab","pmids":["27287808"],"is_preprint":false},{"year":2016,"finding":"TLR3 signaling acts through MYD88 to negatively regulate Disc1 expression in neurons, impairing dendritic arborization. DISC1 overexpression rescues TLR3-induced dendritic defects, placing DISC1 downstream of TLR3-MYD88 in this innate immune signaling pathway regulating neuronal morphology.","method":"TLR3 agonist treatment of cultured neurons and in vivo mouse brain, MYD88 knockout, DISC1 overexpression rescue, dendritic morphology analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (MYD88 KO), overexpression rescue, in vivo validation, single lab","pmids":["27979975"],"is_preprint":false},{"year":2017,"finding":"The high-resolution crystal structure of the DISC1 C-terminal tail in complex with the binding domain of Ndel1 was solved. Mechanistically, DISC1 regulates Ndel1's kinetochore attachment (but not centrosome localization) during mitosis. Disrupting the DISC1/Ndel1 complex prolongs mitotic length, interferes with cell-cycle progression in human cells, and causes cell-cycle deficits in radial glial cells in embryonic mouse cortex and human forebrain organoids.","method":"X-ray crystallography, DISC1/Ndel1 interface mutagenesis, mitosis imaging, cell-cycle analysis, in utero electroporation, human forebrain organoids including schizophrenia patient iPSC-derived organoids","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus multiple functional model systems (human cells, mouse cortex, human organoids)","pmids":["29103808"],"is_preprint":false},{"year":2017,"finding":"HTT forms a ternary protein complex with DISC1 and PDE4. In Huntington's disease, pathological cross-seeding between mutant HTT aggregates and DISC1 reduces soluble DISC1, dysregulating the DISC1–PDE4 complex and aberrantly increasing PDE4 activity. Expression of a modified DISC1 that binds PDE4 but not mutant HTT normalizes PDE4 activity and ameliorates anhedonia in R6/2 mice.","method":"Co-immunoprecipitation, protein aggregation assays, DISC1/PDE4 activity assay, modified DISC1 rescue in R6/2 mice, behavioral assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, enzymatic activity assay, in vivo rescue with structure-function construct, human HD brain validation","pmids":["28263187"],"is_preprint":false},{"year":2017,"finding":"FBXW7, an F-box protein of the SCF ubiquitin ligase complex, binds a DISC1 phosphodegron motif and mediates DISC1 proteasomal degradation. The structure of FBXW7 bound to the DISC1 phosphodegron was solved, and disruption of the FBXW7–DISC1 complex stabilizes DISC1 protein.","method":"Structural biology (FBXW7–DISC1 complex structure), ubiquitination assay, co-immunoprecipitation, pharmacological proteasome inhibition, iPSC-derived neural progenitors from schizophrenia patients","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of complex plus biochemical ubiquitination assay plus iPSC model validation","pmids":["28727686"],"is_preprint":false},{"year":2018,"finding":"DISC1 regulates lactate production in astrocytes: knockdown or dominant-negative DISC1 decreases expression of glucose transporter 4, glucose uptake, oxidative phosphorylation, glycolysis, and lactate production in vitro and in vivo. Lactate treatment rescues abnormal behaviors in DN-DISC1 astrocyte-selective mice.","method":"RNAi knockdown, dominant-negative DISC1 astrocyte-selective mouse model, glucose uptake assay, metabolic flux analysis, lactate measurement, behavioral rescue","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo astrocyte-selective model, metabolic assays, behavioral rescue, single lab","pmids":["29643356"],"is_preprint":false},{"year":2019,"finding":"DISC1 binds to ATF4 (Activating Transcription Factor 4), and the high-resolution atomic structure of the DISC1–ATF4 complex was solved. A patient DISC1 frameshift mutation disrupts DISC1–ATF4 interaction, causing nuclear ATF4 accumulation and excessive ATF4–DNA binding, leading to transcriptional and synaptic dysregulation. CRISPR-mediated heterozygous ATF4 knockout rescues transcriptional and synaptic deficits in DISC1 mutant neurons.","method":"X-ray crystallography of DISC1–ATF4 complex, Co-IP, nuclear fractionation, ChIP, CRISPR ATF4 knockout rescue, iPSC-derived neurons","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus Co-IP plus CRISPR rescue plus iPSC model, multiple orthogonal methods in single study","pmids":["31444471"],"is_preprint":false},{"year":2020,"finding":"DISC1 regulation of mitochondrial trafficking depends on the GTPase state of Miro1. A psychiatric disease-associated DISC1 mutation impairs Miro1-dependent mitochondrial transport. The first Miro1 GTPase domain determines direction of mitochondrial transport, and DISC1 is involved in this directionality determination. Mutant DISC1 also alters positioning of mitochondria at synapses.","method":"Live mitochondria transport imaging in neurons, Miro1 GTPase domain mutants, mutant DISC1 expression, synaptic mitochondria positioning analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus structure-function mutants, single lab","pmids":["32637409"],"is_preprint":false},{"year":2021,"finding":"A rare patient DISC1 frameshift mutation elevates PDE4 transcript levels in iPSC-derived cortical neurons and causes synaptic deficits. Pharmacological inhibition of PDE4 or activation of the cAMP signaling pathway rescues synaptic deficits. A knock-in mouse with the same mutation exhibits elevated PDE4 levels, synaptic abnormalities, and behavioral deficits, all rescued by PDE4 inhibition.","method":"Isogenic iPSC-derived neurons, kinome/transcriptome analysis, PDE4 inhibitor treatment, knock-in mouse model, synaptic electrophysiology, behavioral assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic human iPSC and humanized knock-in mouse, pharmacological rescue, multiple orthogonal methods across two model systems","pmids":["33658519"],"is_preprint":false},{"year":2022,"finding":"DISC1 (Disc1) acts as a mitochondrial transport adaptor promoting anterograde axonal transport. Ocular hypertension causes loss of Disc1 in retinal neurons and disrupts anterograde mitochondrial transport, leading to axonal energy deficit. Disc1 gene delivery rescues anterograde transport, restores axonal ATP production (measured with genetically encoded sensor), promotes neuronal survival, and restores visual responses.","method":"Multiphoton live imaging of mitochondrial transport, Disc1 gene delivery (AAV), genetically encoded ATP sensor, longitudinal in vivo imaging, calcium dynamics, visual electrophysiology","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gene delivery rescue, live transport imaging, ATP biosensor, multiple functional readouts in single rigorous study","pmids":["36103832"],"is_preprint":false},{"year":2008,"finding":"The C-terminus of DISC1 is required for interaction with kendrin and for centrosomal targeting. Overexpression of the DISC1-binding region of kendrin or a DISC1 deletion mutant lacking the kendrin-binding region impairs microtubule organization.","method":"Directed yeast two-hybrid, deletion mutagenesis, co-immunoprecipitation, immunocytochemistry, microtubule organization assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain mapping plus functional microtubule readout, replicated across labs","pmids":["18955030"],"is_preprint":false},{"year":2012,"finding":"The DISC1 promoter region was characterized: a region -300 to -177 bp relative to the TSS contributes positively to DISC1 promoter activity, while -982 to -301 bp confers repression. FOXP2 inhibits DISC1 promoter activity and protein expression; two FOXP2 point mutations associated with verbal dyspraxia diminish this inhibitory effect.","method":"Dual luciferase promoter assay, deletion constructs, FOXP2 overexpression and disease mutant analysis, Western blot for DISC1 protein","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assays plus protein-level validation, single lab","pmids":["22434823"],"is_preprint":false},{"year":2014,"finding":"DISC1 negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 overexpression decreases expression of myelin markers CNPase and MBP and reduces mature oligodendrocyte number; DISC1 knockdown increases both. A truncated DISC1 acting as dominant-negative similarly increases oligodendrocyte differentiation.","method":"Overexpression and RNAi knockdown in primary oligodendrocyte precursor cells, immunocytochemistry for myelin markers, morphological analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional loss- and gain-of-function with defined molecular and cellular readouts, single lab","pmids":["24516667"],"is_preprint":false},{"year":2014,"finding":"Inhibition of intracellular NADH oxidoreductase activity and protein translation by the DISC1-Boymaw (DB7) fusion gene. In humanized DISC1-Boymaw knock-in mice, protein translation activity is decreased in hippocampus and cultured neurons; Gad67, Nmdar1, and Psd95 protein expression are reduced.","method":"Humanized knock-in mice (gene targeting), protein translation assay, NADH oxidoreductase assay, Western blot for synaptic proteins","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model plus in vitro biochemical assays, single lab","pmids":["24908665"],"is_preprint":false},{"year":2009,"finding":"Disc1 is expressed in zebrafish cranial neural crest (CNC) cells and is required for their migration away from the neural rod. Loss of Disc1 perpetuates expression of transcription factors foxd3 and sox10, impairing CNC cell migration and differentiation. Disc1 functions in transcriptional repression of foxd3 and sox10 to mediate CNC cell development.","method":"Morpholino knockdown in zebrafish, time-lapse imaging of CNC cells, in situ hybridization for foxd3/sox10","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with live imaging and molecular readouts, zebrafish model","pmids":["19570850"],"is_preprint":false},{"year":2018,"finding":"Two convergent DISC1 mutations (mimicking Scottish translocation consequences and an American pedigree frameshift) both reduce DISC1 protein levels via nonsense-mediated decay. Both mutations decrease expression of UNC5D (a netrin signaling receptor), and UNC5D knockdown phenocopies DISC1-mutant neurite outgrowth deficit. UNC5D overexpression rescues the neurite phenotype, implicating dysregulated netrin signaling downstream of DISC1.","method":"iPSC-derived NGN2 neurons (isogenic), RNA-seq, UNC5D knockdown and rescue, longitudinal neurite outgrowth imaging","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic iPSC model, RNA-seq plus functional rescue, single lab","pmids":["30410030"],"is_preprint":false}],"current_model":"DISC1 functions as a multifunctional scaffold protein that organizes complexes involved in cytoskeletal regulation (dynein/NDE1/NDEL1/LIS1 at the centrosome and kinetochore), cAMP signaling (via PDE4B/PDE4D with PKA-mediated phosphorylation of NDE1), mitochondrial anterograde axonal transport (via TRAK1/Miro1/Miro2 kinesin adaptor complexes), synaptic composition (via TNIK, FEZ1, and Synaptotagmin-1/FEZ1 vesicle transport), transcriptional regulation (via nuclear ATF4/CREB2 and N-CoR), Wnt–GSK3β/β-catenin signaling during neural progenitor proliferation, D-serine production in astrocytes (by stabilizing serine racemase against ubiquitin-proteasomal degradation mediated by FBXW7), and ER calcium dynamics (through interaction with EXOC1 and IP3R1), with the C-terminal tail mediating centrosomal localization (via kendrin) and Ndel1 binding, and mutations or truncations causing dominant-negative disruption of these complexes leading to neurodevelopmental and synaptic deficits."