{"gene":"DEPDC5","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2013,"finding":"DEPDC5 loss-of-function mutations cause familial focal epilepsy with variable foci; the protein shares homology with G protein signaling molecules and localizes in human neurons, suggesting a role in neuronal signal transduction.","method":"Exome sequencing of affected families; localization by immunostaining in human neurons","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization in neurons reported but without detailed functional follow-up; replicated across two simultaneous papers","pmids":["23542697","23542701"],"is_preprint":false},{"year":2014,"finding":"DEPDC5 is a component of the GATOR1 complex and functions as a negative regulator of mTORC1 in the amino acid-sensing branch; variants disrupt DEPDC5-dependent inhibition of mTORC1 and GATOR1 complex formation.","method":"Functional assays of TORC1 signaling in cells transfected with epilepsy-associated DEPDC5 variants; assessment of GATOR1 complex formation","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct functional assay of mTORC1 inhibition and complex assembly tested for multiple variants in cell-based system; single lab but multiple variants and two orthogonal readouts","pmids":["25366275"],"is_preprint":false},{"year":2014,"finding":"DEPDC5 negatively regulates the mTOR pathway; loss-of-function mutations are associated with mTOR pathway hyperactivation (mTORopathy), and clinicoradiological phenotypes overlap with tuberous sclerosis.","method":"Genetic mutation analysis combined with mTOR pathway activation markers in patient tissue","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway placement via patient tissue analysis; replicated across multiple papers","pmids":["24585383"],"is_preprint":false},{"year":2015,"finding":"Germline, germline mosaic, and brain somatic DEPDC5 mutations can cause focal cortical dysplasia, with a 'two-hit' mutational model (similar to other mTORopathies) proposed for cortical lesion formation; mTOR activation confirmed by immunostaining of resected brain tissue.","method":"Sequencing of blood and brain DNA from patients; histopathological analysis; mTOR activation markers in brain tissue","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent methods (DNA sequencing + tissue immunostaining); single lab but replicated in subsequent studies","pmids":["25623524"],"is_preprint":false},{"year":2015,"finding":"Germline nonsense DEPDC5 mutation (p.Arg555*) causes extensive focal cortical dysplasia IIa with mTOR activation confirmed by immunostaining of resected brain tissue; the DEP domain is critical for DEPDC5 function.","method":"Whole-exome sequencing; immunostaining of resected brain tissue for mTOR activation markers","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct tissue-level mTOR activation measurement + genetic identification; single case series","pmids":["26000329"],"is_preprint":false},{"year":2016,"finding":"Homozygous Depdc5 knockout rat embryos die from embryonic day 14.5 with global growth delay and constitutive mTORC1 hyperactivation in brain and fibroblasts (measured by enhanced phosphorylation of S6K1 and rpS6); prenatal rapamycin treatment rescues the lethal phenotype. Heterozygous rats show cortical cytomegalic neurons and balloon-like cells with phosphorylated rpS6, abolished by prenatal rapamycin.","method":"TALEN-generated knockout rat; phosphorylation assays for S6K1/rpS6; rapamycin rescue experiment; neuropathological analysis","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vivo genetic KO with biochemical readout, pharmacological rescue, and neuropathology; single lab with multiple orthogonal methods","pmids":["26873552"],"is_preprint":false},{"year":2017,"finding":"Neuron-specific Depdc5 conditional knockout mice (Synapsin1-Cre) develop mTORC1 hyperactivation exclusively in neurons (increased phospho-S6), dysplastic and ectopic neurons, reactive astrogliosis, and seizure susceptibility; rapamycin inhibition rescues mTORC1 activity and partially rescues phenotype.","method":"Conditional KO mouse (Cre-lox); phospho-S6 immunostaining; EEG recording; chemoconvulsant seizure threshold assays; rapamycin treatment","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype, biochemical readout, and pharmacological rescue; single lab but multiple orthogonal