},"narrative":{"mechanistic_narrative":"DISC1 is a multifunctional neurodevelopmental scaffold protein that nucleates distinct molecular complexes governing cytoskeletal organization, intracellular signaling, organelle transport, and gene expression in the developing and mature brain [PMID:16299498, PMID:18983980]. At the centrosome it anchors a dynein motor complex and assembles NDE1/NDEL1/LIS1/dynein together with the cAMP phosphodiesterases PDE4B/PDE4D, coupling cytoskeletal organization to PKA-dependent phosphorylation of NDE1 at threonine-131 that tunes NDE1–LIS1/NDEL1 interactions and neurite outgrowth [PMID:18983980, PMID:21677187]; a crystal structure of the DISC1 C-terminal tail bound to Ndel1 established that this interaction controls Ndel1 kinetochore attachment and mitotic progression in radial glia [PMID:29103808]. DISC1 directs neuronal transport machinery, recruiting Grb2/KIF5A for NT-3–driven ERK signaling at axon tips [PMID:17202467], assembling FEZ1–Synaptotagmin-1 kinesin cargo complexes for synaptic vesicle transport [PMID:21664390], and acting as a Miro1/Miro2–TRAK1/TRAK2 adaptor that promotes anterograde axonal mitochondrial transport and ER–mitochondria coupling, with mitochondrial directionality gated by the Miro1 GTPase state [PMID:24092329, PMID:26553875, PMID:32637409]. It controls neural progenitor proliferation and cortical fate through Wnt–GSK3β/β-catenin signaling via direct GSK3 and Dixdc1 binding [PMID:20624590, PMID:22099458, PMID:26299970], and in the nucleus binds ATF4/CREB2 and N-CoR to modulate CRE-dependent transcription, an interaction defined at atomic resolution [PMID:18762802, PMID:31444471]. DISC1 additionally stabilizes serine racemase against ubiquitin-proteasomal degradation to sustain astrocytic D-serine production and NMDA receptor signaling [PMID:22801410], regulates synaptic composition via TNIK [PMID:20838393], and modulates dopamine D2 receptor signaling and trafficking [PMID:25433637]. DISC1 levels are themselves regulated by FBXW7-mediated phosphodegron-dependent degradation [PMID:28727686] and transcriptionally by FOXP2 [PMID:22434823]. Disease-associated truncations and missense variants act dominant-negatively or via nonsense-mediated decay to disrupt these complexes, and patient frameshift mutations cause synaptic and transcriptional deficits rescuable by PDE4 inhibition or ATF4 reduction, linking DISC1 dysfunction to neurodevelopmental and psychiatric pathology [PMID:16299498, PMID:31444471, PMID:33658519].","teleology":[{"year":2004,"claim":"Established a physical basis for DISC1 centrosomal localization, addressing how a psychiatric-risk protein engages the cytoskeletal machinery.","evidence":"Yeast two-hybrid, Co-IP and colocalization mapping the kendrin/pericentrin-B interaction to DISC1 residues 446–533","pmids":["15094396"],"confidence":"Medium","gaps":["No direct functional mutagenesis of the interface","Did not establish consequences for microtubule nucleation in neurons"]},{"year":2005,"claim":"Showed DISC1 is a required component of the centrosomal dynein complex, and that truncating mutations act dominant-negatively, providing a mechanistic link between DISC1 disruption and impaired cortical development.","evidence":"Reciprocal Co-IP, dominant-negative overexpression and RNAi in PC12 cells plus in vivo mouse cortical electroporation","pmids":["16299498"],"confidence":"High","gaps":["Did not resolve the structural basis of dynein anchoring","Self-association domain not atomically mapped"]},{"year":2005,"claim":"Defined the domain architecture of DISC1 targeting, separating mitochondrial/nuclear from centrosomal localization signals.","evidence":"Truncation construct expression and live-cell imaging in COS-7 cells","pmids":["16209927"],"confidence":"Medium","gaps":["Mitochondrial 'ring' reorganization not mechanistically linked to fusion/fission proteins","Overexpression artifact not excluded"]},{"year":2006,"claim":"Mapped a discrete DISC1–NDEL1 interaction domain required for neurite outgrowth, connecting disease-associated variants to a defined molecular contact.","evidence":"Co-IP, deletion mapping to aa 802–835, and PC12 neurite outgrowth assays with disease variants","pmids":["17035248"],"confidence":"High","gaps":["Structural detail of the interface awaited later crystallography","In vivo consequences not yet tested"]},{"year":2007,"claim":"Linked DISC1 to cAMP signaling by showing missense mutations disrupt PDE4B binding and alter enzyme activity, establishing a signaling axis relevant to mood and psychosis.","evidence":"ENU mutant mice (Q31L, L100P), Co-IP, PDE4 activity assay, behavioral pharmacology","pmids":["17481393"],"confidence":"High","gaps":["Did not resolve how DISC1 binding modulates PDE4 catalysis","Downstream PKA substrates not yet identified"]},{"year":2007,"claim":"Identified DISC1 as a kinesin adaptor for growth-factor signaling, showing it recruits Grb2/KIF5A to enable distal-axon ERK activation.","evidence":"Co-IP, RNAi in hippocampal neurons, ERK phosphorylation and immunofluorescence","pmids":["17202467"],"confidence":"Medium","gaps":["Single lab","Direct versus indirect Grb2 binding not fully resolved"]},{"year":2008,"claim":"Consolidated DISC1 as a scaffold integrating cytoskeletal and cAMP machinery by demonstrating co-assembly of NDE1/NDEL1/LIS1/dynein with PDE4 at the centrosome and synapse.","evidence":"Co-IP, immunofluorescence and subcellular fractionation in cultured neurons","pmids":["18983980"],"confidence":"Medium","gaps":["Stoichiometry and assembly order not determined","Single lab"]},{"year":2008,"claim":"Demonstrated a nuclear transcriptional function for DISC1 through ATF4/CREB2 and N-CoR, with mapped nuclear-localization elements and an in vivo behavioral readout.","evidence":"Drosophila transgenics, mammalian Co-IP, CRE luciferase reporter, NLS deletion mapping","pmids":["18762802"],"confidence":"Medium","gaps":["Direct DNA-binding versus co-factor role not separated","Mammalian behavioral relevance not tested here"]},{"year":2008,"claim":"Confirmed the C-terminal kendrin interaction is required for centrosomal targeting and microtubule organization.","evidence":"Directed yeast two-hybrid, deletion mutagenesis, Co-IP and microtubule organization assay","pmids":["18955030"],"confidence":"Medium","gaps":["No structural interface","Effect on gamma-tubulin recruitment inferred indirectly"]},{"year":2009,"claim":"Extended DISC1 function to neural crest by showing it represses foxd3/sox10 to permit cranial neural crest migration, indicating a transcriptional/developmental role beyond the CNS.","evidence":"Morpholino knockdown, time-lapse imaging and in situ hybridization in zebrafish","pmids":["19570850"],"confidence":"Medium","gaps":["Mechanism of transcriptional repression unknown","Morpholino specificity caveats"]},{"year":2010,"claim":"Established a Wnt-dependent and -independent developmental dual function via Dixdc1, linking DISC1 to both progenitor proliferation and neuronal migration.","evidence":"Co-IP, in utero electroporation, Cdk5 phospho-mutant Dixdc1, Wnt reporter","pmids":["20624590"],"confidence":"High","gaps":["Direct GSK3 binding not yet mapped here","Phosphoswitch kinetics undefined"]},{"year":2010,"claim":"Identified TNIK as a synaptic DISC1 partner that stabilizes postsynaptic density proteins, tying DISC1 to synaptic composition and activity.","evidence":"Reciprocal Co-IP, synaptic fractionation, RNAi and electrophysiology","pmids":["20838393"],"confidence":"Medium","gaps":["Single lab","TNIK substrates within the complex not defined"]},{"year":2010,"claim":"Connected DISC1 to ciliogenesis and dopamine receptor compartmentalization, broadening its role to primary cilium biology.","evidence":"GFP-DISC1 localization, RNAi knockdown and cilia marker immunofluorescence in NIH3T3 and striatal neurons","pmids":["20531939"],"confidence":"Medium","gaps":["Mechanism of cilia maintenance unresolved","Functional link to receptor signaling not tested"]},{"year":2011,"claim":"Demonstrated direct DISC1–GSK3 binding and that the L100P mutation dysregulates GSK3, with rescue by GSK3 inhibition establishing a therapeutic node.","evidence":"Co-IP mapping to aa 1–220, genetic and pharmacological GSK3 inactivation, behavioral assays in L100P mice","pmids":["20687110"],"confidence":"Medium","gaps":["Structural interface undefined","Single lab"]},{"year":2011,"claim":"Defined the biochemical mechanism by which the DISC1–PDE4 module controls cytoskeletal assembly: PKA phosphorylation of NDE1 at T131 modulates NDE1–LIS1/NDEL1 binding and neurite outgrowth.","evidence":"In vitro PKA assay, phospho-specific antibody, homology modeling, Co-IP and phospho-mutant neurite assay","pmids":["21677187"],"confidence":"High","gaps":["In vivo relevance of T131 phosphorylation not tested","Other PKA sites not excluded"]},{"year":2011,"claim":"Showed DISC1 drives synaptic vesicle transport by assembling the FEZ1–Syt-1 kinesin cargo complex, with lithium restoring transport.","evidence":"RNAi, dominant-negative DISC1, live vesicle imaging and Co-IP in cortical neurons","pmids":["21664390"],"confidence":"Medium","gaps":["Lithium mechanism of rescue undefined","Single lab"]},{"year":2011,"claim":"Separated parallel DISC1 pathways in adult neurogenesis, distinguishing FEZ1-dependent dendritic growth from NDEL1-dependent cell positioning.","evidence":"Retroviral RNAi in adult hippocampus, Co-IP and genetic epistasis in schizophrenia cohorts","pmids":["22099459"],"confidence":"Medium","gaps":["Molecular branch point not identified","Single lab"]},{"year":2011,"claim":"Dissected variant-specific loss of DISC1 Wnt signaling activity, assigning A83V/R264Q/L607F to proliferation defects and S704C to migration defects across model systems.","evidence":"Wnt reporter, zebrafish rescue, mouse progenitor assays, human lymphoblasts, TALEN/CRISPR mutants","pmids":["22099458"],"confidence":"High","gaps":["Direct molecular consequence of each variant on GSK3 binding not all resolved"]},{"year":2012,"claim":"Placed DISC1-regulated dendritic development of newborn neurons downstream of GABA/NKCC1 depolarization converging on AKT–mTOR, with human genetic epistasis support.","evidence":"Retroviral RNAi, pharmacological NKCC1 and mTOR manipulation, epistasis in two case-control