methods","pmids":["29274432"],"is_preprint":false},{"year":2017,"finding":"CRISPR-generated germline Depdc5 knockout mouse embryos show mTORC1 hyperactivity in brain and in fibroblasts/neurospheres under nutrient-deprived conditions, supporting DEPDC5 as a negative regulator of mTORC1 that is particularly important during amino acid insufficiency.","method":"CRISPR mutagenesis mouse model; mTORC1 activity assays in fibroblasts and neurospheres under nutrient deprivation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vivo genetic KO with in vitro biochemical validation under nutrient deprivation; single lab, multiple cell types tested","pmids":["28974734"],"is_preprint":false},{"year":2018,"finding":"Biallelic two-hit (germline + brain somatic) DEPDC5 mutations cause focal cortical dysplasia with focal epilepsy; somatic second-hit mutation load is higher in seizure-onset zone than surrounding epileptogenic zone. CRISPR-Cas9 + in utero electroporation mosaic Depdc5 inactivation in mice recapitulates focal epilepsy with FCD and SUDEP-like events. Depdc5 inactivation shapes dendrite and spine morphology of excitatory neurons.","method":"Deep sequencing of postoperative human tissue; CRISPR-Cas9 + in utero electroporation mouse model; morphological analysis of dendrites and spines","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — human tissue sequencing + in vivo CRISPR mouse model; multiple orthogonal methods; independently supported by other studies","pmids":["29708508"],"is_preprint":false},{"year":2018,"finding":"DEPDC5 knockdown in zebrafish causes mTOR-dependent motor hyperactivity and neuronal hyperexcitability; rescue by WT human DEPDC5 but not by epilepsy-associated mutants (p.Arg487* and p.Arg485Gln) confirms loss-of-function mechanism; rapamycin treatment rescues phenotype.","method":"Zebrafish Depdc5 knockdown model; behavioral assays; overexpression of WT and mutant DEPDC5; rapamycin treatment","journal":"Annals of clinical and translational neurology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo vertebrate model with WT rescue, mutant non-rescue, and pharmacological rescue; multiple orthogonal methods","pmids":["29761115"],"is_preprint":false},{"year":2018,"finding":"Somatic focal Depdc5 deletion via CRISPR + in utero electroporation in rat brain produces spontaneous seizures with electroclinical features of focal cortical dysplasia type IIA, establishing a causal link between somatic DEPDC5 loss and FCD-related epilepsy.","method":"In utero electroporation with CRISPR gene deletion in rat; EEG recording; histopathological analysis","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo somatic KO model with defined electroclinical phenotype; single lab but rigorous animal model","pmids":["30080265"],"is_preprint":false},{"year":2018,"finding":"DEPDC5 knockdown in neural progenitor cells and neurons causes mTORC1 (but not mTORC2) hyperactivation, soma enlargement, increased filopodia, and inappropriate localization of mTOR at the lysosome during amino acid starvation; these effects are reversed by rapamycin.","method":"shRNA knockdown in neuroblastoma cells and mouse neural progenitor cells; mTOR subcellular localization by confocal imaging; rapamycin rescue","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization experiment tied to functional consequence; multiple cell types; pharmacological rescue","pmids":["29481864"],"is_preprint":false},{"year":2018,"finding":"DEPDC5 maintains HIV-1 latency by suppressing the mTORC1 pathway through RagA (distinct from TSC1 which acts via Rheb); knockout of DEPDC5 leads to enhanced HIV-1 reactivation antagonized by rapamycin.","method":"Genome-wide CRISPR screening; DEPDC5 KO in T-cell and monocyte latency models; rapamycin antagonism assay","journal":"Emerging microbes & infections","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional CRISPR KO in two cell line models with mechanistic pathway dissection; single lab","pmids":["30087333"],"is_preprint":false},{"year":2019,"finding":"DEPDC5 is phosphorylated by Pim1 and AKT kinases; phosphorylation of DEPDC5 releases inhibition of mTORC1. A phospho-mimic S1530E DEPDC5 confers resistance to Pim and AKT inhibitors in tumor cells in vitro and in vivo.","method":"Phospho-specific antibodies; transfection of phospho-inactive DEPDC5 mutants; kinase