cohorts","pmids":["22385968"],"confidence":"High","gaps":["Direct DISC1–mTOR molecular link not defined","Mechanism of NKCC1 convergence indirect"]},{"year":2012,"claim":"Revealed a neurochemical function: DISC1 stabilizes serine racemase to sustain D-serine and NMDA receptor signaling, with mutant DISC1 promoting SR degradation.","evidence":"Co-IP, astrocyte-selective dominant-negative mouse, ubiquitination assay, D-serine measurement, behavioral rescue","pmids":["22801410"],"confidence":"High","gaps":["E3 ligase for SR not identified here","Interface mapping incomplete"]},{"year":2012,"claim":"Characterized DISC1 transcriptional regulation, identifying FOXP2 as a repressor whose dyspraxia mutations relieve repression.","evidence":"Dual luciferase promoter assays, deletion constructs, FOXP2 mutant analysis, Western blot","pmids":["22434823"],"confidence":"Medium","gaps":["Direct FOXP2 promoter occupancy not shown","Single lab"]},{"year":2013,"claim":"Identified DISC1 as a TRAK1/Miro1 mitochondrial transport adaptor specifically promoting anterograde movement, with a rare variant impairing this function.","evidence":"Co-IP and live axonal mitochondria imaging with variant-specific analysis","pmids":["24092329"],"confidence":"Medium","gaps":["Single lab","Directionality mechanism not yet defined"]},{"year":2014,"claim":"Demonstrated a DISC1–D2R complex controlling D2R-mediated GSK3 signaling and internalization, with disease relevance shown in postmortem brain and rescue by an interfering peptide.","evidence":"Reciprocal Co-IP, postmortem biochemistry, in vivo interfering peptide, behavioral assays","pmids":["25433637"],"confidence":"High","gaps":["Interface not structurally defined","Cell-type specificity of complex not resolved"]},{"year":2014,"claim":"Connected DISC1 to APP processing and trafficking, showing knockdown shifts APP toward non-amyloidogenic processing and surface retention.","evidence":"RNAi in cortical neurons, Aβ/sAPP ELISA, surface biotinylation, interaction-deficient mutant rescue","pmids":["25224257"],"confidence":"Medium","gaps":["Direct binding interface not mapped","Single lab"]},{"year":2014,"claim":"Defined a DISC1 role in oligodendrocyte differentiation, showing it negatively regulates myelin marker expression.","evidence":"Bidirectional overexpression/RNAi in oligodendrocyte precursors with myelin marker immunocytochemistry","pmids":["24516667"],"confidence":"Medium","gaps":["Molecular pathway unidentified","Single lab"]},{"year":2014,"claim":"Characterized the DISC1-Boymaw fusion as inhibiting NADH oxidoreductase activity and protein translation, reducing synaptic protein levels in knock-in mice.","evidence":"Humanized knock-in mice, translation and NADH oxidoreductase assays, Western blot","pmids":["24908665"],"confidence":"Medium","gaps":["Mechanism linking fusion to translation block unclear","Relevance to non-fusion DISC1 limited"]},{"year":2015,"claim":"Expanded the mitochondrial transport/fusion role by showing DISC1 binds Miro1/Miro2/TRAK1/TRAK2/mitofusins and that the Boymaw fusion disrupts ER–mitochondria contacts and dendritic development.","evidence":"Multiple Co-IPs, live transport imaging, super-resolution microscopy, dominant-negative expression, dendritic analysis","pmids":["26553875"],"confidence":"High","gaps":["Direct versus indirect mitofusin binding not resolved","Quantitative complex stoichiometry undefined"]},{"year":2015,"claim":"Identified an interneuron-specific DISC1 function inhibiting NRG1–ErbB4 signaling, implicating DISC1 in excitatory–inhibitory circuit balance.","evidence":"Cell-type-specific viral manipulation, mutant mouse, ErbB4 phosphorylation assay and Co-IP","pmids":["26656849"],"confidence":"Medium","gaps":["Competitive PSD95 mechanism shown as likely but not proven","Single lab"]},{"year":2015,"claim":"Linked DISC1 to ER calcium dynamics via EXOC1-mediated recruitment to IP3R1, with antipsychotic-reversible calcium dysregulation upon knockdown.","evidence":"Subcellular fractionation, Co-IP, calcium imaging, RNAi and KO mouse neurons","pmids":["25732993"],"confidence":"Medium","gaps":["Direct IP3R1 binding versus EXOC1-bridged recruitment unresolved","Single lab"]},{"year":2016,"claim":"Showed DISC1 promotes astrogenesis via RASSF7-dependent RAS/MEK/ERK activation and pERK nuclear translocation.","evidence":"Co-IP, in utero electroporation, in vitro astrogenesis assay, pERK translocation analysis","pmids":["27287808"],"confidence":"Medium","gaps":["Direct RASSF7 binding interface undefined","Single lab"]},{"year":2016,"claim":"Placed DISC1 downstream of TLR3–MYD88 innate immune signaling regulating dendritic arborization.","evidence":"TLR3 agonist, MYD88 knockout, DISC1 overexpression rescue, dendritic morphology","pmids":["27979975"],"confidence":"Medium","gaps":["Transcriptional mechanism of Disc1 repression undefined","Single lab"]},{"year":2017,"claim":"Provided the first crystal structure of the DISC1 C-terminal tail–Ndel1 complex and showed DISC1 controls Ndel1 kinetochore attachment and mitotic progression in radial glia and human organoids.","evidence":"X-ray crystallography, interface mutagenesis, mitosis/cell-cycle imaging, in utero electroporation, patient iPSC organoids","pmids":["29103808"],"confidence":"High","gaps":["Kinetochore-recruitment partners of the complex not fully defined"]},{"year":2017,"claim":"Connected DISC1 to Huntington's disease, showing mutant HTT cross-seeds DISC1 to deplete soluble DISC1 and aberrantly activate PDE4.","evidence":"Co-IP, aggregation assays, PDE4 activity assay, modified DISC1 rescue in R6/2 mice, HD brain validation","pmids":["28263187"],"confidence":"High","gaps":["Structural basis of cross-seeding undefined","Generality across HD models untested"]},{"year":2017,"claim":"Defined DISC1 protein turnover by identifying the FBXW7 phosphodegron and solving the complex structure, establishing how DISC1 levels are post-translationally controlled.","evidence":"Structural biology of FBXW7–DISC1, ubiquitination assay, Co-IP, proteasome inhibition, patient iPSC NPCs","pmids":["28727686"],"confidence":"High","gaps":["Kinase generating the phosphodegron not identified","Physiological triggers of degradation unknown"]},{"year":2018,"claim":"Showed DISC1 supports astrocyte energy metabolism, with knockdown reducing glucose uptake and lactate production and lactate rescuing behavior.","evidence":"Astrocyte-selective dominant-negative mouse, metabolic flux and lactate assays, behavioral rescue","pmids":["29643356"],"confidence":"Medium","gaps":["Molecular link from DISC1 to GLUT4 expression undefined","Single lab"]},{"year":2018,"claim":"Showed convergent DISC1 mutations reduce protein via NMD and dysregulate UNC5D netrin signaling to impair neurite outgrowth.","evidence":"Isogenic iPSC NGN2 neurons, RNA-seq, UNC5D knockdown/rescue, longitudinal neurite imaging","pmids":["30410030"],"confidence":"Medium","gaps":["Direct transcriptional control of UNC5D by DISC1 not shown","Single lab"]},{"year":2019,"claim":"Solved the DISC1–ATF4 atomic structure and showed a patient frameshift mutation causes nuclear ATF4 accumulation and transcriptional/synaptic deficits rescuable by ATF4 reduction.","evidence":"X-ray crystallography, Co-IP, nuclear fractionation, ChIP, CRISPR ATF4 knockout rescue, iPSC neurons","pmids":["31444471"],"confidence":"High","gaps":["Genome-wide ATF4 target dysregulation incompletely mapped"]},{"year":2020,"claim":"Established that DISC1-dependent mitochondrial transport directionality is gated by the Miro1 GTPase state, with a psychiatric mutation impairing transport and synaptic positioning.","evidence":"Live transport imaging, Miro1 GTPase domain mutants, mutant DISC1 expression","pmids":["32637409"],"confidence":"Medium","gaps":["Molecular sensing of GTPase state by DISC1 undefined","Single lab"]},{"year":2021,"claim":"Demonstrated a patient frameshift mutation elevates PDE4 levels and causes synaptic deficits rescuable by PDE4 inhibition across iPSC neurons and knock-in mice, validating the DISC1–cAMP axis therapeutically.","evidence":"Isogenic iPSC neurons, transcriptome/kinome analysis, PDE4 inhibitor, knock-in mouse, electrophysiology and behavior","pmids":["33658519"],"confidence":"High","gaps":["Mechanism by which mutant DISC1 elevates PDE4 transcript not defined"]},{"year":2022,"claim":"Provided in vivo therapeutic proof-of-concept that DISC1 sustains anterograde mitochondrial transport and axonal ATP, with gene delivery rescuing neurons in ocular hypertension.","evidence":"Multiphoton live transport imaging, AAV Disc1 delivery, genetically encoded ATP sensor, visual electrophysiology","pmids":["36103832"],"confidence":"High","gaps":["Translation to CNS disease contexts untested","Adaptor stoichiometry in vivo undefined"]},{"year":null,"claim":"How DISC1's many spatially distinct complexes are coordinately regulated in a single neuron, and which interactions are direct versus scaffold-bridged, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model of how DISC1 partitions between centrosome, mitochondria, ER, synapse and nucleus","Full-length DISC1 structure and conformational regulation undefined","Relative contribution of each pathway to disease phenotypes not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,6,11,18,19]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,27,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,10,15,20,28]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,31,39]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[15,31]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3,4,35]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,18,19,32]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,31]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[24,19]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[17]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[27]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,13,20,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,8,13,22,39]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11,18,19,34]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,29,38]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,31,36]}],"complexes":["NDE1/NDEL1/LIS1/dynein complex","DISC1–Miro1/Miro2–TRAK1/TRAK2 mitochondrial transport complex","Grb2–KIF5A kinesin complex","SCF(FBXW7) ubiquitin ligase substrate complex"],"partners":["NDEL1","PDE4B","GSK3B","ATF4","FEZ1","MIRO1","TRAK1","FBXW7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRI5","full_name":"Disrupted in schizophrenia 1 protein","aliases":[],"length_aa":854,"mass_kda":93.6,"function":"Involved in the regulation of multiple aspects of embryonic and adult neurogenesis (PubMed:19303846, PubMed:19502360). Required for neural progenitor proliferation in the ventrical/subventrical zone during embryonic brain development and in the adult dentate gyrus of the hippocampus (By similarity). Participates in the Wnt-mediated neural progenitor proliferation as a positive regulator by modulating GSK3B activity and CTNNB1 abundance (PubMed:19303846). Plays a role as a modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including neuron positioning, dendritic development and synapse formation (By similarity). Inhibits the activation of AKT-mTOR signaling upon interaction with CCDC88A (By similarity). Regulates the migration of early-born granule cell precursors toward the dentate gyrus during the hippocampal development (PubMed:19502360). Inhibits ATF4 transcription factor activity in neurons by disrupting ATF4 dimerization and DNA-binding (By similarity). Plays a role, together with PCNT, in the microtubule network formation (PubMed:18955030)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Mitochondrion; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Postsynaptic density","url":"https://www.uniprot.org/uniprotkb/Q9NRI5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DISC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DISC1","total_profiled":1310},"omim":[{"mim_id":"616031","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 141; CCDC141","url":"https://www.omim.org/entry/616031"},{"mim_id":"615634","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 6; CHCHD6","url":"https://www.omim.org/entry/615634"},{"mim_id":"614574","title":"ROGDI ATYPICAL LEUCINE ZIPPER; ROGDI","url":"https://www.omim.org/entry/614574"},{"mim_id":"614453","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 7; LRRC7","url":"https://www.omim.org/entry/614453"},{"mim_id":"610005","title":"TRAF2- AND NCK-INTERACTING KINASE; TNIK","url":"https://www.omim.org/entry/610005"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":20.2}],"url":"https://www.proteinatlas.org/search/DISC1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NRI5","domains":[{"cath_id":"1.10.287,1.10.287","chopping":"551-681","consensus_level":"medium","plddt":94.2564,"start":551,"end":681},{"cath_id":"-","chopping":"783-826","consensus_level":"medium","plddt":88.7559,"start":783,"end":826}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRI5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRI5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRI5-F1-predicted_aligned_error_v6.png","plddt_mean":63.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DISC1","jax_strain_url":"https://www.jax.org/strain/search?query=DISC1"},"sequence":{"accession":"Q9NRI5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRI5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRI5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRI5"}},"corpus_meta":[{"pmid":"16299498","id":"PMC_16299498","title":"A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16299498","citation_count":447,"is_preprint":false},{"pmid":"17481393","id":"PMC_17481393","title":"Behavioral phenotypes of Disc1 missense mutations in mice.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/17481393","citation_count":415,"is_preprint":false},{"pmid":"15939883","id":"PMC_15939883","title":"Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15939883","citation_count":385,"is_preprint":false},{"pmid":"22095064","id":"PMC_22095064","title":"Linking neurodevelopmental and synaptic theories of mental illness through DISC1.","date":"2011","source":"Nature reviews. 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C-terminally truncated mutant DISC1 acts 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 cerebral cortex development in vivo.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, RNA interference knockdown in PC12 cells and in vivo mouse cortical electroporation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi loss-of-function, in vivo cortical phenotype, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16299498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A specific interaction between DISC1 and NDEL1 (mapped to amino acids 802–835 of DISC1, corresponding to exon 13) is required for neurite outgrowth in differentiating PC12 cells. Genetic variants of DISC1 proximal to this binding site alter the DISC1–NDEL1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, PC12 cell neurite outgrowth assay, analysis of disease-associated DISC1 variants\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-mapping with deletion constructs, functional neurite outgrowth assay, replicated across labs\",\n      \"pmids\": [\"17035248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DISC1 missense mutations Q31L and L100P both exhibit reduced binding to PDE4B. Q31L mutants show lower PDE4B activity consistent with reduced PDE4 engagement. The DISC1–PDE4B interaction is thus required for normal cAMP signaling relevant to mood and psychosis-related behaviors.\",\n      \"method\": \"ENU mutagenesis in mice, co-immunoprecipitation, PDE4 enzymatic activity assay, behavioral pharmacology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical binding assay, enzymatic activity measurement, and behavioral rescue combined in one study\",\n      \"pmids\": [\"17481393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DISC1 localizes to the centrosome by binding to kendrin/pericentrin-B. The interaction domain was mapped to residues 446–533 of DISC1. Kendrin anchors gamma-tubulin to the centrosome, implicating DISC1 in centrosomal microtubule nucleation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunocytochemistry colocalization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-IP and colocalization, replicated in later studies, but no direct functional mutagenesis\",\n      \"pmids\": [\"15094396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DISC1 acts as a scaffold assembling a complex containing NDE1, NDEL1, LIS1, dynein, PDE4B, and PDE4D at the centrosome and synapse. NDE1 is phosphorylated by PKA, whose activity is regulated by PDE4; DISC1 scaffolds both PDE4 and NDE1/NDEL1/LIS1/dynein at the centrosome and synapse.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence in cultured neurons, subcellular fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple Co-IPs and colocalization, single lab, several orthogonal approaches\",\n      \"pmids\": [\"18983980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DISC1 in the nucleus co-localizes with PML bodies and interacts with ATF4/CREB2 and the co-repressor N-CoR, modulating CRE-mediated gene transcription. Three functional cis-elements regulating nuclear localization of DISC1 were identified. In Drosophila, nuclear DISC1 accumulation disturbs sleep homeostasis linked to CRE-mediated transcription.\",\n      \"method\": \"Drosophila transgenic model, mammalian cell immunofluorescence, co-immunoprecipitation, luciferase CRE reporter assay, deletion mapping of nuclear localization signals\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila model plus Co-IP and reporter assay, single lab\",\n      \"pmids\": [\"18762802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DISC1 interacts with Grb2 and forms a ternary complex with Grb2 and kinesin heavy chain KIF5A. DISC1 is required for NT-3-induced axon elongation by recruiting Grb2 to axonal tips, enabling ERK-1/2 phosphorylation at the distal axon. Knockdown of DISC1 or kinesin light chains inhibits Grb2 accumulation at axon tips and NT-3-induced ERK activation.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference in hippocampal neurons, immunofluorescence, ERK phosphorylation assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined molecular readout, Co-IP, single lab\",\n      \"pmids\": [\"17202467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The N-terminal head domain of DISC1 is sufficient for mitochondrial and nuclear targeting, while C-terminal sequence facilitates centrosomal association. DISC1 overexpression produces striking mitochondrial ring-like reorganization, indicating a role in mitochondrial fusion and/or fission.\",\n      \"method\": \"Truncation construct expression in COS-7 cells, immunofluorescence, live-cell imaging of mitochondria\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain truncation mapping with fluorescence microscopy, single lab, two orthogonal approaches\",\n      \"pmids\": [\"16209927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dixdc1 interacts with DISC1 to regulate neural progenitor proliferation via Wnt–GSK3β/β-catenin signaling, and regulates neuronal migration through a distinct pathway requiring Cdk5-mediated phosphorylation of Dixdc1, which then facilitates interaction with the DISC1-binding partner Ndel1. DISC1 and Dixdc1 thus integrate Wnt-dependent and -independent signaling during cortical development.\",\n      \"method\": \"Co-immunoprecipitation, in utero electroporation (mouse cortex), phosphorylation-defective/mimetic Dixdc1 mutants, Wnt reporter assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vivo electroporation, phospho-mutants, reporter assay) in a single rigorous study\",\n      \"pmids\": [\"20624590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DISC1 binds directly to GSK3α/β via its N-terminal region (aa 1–220). The L100P mutation reduces DISC1–GSK3 interaction, leading to dysregulated GSK3 activity. Pharmacological or genetic inactivation of GSK3 reverses schizophrenia-related behavioral deficits in Disc1-L100P mice.\",\n      \"method\": \"Co-immunoprecipitation, genetic GSK3 inactivation, pharmacological GSK3 inhibition, prepulse/latent inhibition behavioral assays\",\n      \"journal\": \"Synapse\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic and pharmacological rescue, single lab\",\n      \"pmids\": [\"20687110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DISC1 and PDE4 modulate phosphorylation of NDE1 by PKA at a novel substrate site threonine-131 (T131). Phosphorylation at T131 modulates NDE1–LIS1 and NDE1–NDEL1 interactions; mimicking PKA phosphorylation at T131 inhibits neurite outgrowth. Thus DISC1–PDE4 interaction regulates organization of the NDE1/NDEL1/LIS1 complex.\",\n      \"method\": \"In vitro PKA phosphorylation assay, phospho-specific antibody, homology modeling, Co-immunoprecipitation, neurite outgrowth assay with phospho-mutants\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay plus mutagenesis plus Co-IP plus functional neurite assay, multiple orthogonal methods\",\n      \"pmids\": [\"21677187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DISC1 regulates synaptic vesicle transport along microtubules via FEZ1. Knockdown or dominant-negative DISC1 disrupts assembly of the kinesin-1 adaptor FEZ1 with the cargo protein Synaptotagmin-1 (Syt-1), attenuating vesicle transport. Lithium restores FEZ1–Syt-1 assembly and normalizes defective transport.\",\n      \"method\": \"RNAi knockdown, dominant-negative DISC1 expression, live vesicle transport imaging in cortical neurons, co-immunoprecipitation\",\n      \"journal\": \"Neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus RNAi plus Co-IP, single lab\",\n      \"pmids\": [\"21664390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DISC1 interacts with FEZ1 to regulate dendritic growth of newborn neurons in the adult hippocampus, functioning in a pathway parallel to and distinct from the DISC1–NDEL1 interaction that regulates cell positioning and morphogenesis.