assays; knock-in phospho-mimic glutamic acid substitution; in vivo tumor experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phospho-specific antibodies + mutagenesis + in vivo knock-in; multiple orthogonal methods in single study","pmids":["31548394"],"is_preprint":false},{"year":2019,"finding":"DEPDC5 inactivation mutations in GISTs promote tumor growth via the mTORC1 signaling pathway, leading to cell-cycle arrest when DEPDC5 is present; DEPDC5 loss reduces cell proliferation and modulates sensitivity to KIT inhibitors.","method":"Whole exome sequencing; in vitro and nude mouse in vivo DEPDC5 inactivation experiments; mTORC1 pathway assays; cell proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional in vitro and in vivo validation of DEPDC5 loss with mTORC1 readout; multiple methods","pmids":["31636198"],"is_preprint":false},{"year":2019,"finding":"Neuronal Depdc5 knockout (Depdc5cc+) mice exhibit mTORC1 hyperactivation, hyperactivity, enlarged brain and neuronal soma, and rare seizures; rapamycin treatment prolongs survival, partially rescues hyperactivity, and reduces brain/neuronal size by suppressing downstream mTORC1 (phospho-S6) but not GATOR1 protein levels. Loss of Depdc5 leads to decreased levels of other GATOR1 proteins NPRL2 and NPRL3.","method":"Conditional KO mouse; video-EEG monitoring; open-field and elevated-plus maze testing; rapamycin treatment; Western blot for NPRL2, NPRL3, phospho-S6","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with behavioral, EEG, biochemical phenotyping; pharmacological rescue; single lab but multiple orthogonal methods","pmids":["31174205"],"is_preprint":false},{"year":2019,"finding":"Second-hit DEPDC5 somatic mutation is limited to dysmorphic neurons in focal cortical dysplasia type IIA, and the somatic mutation load correlates with dysmorphic neuron density and the epileptogenic zone.","method":"Deep sequencing of surgical tissue; correlation of variant allele frequency with cell-type-specific histopathology","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular measurement in identified cell types; single lab, single case","pmids":["31353856"],"is_preprint":false},{"year":2020,"finding":"Acute Depdc5 knockdown (~80%) in cortical neurons causes dose-dependent mTOR hyperactivation, soma enlargement, increased dendritic arborization, increased excitatory (but not inhibitory) synaptic transmission, and increased intrinsic excitability; the synaptic phenotype is driven specifically by excitatory synapses, with increased mEPSC frequency/amplitude, excitatory synapse density, and glutamate receptor expression.","method":"RNA interference in primary cortical cultures; mEPSC recording; synapse density analysis; glutamate receptor expression; comparison with heterozygous Depdc5+/- neurons","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct electrophysiology + molecular characterization of synaptic mechanism; dose-response established; single lab but multiple orthogonal methods","pmids":["32113911"],"is_preprint":false},{"year":2020,"finding":"Depdc5 KO (but not Tsc2 KO) cells fail to respond to amino acid withdrawal by moving mTOR off the lysosome; Depdc5 KO cells maintain mTOR lysosomal localization and 4E-BP1 phosphorylation even under amino acid-free conditions, whereas Tsc2 KO cells show partial reduction under amino acid starvation.","method":"CRISPR-edited Neuro2a cells; FRET-biosensor for 4E-BP1 phosphorylation in living cells; confocal imaging of mTOR lysosomal localization","journal":"Experimental neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — live-cell FRET biosensor + confocal localization; direct mechanistic comparison of two KO genotypes; single lab","pmids":["32781001"],"is_preprint":false},{"year":2020,"finding":"DEPDC5 haploinsufficiency in human iPSC-derived cortical neurons causes increased phosphorylation of ribosomal protein S6, increased iPSC proliferation rate, and enlarged soma in neurons; rapamycin rescues soma size, demonstrating mTORC1 haploinsufficiency in human cells.","method":"Patient iPSC-derived cortical neurons; phospho-S6 Western blot; soma size measurement; rapamycin rescue","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC model with pharmacological rescue; single lab; limited to heterozygous haploinsufficiency","pmids":["32574724"],"is_preprint":false},{"year":2021,"finding":"Hepatocyte-specific