\",\n      \"method\": \"RNAi in adult mouse hippocampus (retroviral), co-immunoprecipitation, genetic epistasis analysis in schizophrenia cohorts\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo RNAi, Co-IP, genetic epistasis, single lab\",\n      \"pmids\": [\"22099459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DISC1 regulates neural progenitor proliferation through Wnt–GSK3β/β-catenin signaling. Common DISC1 variants A83V, R264Q, and L607F are loss-of-function for Wnt signaling and reduce neural progenitor proliferation, whereas S704C inhibits neuronal migration. These variants fail to rescue DISC1 knockdown-mediated brain development defects in zebrafish.\",\n      \"method\": \"Wnt reporter assay, zebrafish knockdown rescue, mouse cortical progenitor proliferation assay, human lymphoblast Wnt signaling, TALEN/CRISPR mutants\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple model systems (mouse, zebrafish, human cells), multiple orthogonal methods, variant-specific functional dissection\",\n      \"pmids\": [\"22099458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DISC1 regulation of dendritic development of newborn neurons during adult hippocampal neurogenesis requires GABA-induced, NKCC1-dependent depolarization converging on the AKT–mTOR pathway. Genetic epistasis between DISC1 and NKCC1 (SLC12A2) affects schizophrenia risk.\",\n      \"method\": \"Retroviral RNAi in adult mouse hippocampus, pharmacological NKCC1 inhibition, mTOR pathway inhibitor/activator, genetic epistasis in two human case-control cohorts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo RNAi, pharmacological dissection of pathway, human genetic epistasis replication in two cohorts\",\n      \"pmids\": [\"22385968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine. Mutant DISC1 fails to bind SR, facilitating its ubiquitination and proteasomal degradation, decreasing D-serine production and impairing NMDA receptor signaling.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative DISC1 mouse model (astrocyte-selective), ubiquitination assay, D-serine measurement, NMDA antagonist behavioral tests\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, in vivo mouse model, pharmacological rescue with D-serine, multiple orthogonal methods\",\n      \"pmids\": [\"22801410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DISC1 interacts with TNIK (Traf2 and Nck-interacting kinase) at synapses. The DISC1–TNIK interaction stabilizes key postsynaptic density proteins, regulating synaptic composition and activity.\",\n      \"method\": \"Co-immunoprecipitation, synaptic fractionation, RNAi knockdown, electrophysiology\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional synaptic readout, single lab\",\n      \"pmids\": [\"20838393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DISC1 localizes near the base of primary cilia and is required for primary cilia formation/maintenance. RNAi-mediated knockdown of DISC1 markedly reduces the number of cells bearing primary cilia in NIH3T3 cells and striatal neurons. Specific dopamine receptor subtypes (D1, D2, D5 but not D3/D4) are concentrated on the ciliary surface.\",\n      \"method\": \"GFP-DISC1 localization imaging, RNAi knockdown, immunofluorescence for primary cilia markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNAi loss-of-function plus localization imaging, single lab\",\n      \"pmids\": [\"20531939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DISC1 associates with TRAK1 (trafficking-protein kinesin-binding 1) and Miro1, forming a functional mitochondrial transport complex. In neuronal axons, DISC1 specifically promotes anterograde mitochondrial transport. A rare human DISC1 sequence variant (37W) impairs this anterograde transport function.\",\n      \"method\": \"Co-immunoprecipitation, live axonal mitochondria transport imaging, variant-specific functional analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus live transport imaging plus human variant functional test, single lab\",\n      \"pmids\": [\"24092329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DISC1 couples to mitochondrial transport and fusion machinery via interactions with Miro1, Miro2, TRAK1, TRAK2, and mitofusins. Disruption of the DISC1–Miro–TRAK complex inhibits mitochondrial transport in neurons. DISC1–Boymaw fusion protein localizes to mitochondria, disrupts mitochondrial dynamics, decreases ER–mitochondria contact area (shown by super-resolution microscopy), and impairs neuronal dendritic development.\",\n      \"method\": \"Co-immunoprecipitation, live-cell mitochondria transport imaging, super-resolution microscopy, dominant-negative expression, dendritic morphology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs, live imaging, super-resolution microscopy, functional dendritic phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26553875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DISC1 forms a protein complex with the dopamine D2 receptor (D2R), facilitating D2R-mediated GSK-3 signaling and inhibiting agonist-induced D2R internalization. D2R–DISC1 complex levels are increased and GSK-3 phospho-inhibition is decreased in schizophrenia postmortem brain and in Disc1-L100P mice. An interfering peptide disrupting this complex reverses schizophrenia-relevant behaviors without inducing catalepsy.\",\n      \"method\": \"Co-immunoprecipitation, postmortem brain biochemistry, interfering peptide in vivo, behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, human postmortem validation, in vivo peptide rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"25433637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DISC1 interaction with APP (amyloid precursor protein) regulates APP proteolytic processing: DISC1 knockdown increases APP-CTFα and sAPPα while decreasing Aβ42 and Aβ40 levels. DISC1 knockdown increases APP at the cell surface and decreases its internalization. Rescue with wild-type but not APP-interaction-deficient DISC1 confirms the interaction is required.\",\n      \"method\": \"RNAi knockdown in cortical neurons, ELISA for Aβ and sAPP fragments, surface biotinylation, rescue with DISC1 interaction-deficient mutant\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi plus biochemical assays plus mutant rescue, single lab\",\n      \"pmids\": [\"25224257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DISC1 disruption near the translocation site results in decreased DISC1 protein due to nonsense-mediated decay of long splice variants, causing increased canonical Wnt signaling in neural progenitor cells and altered expression of cortical fate markers (Foxg1, Tbr2). WNT antagonism during a critical developmental window rescues these gene expression changes.\",\n      \"method\": \"TALEN/CRISPR-Cas9 DISC1 targeting in hiPSCs, Wnt reporter assay, RT-qPCR, pharmacological Wnt antagonism rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic human iPSC models, multiple genome editing strategies, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"26299970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DISC1 inhibits NRG1-induced ErbB4 activation and downstream signaling in mature cortical interneurons. This is likely mediated by competitive inhibition of ErbB4 binding to PSD95. Interneuronal DISC1 thus affects the fast-spiking interneuron–pyramidal neuron excitatory–inhibitory circuit.\",\n      \"method\": \"Cell type-specific viral gene knockdown/overexpression in vitro and in vivo, mutant DISC1 mouse model, ErbB4 phosphorylation assay, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific in vivo manipulation, biochemical signaling readout, single lab\",\n      \"pmids\": [\"26656849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DISC1 localizes to the outer surface of the endoplasmic reticulum (ER). EXOC1 (a subunit of the exocyst complex) interacts with DISC1 and affects its recruitment to IP3R1. DISC1 knockdown elicits exaggerated ER calcium responses upon IP3R agonist stimulation, an effect reversed by antipsychotic drugs.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, calcium imaging, RNAi knockdown, DISC1-deficient mutant mouse neurons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, calcium imaging, KO mouse validation, pharmacological rescue, single lab\",\n      \"pmids\": [\"25732993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DISC1 regulates astrogenesis through direct association with RASSF7, activating the RAS/MEK/ERK signaling pathway. The pERK complex undergoes nuclear translocation and influences expression of astrogenesis-related genes. DISC1 knockdown represses astrogenesis; overexpression enhances it.\",\n      \"method\": \"Co-immunoprecipitation, in utero electroporation (knockdown and overexpression), in vitro astrogenesis assay, phospho-ERK nuclear translocation analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo and in vitro functional assays, single lab\",\n      \"pmids\": [\"27287808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TLR3 signaling acts through MYD88 to negatively regulate Disc1 expression in neurons, impairing dendritic arborization. DISC1 overexpression rescues TLR3-induced dendritic defects, placing DISC1 downstream of TLR3-MYD88 in this innate immune signaling pathway regulating neuronal morphology.\",\n      \"method\": \"TLR3 agonist treatment of cultured neurons and in vivo mouse brain, MYD88 knockout, DISC1 overexpression rescue, dendritic morphology analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (MYD88 KO), overexpression rescue, in vivo validation, single lab\",\n      \"pmids\": [\"27979975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The high-resolution crystal structure of the DISC1 C-terminal tail in complex with the binding domain of Ndel1 was solved. Mechanistically, DISC1 regulates Ndel1's kinetochore attachment (but not centrosome localization) during mitosis. Disrupting the DISC1/Ndel1 complex prolongs mitotic length, interferes with cell-cycle progression in human cells, and causes cell-cycle deficits in radial glial cells in embryonic mouse cortex and human forebrain organoids.\",\n      \"method\": \"X-ray crystallography, DISC1/Ndel1 interface mutagenesis, mitosis imaging, cell-cycle analysis, in utero electroporation, human forebrain organoids including schizophrenia patient iPSC-derived organoids\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus multiple functional model systems (human cells, mouse cortex, human organoids)\",\n      \"pmids\": [\"29103808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HTT forms a ternary protein complex with DISC1 and PDE4. In Huntington's disease, pathological cross-seeding between mutant HTT aggregates and DISC1 reduces soluble DISC1, dysregulating the DISC1–PDE4 complex and aberrantly increasing PDE4 activity. Expression of a modified DISC1 that binds PDE4 but not mutant HTT normalizes PDE4 activity and ameliorates anhedonia in R6/2 mice.