Depdc5 knockout activates mTORC1 constitutively; in ethanol-fed Depdc5-LKO mice, severe hepatic steatosis and inflammation develop via suppression of PPARα (master regulator of fatty acid oxidation); fenofibrate (PPARα agonist) reverses the steatosis, linking DEPDC5-mTORC1 to PPARα-mediated fatty acid oxidation.","method":"Hepatocyte-specific conditional KO mouse; Torin1 and fenofibrate pharmacological intervention; mTORC1 and PPARα pathway assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular mechanism (mTORC1→PPARα suppression) and two pharmacological rescues; single lab but multiple orthogonal approaches","pmids":["34267188"],"is_preprint":false},{"year":2022,"finding":"Brain mTORC1 signaling is reduced after acute fasting; neuronal mTORC1 integrates GATOR1 (amino acid sensing via DEPDC5) and TSC (growth factor sensing). Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine in a DEPDC5-dependent manner. Depdc5 neuronal-specific KO mice are resistant to changes in brain amino acid levels after fasting and do not benefit from fasting-induced seizure protection.","method":"Neuronal-specific Depdc5 KO mice; metabolomic analysis of brain amino acids; seizure susceptibility assays with fasting; comparison with amino acid withdrawal","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with metabolomics and functional seizure assay; mechanistic dissection of amino acid sensing specificity; single lab but multiple methods","pmids":["36044864"],"is_preprint":false},{"year":2022,"finding":"Long before seizure onset in a mouse model of DEPDC5-related epilepsy with cortical dysplasia (dorsal progenitor-specific Depdc5 deletion), microglia inflammation and proteolytic enzyme activity degrade perineuronal nets (PNNs) in malformed cortex, resulting in parvalbumin interneuron loss and impaired presynaptic inhibition.","method":"Forebrain dorsal progenitor-specific conditional KO mouse; immunostaining for PNNs, PV+ interneurons, microglia markers; electrophysiology of inhibitory synapses","journal":"Developmental neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — non-cell-autonomous interneuron loss mechanism identified with direct histological and functional readouts; single lab, single study","pmids":["35580549"],"is_preprint":false},{"year":2023,"finding":"Depdc5 deletion in excitatory (but not inhibitory) cortical neurons causes frequent generalized tonic-clonic seizures and SUDEP; SUDEP is preceded by ictal apnea and respiratory dysregulation rather than cardiac arrhythmia, with EEG suppression at ictal offset and loss of theta activity only in fatal seizures.","method":"Neuron subtype-specific conditional KO mice (excitatory vs inhibitory); EEG, cardiac, and respiratory recording; respiratory challenge assays","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with simultaneous multi-modal physiological recording; mechanistic dissection of SUDEP mechanism; single lab but rigorous experimental design","pmids":["37606181"],"is_preprint":false},{"year":2021,"finding":"Cardiac investigations in DEPDC5/NPRL2/NPRL3 patients and novel Depdc5 mouse strains reveal no structural or functional cardiac damage; HA-tagged Depdc5 mouse shows Depdc5 expression in brain, heart, and lungs; simultaneous EEG-ECG in Depdc5c/- mice shows seizure-induced SUDEP-like events are not preceded by cardiac arrhythmia.","method":"HA-tagged Depdc5 knock-in mouse; neuron-specific second-allele deletion mouse; simultaneous EEG-ECG recording; human cardiac investigations (Holter, Echo, ECG); autopsy","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multi-modal approach in both mouse and human; negative cardiac finding rigorously established; HA-tagging confirmed tissue-level expression","pmids":["34693554"],"is_preprint":false},{"year":2024,"finding":"DEPDC5 deficiency in CD8+ T cells causes hyper-mTORC1-induced ATF4 expression, leading to elevated xanthine oxidase and lipid ROS production, spontaneous ferroptosis, and reduced peripheral CD8+ T cell numbers; T cell-specific Depdc5 KO mice confirm impaired anti-tumor immunity.","method":"T cell-specific Depdc5 conditional KO mouse; ROS measurement; xanthine oxidase assay; ATF4 expression analysis; tumor immunity assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular cascade (mTORC1→ATF4→xanthine oxidase/lipid