\",\n      \"method\": \"Co-immunoprecipitation, protein aggregation assays, DISC1/PDE4 activity assay, modified DISC1 rescue in R6/2 mice, behavioral assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, enzymatic activity assay, in vivo rescue with structure-function construct, human HD brain validation\",\n      \"pmids\": [\"28263187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FBXW7, an F-box protein of the SCF ubiquitin ligase complex, binds a DISC1 phosphodegron motif and mediates DISC1 proteasomal degradation. The structure of FBXW7 bound to the DISC1 phosphodegron was solved, and disruption of the FBXW7–DISC1 complex stabilizes DISC1 protein.\",\n      \"method\": \"Structural biology (FBXW7–DISC1 complex structure), ubiquitination assay, co-immunoprecipitation, pharmacological proteasome inhibition, iPSC-derived neural progenitors from schizophrenia patients\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of complex plus biochemical ubiquitination assay plus iPSC model validation\",\n      \"pmids\": [\"28727686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DISC1 regulates lactate production in astrocytes: knockdown or dominant-negative DISC1 decreases expression of glucose transporter 4, glucose uptake, oxidative phosphorylation, glycolysis, and lactate production in vitro and in vivo. Lactate treatment rescues abnormal behaviors in DN-DISC1 astrocyte-selective mice.\",\n      \"method\": \"RNAi knockdown, dominant-negative DISC1 astrocyte-selective mouse model, glucose uptake assay, metabolic flux analysis, lactate measurement, behavioral rescue\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo astrocyte-selective model, metabolic assays, behavioral rescue, single lab\",\n      \"pmids\": [\"29643356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DISC1 binds to ATF4 (Activating Transcription Factor 4), and the high-resolution atomic structure of the DISC1–ATF4 complex was solved. A patient DISC1 frameshift mutation disrupts DISC1–ATF4 interaction, causing nuclear ATF4 accumulation and excessive ATF4–DNA binding, leading to transcriptional and synaptic dysregulation. CRISPR-mediated heterozygous ATF4 knockout rescues transcriptional and synaptic deficits in DISC1 mutant neurons.\",\n      \"method\": \"X-ray crystallography of DISC1–ATF4 complex, Co-IP, nuclear fractionation, ChIP, CRISPR ATF4 knockout rescue, iPSC-derived neurons\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus Co-IP plus CRISPR rescue plus iPSC model, multiple orthogonal methods in single study\",\n      \"pmids\": [\"31444471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DISC1 regulation of mitochondrial trafficking depends on the GTPase state of Miro1. A psychiatric disease-associated DISC1 mutation impairs Miro1-dependent mitochondrial transport. The first Miro1 GTPase domain determines direction of mitochondrial transport, and DISC1 is involved in this directionality determination. Mutant DISC1 also alters positioning of mitochondria at synapses.\",\n      \"method\": \"Live mitochondria transport imaging in neurons, Miro1 GTPase domain mutants, mutant DISC1 expression, synaptic mitochondria positioning analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus structure-function mutants, single lab\",\n      \"pmids\": [\"32637409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A rare patient DISC1 frameshift mutation elevates PDE4 transcript levels in iPSC-derived cortical neurons and causes synaptic deficits. Pharmacological inhibition of PDE4 or activation of the cAMP signaling pathway rescues synaptic deficits. A knock-in mouse with the same mutation exhibits elevated PDE4 levels, synaptic abnormalities, and behavioral deficits, all rescued by PDE4 inhibition.\",\n      \"method\": \"Isogenic iPSC-derived neurons, kinome/transcriptome analysis, PDE4 inhibitor treatment, knock-in mouse model, synaptic electrophysiology, behavioral assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic human iPSC and humanized knock-in mouse, pharmacological rescue, multiple orthogonal methods across two model systems\",\n      \"pmids\": [\"33658519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DISC1 (Disc1) acts as a mitochondrial transport adaptor promoting anterograde axonal transport. Ocular hypertension causes loss of Disc1 in retinal neurons and disrupts anterograde mitochondrial transport, leading to axonal energy deficit. Disc1 gene delivery rescues anterograde transport, restores axonal ATP production (measured with genetically encoded sensor), promotes neuronal survival, and restores visual responses.\",\n      \"method\": \"Multiphoton live imaging of mitochondrial transport, Disc1 gene delivery (AAV), genetically encoded ATP sensor, longitudinal in vivo imaging, calcium dynamics, visual electrophysiology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gene delivery rescue, live transport imaging, ATP biosensor, multiple functional readouts in single rigorous study\",\n      \"pmids\": [\"36103832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The C-terminus of DISC1 is required for interaction with kendrin and for centrosomal targeting. Overexpression of the DISC1-binding region of kendrin or a DISC1 deletion mutant lacking the kendrin-binding region impairs microtubule organization.\",\n      \"method\": \"Directed yeast two-hybrid, deletion mutagenesis, co-immunoprecipitation, immunocytochemistry, microtubule organization assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain mapping plus functional microtubule readout, replicated across labs\",\n      \"pmids\": [\"18955030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The DISC1 promoter region was characterized: a region -300 to -177 bp relative to the TSS contributes positively to DISC1 promoter activity, while -982 to -301 bp confers repression. FOXP2 inhibits DISC1 promoter activity and protein expression; two FOXP2 point mutations associated with verbal dyspraxia diminish this inhibitory effect.\",\n      \"method\": \"Dual luciferase promoter assay, deletion constructs, FOXP2 overexpression and disease mutant analysis, Western blot for DISC1 protein\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assays plus protein-level validation, single lab\",\n      \"pmids\": [\"22434823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DISC1 negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 overexpression decreases expression of myelin markers CNPase and MBP and reduces mature oligodendrocyte number; DISC1 knockdown increases both. A truncated DISC1 acting as dominant-negative similarly increases oligodendrocyte differentiation.\",\n      \"method\": \"Overexpression and RNAi knockdown in primary oligodendrocyte precursor cells, immunocytochemistry for myelin markers, morphological analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional loss- and gain-of-function with defined molecular and cellular readouts, single lab\",\n      \"pmids\": [\"24516667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Inhibition of intracellular NADH oxidoreductase activity and protein translation by the DISC1-Boymaw (DB7) fusion gene. In humanized DISC1-Boymaw knock-in mice, protein translation activity is decreased in hippocampus and cultured neurons; Gad67, Nmdar1, and Psd95 protein expression are reduced.\",\n      \"method\": \"Humanized knock-in mice (gene targeting), protein translation assay, NADH oxidoreductase assay, Western blot for synaptic proteins\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model plus in vitro biochemical assays, single lab\",\n      \"pmids\": [\"24908665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Disc1 is expressed in zebrafish cranial neural crest (CNC) cells and is required for their migration away from the neural rod. Loss of Disc1 perpetuates expression of transcription factors foxd3 and sox10, impairing CNC cell migration and differentiation. Disc1 functions in transcriptional repression of foxd3 and sox10 to mediate CNC cell development.\",\n      \"method\": \"Morpholino knockdown in zebrafish, time-lapse imaging of CNC cells, in situ hybridization for foxd3/sox10\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with live imaging and molecular readouts, zebrafish model\",\n      \"pmids\": [\"19570850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Two convergent DISC1 mutations (mimicking Scottish translocation consequences and an American pedigree frameshift) both reduce DISC1 protein levels via nonsense-mediated decay. Both mutations decrease expression of UNC5D (a netrin signaling receptor), and UNC5D knockdown phenocopies DISC1-mutant neurite outgrowth deficit. UNC5D overexpression rescues the neurite phenotype, implicating dysregulated netrin signaling downstream of DISC1.\",\n      \"method\": \"iPSC-derived NGN2 neurons (isogenic), RNA-seq, UNC5D knockdown and rescue, longitudinal neurite outgrowth imaging\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic iPSC model, RNA-seq plus functional rescue, single lab\",\n      \"pmids\": [\"30410030\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DISC1 functions as a multifunctional scaffold protein that organizes complexes involved in cytoskeletal regulation (dynein/NDE1/NDEL1/LIS1 at the centrosome and kinetochore), cAMP signaling (via PDE4B/PDE4D with PKA-mediated phosphorylation of NDE1), mitochondrial anterograde axonal transport (via TRAK1/Miro1/Miro2 kinesin adaptor complexes), synaptic composition (via TNIK, FEZ1, and Synaptotagmin-1/FEZ1 vesicle transport), transcriptional regulation (via nuclear ATF4/CREB2 and N-CoR), Wnt–GSK3β/β-catenin signaling during neural progenitor proliferation, D-serine production in astrocytes (by stabilizing serine racemase against ubiquitin-proteasomal degradation mediated by FBXW7), and ER calcium dynamics (through interaction with EXOC1 and IP3R1), with the C-terminal tail mediating centrosomal localization (via kendrin) and Ndel1 binding, and mutations or truncations causing dominant-negative disruption of these complexes leading to neurodevelopmental and synaptic deficits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DISC1 is a multifunctional neurodevelopmental scaffold protein that nucleates distinct molecular complexes governing cytoskeletal organization, intracellular signaling, organelle transport, and gene expression in the developing and mature brain [#0, #4]. At the centrosome it anchors a dynein motor complex and assembles NDE1/NDEL1/LIS1/dynein together with the cAMP phosphodiesterases PDE4B/PDE4D, coupling cytoskeletal organization to PKA-dependent phosphorylation of NDE1 at threonine-131 that tunes NDE1\\u2013LIS1/NDEL1 interactions and neurite outgrowth [#4, #10]; a crystal structure of the DISC1 C-terminal