ROS→ferroptosis); multiple biochemical readouts; single lab","pmids":["38763950"],"is_preprint":false},{"year":2024,"finding":"Biallelic inactivation of DEPDC5 in mosaic human cortical organoids (two-hit model) increases mTOR activity rescued by rapamycin, produces dysmorphic-like neurons and enhanced neuronal excitability, disrupts neuronal differentiation, and alters expression of Notch/Wnt signaling pathway genes and synaptic/epilepsy-associated genes.","method":"Patient-derived human cortical organoids with CRISPR-based two-hit DEPDC5 inactivation; single-cell transcriptomics; mTOR activity assays; electrophysiology; rapamycin rescue","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — human organoid model with single-cell transcriptomics + electrophysiology + pharmacological rescue; multiple orthogonal methods","pmids":["41789478"],"is_preprint":false},{"year":2024,"finding":"Biallelic inactivation of Depdc5 in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability with other mTORC1 repressor gene knockouts, but different changes in excitatory synaptic transmission compared to Tsc1 or Pten loss, indicating gene-specific synaptic mechanisms.","method":"In utero electroporation-based biallelic inactivation; electrophysiology; morphological analysis; comparison across mTORC1 pathway genes","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo comparison across multiple mTOR pathway genes with electrophysiology; single lab","pmids":["38411613"],"is_preprint":false},{"year":2025,"finding":"DEPDC5 interacts with USP46 (ubiquitin-specific protease that regulates GluA1), WDR48, and WDR20 as binding partners. In Depdc5 cKO neurons, loss of DEPDC5 leads to mTORC1-dependent USP46 upregulation, decreased ubiquitination of GluA1, and surface redistribution of GluA1-containing AMPA receptors, increasing excitatory quantal size. USP46 knockdown or rapamycin rescues the increased glutamate quantal size and USP46 elevation.","method":"Conditional KO mouse; co-immunoprecipitation/protein interaction network; electrophysiology (mEPSC); GluA1 ubiquitination assay; surface biotinylation; USP46 knockdown; rapamycin rescue","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal IP for binding partners + electrophysiology + ubiquitination assay + two independent rescue strategies; single lab but multiple orthogonal methods","pmids":["40467011"],"is_preprint":false},{"year":2025,"finding":"Postnatal focal cortical DEPDC5 loss (AAV-Cre injection in postnatal day 0-1 mice) without disruption to cortical lamination is sufficient to cause mTOR hyperactivation, FCD pathological hallmarks (SMI-311 neurofilament staining, hypomyelination, astrogliosis, microglial activation), lower seizure thresholds, increased focal seizures, and seizure-induced death.","method":"AAV-Cre postnatal conditional KO mouse; immunohistochemistry for FCD markers; seizure threshold assays; seizure monitoring","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — postnatal focal KO separating developmental from postnatal mechanisms; multiple histological and functional readouts; single lab","pmids":["40996830"],"is_preprint":false},{"year":2018,"finding":"DEPDC5 knockout in hepatocellular carcinoma cells causes resistance to leucine starvation; DEPDC5-KO reduces LC3-II and accumulates p62, inducing ROS tolerance. DEPDC5 overexpression suppresses cell proliferation and tumorigenicity in immunocompromised mice and triggers p62 degradation with increased ROS susceptibility.","method":"CRISPR/Cas9 DEPDC5 KO in HCC cells; overexpression in immunocompromised mice; autophagy markers (LC3-II, p62); ROS measurement","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo; multiple molecular readouts; single lab","pmids":["29311600"],"is_preprint":false},{"year":2015,"finding":"DEPDC5 downregulation in hepatic stellate cells (LX-2) increases β-catenin expression and production of MMP2 (matrix metallopeptidase 2), a secreted enzyme involved in fibrosis progression, linking DEPDC5 to the β-catenin pathway in liver fibrosis.","method":"In vitro DEPDC5 downregulation in LX-2 cells; β-catenin and MMP2 expression assays","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single in vitro experiment in cell line; single lab; limited mechanistic depth","pmids":["26517016"],"is_preprint":false},{"year":2024,"finding":"GPR81 activation by