tail bound to Ndel1 established that this interaction controls Ndel1 kinetochore attachment and mitotic progression in radial glia [#27]. DISC1 directs neuronal transport machinery, recruiting Grb2/KIF5A for NT-3\\u2013driven ERK signaling at axon tips [#6], assembling FEZ1\\u2013Synaptotagmin-1 kinesin cargo complexes for synaptic vesicle transport [#11], and acting as a Miro1/Miro2\\u2013TRAK1/TRAK2 adaptor that promotes anterograde axonal mitochondrial transport and ER\\u2013mitochondria coupling, with mitochondrial directionality gated by the Miro1 GTPase state [#18, #19, #32]. It controls neural progenitor proliferation and cortical fate through Wnt\\u2013GSK3\\u03b2/\\u03b2-catenin signaling via direct GSK3 and Dixdc1 binding [#8, #13, #22], and in the nucleus binds ATF4/CREB2 and N-CoR to modulate CRE-dependent transcription, an interaction defined at atomic resolution [#5, #31]. DISC1 additionally stabilizes serine racemase against ubiquitin-proteasomal degradation to sustain astrocytic D-serine production and NMDA receptor signaling [#15], regulates synaptic composition via TNIK [#16], and modulates dopamine D2 receptor signaling and trafficking [#20]. DISC1 levels are themselves regulated by FBXW7-mediated phosphodegron-dependent degradation [#29] and transcriptionally by FOXP2 [#36]. Disease-associated truncations and missense variants act dominant-negatively or via nonsense-mediated decay to disrupt these complexes, and patient frameshift mutations cause synaptic and transcriptional deficits rescuable by PDE4 inhibition or ATF4 reduction, linking DISC1 dysfunction to neurodevelopmental and psychiatric pathology [#0, #31, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established a physical basis for DISC1 centrosomal localization, addressing how a psychiatric-risk protein engages the cytoskeletal machinery.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP and colocalization mapping the kendrin/pericentrin-B interaction to DISC1 residues 446\\u2013533\",\n      \"pmids\": [\"15094396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional mutagenesis of the interface\", \"Did not establish consequences for microtubule nucleation in neurons\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed DISC1 is a required component of the centrosomal dynein complex, and that truncating mutations act dominant-negatively, providing a mechanistic link between DISC1 disruption and impaired cortical development.\",\n      \"evidence\": \"Reciprocal Co-IP, dominant-negative overexpression and RNAi in PC12 cells plus in vivo mouse cortical electroporation\",\n      \"pmids\": [\"16299498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of dynein anchoring\", \"Self-association domain not atomically mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the domain architecture of DISC1 targeting, separating mitochondrial/nuclear from centrosomal localization signals.\",\n      \"evidence\": \"Truncation construct expression and live-cell imaging in COS-7 cells\",\n      \"pmids\": [\"16209927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial 'ring' reorganization not mechanistically linked to fusion/fission proteins\", \"Overexpression artifact not excluded\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped a discrete DISC1\\u2013NDEL1 interaction domain required for neurite outgrowth, connecting disease-associated variants to a defined molecular contact.\",\n      \"evidence\": \"Co-IP, deletion mapping to aa 802\\u2013835, and PC12 neurite outgrowth assays with disease variants\",\n      \"pmids\": [\"17035248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the interface awaited later crystallography\", \"In vivo consequences not yet tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked DISC1 to cAMP signaling by showing missense mutations disrupt PDE4B binding and alter enzyme activity, establishing a signaling axis relevant to mood and psychosis.\",\n      \"evidence\": \"ENU mutant mice (Q31L, L100P), Co-IP, PDE4 activity assay, behavioral pharmacology\",\n      \"pmids\": [\"17481393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how DISC1 binding modulates PDE4 catalysis\", \"Downstream PKA substrates not yet identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified DISC1 as a kinesin adaptor for growth-factor signaling, showing it recruits Grb2/KIF5A to enable distal-axon ERK activation.\",\n      \"evidence\": \"Co-IP, RNAi in hippocampal neurons, ERK phosphorylation and immunofluorescence\",\n      \"pmids\": [\"17202467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct versus indirect Grb2 binding not fully resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Consolidated DISC1 as a scaffold integrating cytoskeletal and cAMP machinery by demonstrating co-assembly of NDE1/NDEL1/LIS1/dynein with PDE4 at the centrosome and synapse.\",\n      \"evidence\": \"Co-IP, immunofluorescence and subcellular fractionation in cultured neurons\",\n      \"pmids\": [\"18983980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and assembly order not determined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated a nuclear transcriptional function for DISC1 through ATF4/CREB2 and N-CoR, with mapped nuclear-localization elements and an in vivo behavioral readout.\",\n      \"evidence\": \"Drosophila transgenics, mammalian Co-IP, CRE luciferase reporter, NLS deletion mapping\",\n      \"pmids\": [\"18762802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding versus co-factor role not separated\", \"Mammalian behavioral relevance not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirmed the C-terminal kendrin interaction is required for centrosomal targeting and microtubule organization.\",\n      \"evidence\": \"Directed yeast two-hybrid, deletion mutagenesis, Co-IP and microtubule organization assay\",\n      \"pmids\": [\"18955030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural interface\", \"Effect on gamma-tubulin recruitment inferred indirectly\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended DISC1 function to neural crest by showing it represses foxd3/sox10 to permit cranial neural crest migration, indicating a transcriptional/developmental role beyond the CNS.\",\n      \"evidence\": \"Morpholino knockdown, time-lapse imaging and in situ hybridization in zebrafish\",\n      \"pmids\": [\"19570850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of transcriptional repression unknown\", \"Morpholino specificity caveats\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established a Wnt-dependent and -independent developmental dual function via Dixdc1, linking DISC1 to both progenitor proliferation and neuronal migration.\",\n      \"evidence\": \"Co-IP, in utero electroporation, Cdk5 phospho-mutant Dixdc1, Wnt reporter\",\n      \"pmids\": [\"20624590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GSK3 binding not yet mapped here\", \"Phosphoswitch kinetics undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified TNIK as a synaptic DISC1 partner that stabilizes postsynaptic density proteins, tying DISC1 to synaptic composition and activity.\",\n      \"evidence\": \"Reciprocal Co-IP, synaptic fractionation, RNAi and electrophysiology\",\n      \"pmids\": [\"20838393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"TNIK substrates within the complex not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected DISC1 to ciliogenesis and dopamine receptor compartmentalization, broadening its role to primary cilium biology.\",\n      \"evidence\": \"GFP-DISC1 localization, RNAi knockdown and cilia marker immunofluorescence in NIH3T3 and striatal neurons\",\n      \"pmids\": [\"20531939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cilia maintenance unresolved\", \"Functional link to receptor signaling not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated direct DISC1\\u2013GSK3 binding and that the L100P mutation dysregulates GSK3, with rescue by GSK3 inhibition establishing a therapeutic node.\",\n      \"evidence\": \"Co-IP mapping to aa 1\\u2013220, genetic and pharmacological GSK3 inactivation, behavioral assays in L100P mice\",\n      \"pmids\": [\"20687110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural interface undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the biochemical mechanism by which the DISC1\\u2013PDE4 module controls cytoskeletal assembly: PKA phosphorylation of NDE1 at T131 modulates NDE1\\u2013LIS1/NDEL1 binding and neurite outgrowth.\",\n      \"evidence\": \"In vitro PKA assay, phospho-specific antibody, homology modeling, Co-IP and phospho-mutant neurite assay\",\n      \"pmids\": [\"21677187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of T131 phosphorylation not tested\", \"Other PKA sites not excluded\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed DISC1 drives synaptic vesicle transport by assembling the FEZ1\\u2013Syt-1 kinesin cargo complex, with lithium restoring transport.\",\n      \"evidence\": \"RNAi, dominant-negative DISC1, live vesicle imaging and Co-IP in cortical neurons\",\n      \"pmids\": [\"21664390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lithium mechanism of rescue undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Separated parallel DISC1 pathways in adult neurogenesis, distinguishing FEZ1-dependent dendritic growth from NDEL1-dependent cell positioning.\",\n      \"evidence\": \"Retroviral RNAi in adult hippocampus, Co-IP and genetic epistasis in schizophrenia cohorts\",\n      \"pmids\": [\"22099459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular branch point not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Dissected variant-specific loss of DISC1 Wnt signaling activity, assigning A83V/R264Q/L607F to proliferation defects and S704C to migration defects across model systems.\",\n      \"evidence\": \"Wnt reporter, zebrafish rescue, mouse progenitor assays, human lymphoblasts, TALEN/CRISPR mutants\",\n      \"pmids\": [\"22099458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular consequence of each variant on GSK3 binding not all resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed DISC1-regulated dendritic development of newborn neurons downstream of GABA/NKCC1 depolarization converging on AKT\\u2013mTOR, with human genetic epistasis support.\",\n      \"evidence\": \"Retroviral RNAi, pharmacological NKCC1 and mTOR manipulation, epistasis in two case-control cohorts\",\n      \"pmids\": [\"22385968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DISC1\\u2013mTOR molecular link not defined\", \"Mechanism of NKCC1 convergence indirect\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a neurochemical function: DISC1 stabilizes serine racemase to sustain D-serine and NMDA receptor signaling, with mutant DISC1 promoting SR degradation.\",\n      \"evidence\": \"Co-IP, astrocyte-selective dominant-negative mouse, ubiquitination assay, D-serine measurement, behavioral rescue\",\n      \"pmids\": [\"22801410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase for SR not identified here\", \"Interface mapping incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Characterized DISC1 transcriptional regulation, identifying FOXP2 as a repressor whose dyspraxia mutations relieve repression.\",\n      \"evidence\": \"Dual luciferase promoter assays, deletion constructs, FOXP2 mutant analysis, Western blot\",\n      \"pmids\": [\"22434823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FOXP2 promoter occupancy not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified DISC1 as a TRAK1/Miro1 mitochondrial transport adaptor specifically promoting anterograde movement, with a rare variant impairing this function.\",\n      \"evidence\": \"Co-IP and live axonal mitochondria imaging with variant-specific analysis\",\n      \"pmids\": [\"24092329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Directionality mechanism not yet defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a DISC1\\u2013D2R complex controlling D2R-mediated GSK3 signaling and internalization, with disease relevance shown in postmortem brain and rescue by an interfering peptide.\",\n      \"evidence\": \"Reciprocal Co-IP, postmortem biochemistry, in vivo interfering peptide, behavioral assays\",\n      \"pmids\": [\"25433637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interface not structurally defined\", \"Cell-type specificity of complex not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected DISC1 to APP processing and trafficking, showing knockdown shifts APP toward non-amyloidogenic processing and surface retention.\",\n      \"evidence\": \"RNAi in cortical neurons, A\\u03b2/sAPP ELISA, surface biotinylation, interaction-deficient mutant rescue\",\n      \"pmids\": [\"25224257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a DISC1 role in oligodendrocyte differentiation, showing it negatively regulates myelin marker expression.\",\n      \"evidence\": \"Bidirectional overexpression/RNAi in oligodendrocyte precursors with myelin marker immunocytochemistry\",\n      \"pmids\": [\"24516667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterized the DISC1-Boymaw fusion as inhibiting NADH oxidoreductase activity and protein translation, reducing synaptic protein levels in knock-in mice.\",\n      \"evidence\": \"Humanized knock-in mice, translation and NADH oxidoreductase assays, Western blot\",\n      \"pmids\": [\"24908665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking fusion to translation block unclear\", \"Relevance to non-fusion DISC1 limited\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded the mitochondrial transport/fusion role by showing DISC1 binds Miro1/Miro2/TRAK1/TRAK2/mitofusins and that the Boymaw fusion disrupts ER\\u2013mitochondria contacts and dendritic development.\",\n      \"evidence\": \"Multiple Co-IPs, live transport imaging, super-resolution microscopy, dominant-negative expression, dendritic analysis\",\n      \"pmids\": [\"26553875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect mitofusin binding not resolved\", \"Quantitative complex stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an interneuron-specific DISC1 function inhibiting NRG1\\u2013ErbB4 signaling, implicating DISC1 in excitatory\\u2013inhibitory circuit balance.\",\n      \"evidence\": \"Cell-type-specific viral manipulation, mutant mouse, ErbB4 phosphorylation assay and Co-IP\",\n      \"pmids\": [\"26656849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competitive PSD95 mechanism shown as likely but not proven\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked DISC1 to ER calcium dynamics via EXOC1-mediated recruitment to IP3R1, with antipsychotic-reversible calcium dysregulation upon knockdown.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP, calcium imaging, RNAi and KO mouse neurons\",\n      \"pmids\": [\"25732993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IP3R1 binding versus EXOC1-bridged recruitment unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed DISC1 promotes astrogenesis via RASSF7-dependent RAS/MEK/ERK activation and pERK nuclear translocation.\",\n      \"evidence\": \"Co-IP, in utero electroporation, in vitro astrogenesis assay, pERK translocation analysis\",\n      \"pmids\": [\"27287808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RASSF7 binding interface undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed DISC1 downstream of TLR3\\u2013MYD88 innate immune signaling regulating dendritic arborization.\",\n      \"evidence\": \"TLR3 agonist, MYD88 knockout, DISC1 overexpression rescue, dendritic morphology\",\n      \"pmids\": [\"27979975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional mechanism of Disc1 repression undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the first crystal structure of the DISC1 C-terminal tail\\u2013Ndel1 complex and showed DISC1 controls Ndel1 kinetochore attachment and mitotic progression in radial glia and human organoids.\",\n      \"evidence\": \"X-ray crystallography, interface mutagenesis, mitosis/cell-cycle imaging, in utero electroporation, patient iPSC organoids\",\n      \"pmids\": [\"29103808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetochore-recruitment partners of the complex not fully defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected DISC1 to Huntington's disease, showing mutant HTT cross-seeds DISC1 to deplete soluble DISC1 and aberrantly activate PDE4.\",\n      \"evidence\": \"Co-IP, aggregation assays, PDE4 activity assay, modified DISC1 rescue in R6/2 mice, HD brain validation\",\n      \"pmids\": [\"28263187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cross-seeding undefined\", \"Generality across HD models untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined DISC1 protein turnover by identifying the FBXW7 phosphodegron and solving the complex structure, establishing how DISC1 levels are post-translationally controlled.\",\n      \"evidence\": \"Structural biology of FBXW7\\u2013DISC1, ubiquitination assay, Co-IP, proteasome inhibition, patient iPSC NPCs\",\n      \"pmids\": [\"28727686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase generating the phosphodegron not identified\", \"Physiological triggers of degradation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed DISC1 supports astrocyte energy metabolism, with knockdown reducing glucose uptake and lactate production and lactate rescuing behavior.\",\n      \"evidence\": \"Astrocyte-selective dominant-negative mouse, metabolic flux and lactate assays, behavioral rescue\",\n      \"pmids\": [\"29643356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from DISC1 to GLUT4 expression undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed convergent DISC1 mutations reduce protein via NMD and dysregulate UNC5D netrin signaling to impair neurite outgrowth.\",\n      \"evidence\": \"Isogenic iPSC NGN2 neurons, RNA-seq, UNC5D knockdown/rescue, longitudinal neurite imaging\",\n      \"pmids\": [\"30410030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional control of UNC5D by DISC1 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Solved the DISC1\\u2013ATF4 atomic structure and showed a patient frameshift mutation causes nuclear ATF4 accumulation and transcriptional/synaptic deficits rescuable by ATF4 reduction.\",\n      \"evidence\": \"X-ray crystallography, Co-IP, nuclear fractionation, ChIP, CRISPR ATF4 knockout rescue, iPSC neurons\",\n      \"pmids\": [\"31444471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide ATF4 target dysregulation incompletely mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that DISC1-dependent mitochondrial transport directionality is gated by the Miro1 GTPase state, with a psychiatric mutation impairing transport and synaptic positioning.\",\n      \"evidence\": \"Live transport imaging, Miro1 GTPase domain mutants, mutant DISC1 expression\",\n      \"pmids\": [\"32637409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular sensing of GTPase state by DISC1 undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a patient frameshift mutation elevates PDE4 levels and causes synaptic deficits rescuable by PDE4 inhibition across iPSC neurons and knock-in mice, validating the DISC1\\u2013cAMP axis therapeutically.\",\n      \"evidence\": \"Isogenic iPSC neurons, transcriptome/kinome analysis, PDE4 inhibitor, knock-in mouse, electrophysiology and behavior\",\n      \"pmids\": [\"33658519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which mutant DISC1 elevates PDE4 transcript not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided in vivo therapeutic proof-of-concept that DISC1 sustains anterograde mitochondrial transport and axonal ATP, with gene delivery rescuing neurons in ocular hypertension.\",\n      \"evidence\": \"Multiphoton live transport imaging, AAV Disc1 delivery, genetically encoded ATP sensor, visual electrophysiology\",\n      \"pmids\": [\"36103832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Translation to CNS disease contexts untested\", \"Adaptor stoichiometry in vivo undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DISC1's many spatially distinct complexes are coordinately regulated in a single neuron, and which interactions are direct versus scaffold-bridged, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model of how DISC1 partitions between centrosome, mitochondria, ER, synapse and nucleus\", \"Full-length DISC1 structure and conformational regulation undefined\", \"Relative contribution of each pathway to disease phenotypes not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 6, 11, 18, 19]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 27, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 10, 15, 20, 28]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 31, 39]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [15, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3, 4, 35]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 18, 19, 32]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 31]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [24, 19]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 13, 20, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 8, 13, 22, 39]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11, 18, 19, 34]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 29, 38]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 31, 36]}\n    ],\n    \"complexes\": [\n      \"NDE1/NDEL1/LIS1/dynein complex\",\n      \"DISC1\\u2013Miro1/Miro2\\u2013TRAK1/TRAK2 mitochondrial transport complex\",\n      \"Grb2\\u2013KIF5A kinesin complex\",\n      \"SCF(FBXW7) ubiquitin ligase substrate complex\"\n    ],\n    \"partners\": [\n      \"NDEL1\",\n      \"PDE4B\",\n      \"GSK3B\",\n      \"ATF4\",\n      \"FEZ1\",\n      \"MIRO1\",\n      \"TRAK1\",\n      \"FBXW7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}