lactate promotes chaperone-mediated autophagy (CMA)-mediated degradation of DEPDC5 protein, activating mTOR signaling and promoting EMT/metastasis in colorectal cancer; gentisic acid inhibits GPR81 and blocks DEPDC5 degradation.","method":"siRNA knockdown; Western blotting; immunofluorescence; in vivo lung metastasis mouse model; CMA pathway analysis","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments linking GPR81→CMA→DEPDC5 degradation→mTOR; single lab; mechanistic pathway established","pmids":["38615493"],"is_preprint":false},{"year":2025,"finding":"SNX10 interacts directly with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation; SNX10 knockdown accelerates DEPDC5 degradation, activates mTORC1, and elevates glycolysis; α-hederin binds the SNX10-DEPDC5 complex and impairs the SNX10-DEPDC5 interaction to inhibit CMA-mediated DEPDC5 degradation.","method":"Co-immunoprecipitation (SNX10-DEPDC5 interaction); lysosomal recruitment assay; siRNA knockdown; Western blotting; glycolysis measurement","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct Co-IP of interaction + functional assays of degradation and downstream signaling; single lab","pmids":["41487148"],"is_preprint":false},{"year":2026,"finding":"In excitatory neurons of the malformed cortex of a DEPDC5-related epilepsy rat model and human patient tissue, Slc6a5 (glycine transporter GlyT2) is ectopically overexpressed. Simultaneous CRISPR KO of Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration.","method":"CRISPR in utero electroporation for simultaneous Depdc5/Slc6a5 KO; seizure monitoring; expression profiling in rat and human tissue","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional rescue by double KO establishes SLC6A5 as downstream effector; single lab, mechanism not fully elucidated per abstract","pmids":["41587632"],"is_preprint":false}],"current_model":"DEPDC5 is a component of the GATOR1 complex (with NPRL2 and NPRL3) that functions as a negative regulator of mTORC1 in the amino acid-sensing branch; it prevents constitutive mTOR lysosomal localization and activation under amino acid-poor conditions, and its loss causes mTORC1 hyperactivation leading to neuronal soma enlargement, dysplastic morphology, increased excitatory synaptic strength (via mTORC1→USP46→GluA1 deubiquitination and surface redistribution), dendritic/spine abnormalities, and cortical hyperexcitability; DEPDC5 phosphorylation by Pim1/AKT kinases releases its mTORC1 inhibition, while chaperone-mediated autophagy via SNX10 or GPR81/CMA can degrade DEPDC5 protein; in excitatory neurons it also protects against ferroptosis by limiting mTORC1-induced ATF4/xanthine oxidase/lipid ROS, and biallelic loss-of-function (germline plus somatic second-hit) in cortical progenitors causes focal cortical dysplasia with drug-resistant epilepsy and SUDEP risk predominantly driven by ictal apnea."},"narrative":{"mechanistic_narrative":"DEPDC5 is a component of the GATOR1 complex (with NPRL2 and NPRL3) that acts as a negative regulator of mTORC1 within the amino acid-sensing branch of the pathway [PMID:25366275, PMID:31174205]. Mechanistically, DEPDC5 prevents constitutive mTOR retention at the lysosome under amino acid-poor conditions; its loss leaves mTOR lysosomally localized and signaling active even during amino acid withdrawal, distinguishing it from TSC2-dependent growth-factor sensing [PMID:32781001, PMID:29481864]. Loss-of-function causes cell-autonomous mTORC1 (but not mTORC2) hyperactivation, neuronal soma enlargement, dysplastic and ectopic neurons, increased dendritic arborization, and a selective increase in excitatory synaptic transmission and intrinsic excitability [PMID:29481864, PMID:32113911, PMID:29274432]; the excitatory synaptic phenotype is driven by an mTORC1-dependent rise in USP46, which deubiquitinates GluA1 and redistributes AMPA receptors to the neuronal surface, an effect reversed by USP46 knockdown or rapamycin [PMID:40467011]. In neurons, DEPDC5 integrates amino acid availability (leucine, arginine, glutamine) into mTORC1 tone and mediates fasting-induced seizure protection [PMID:36044864]. DEPDC5 inhibition of mTORC1 is released by Pim1/AKT phosphorylation [PMID:31548394], and DEPDC5 protein is degraded through chaperone-mediated autophagy via SNX10 or lactate-GPR81 signaling [PMID:41487148, PMID:38615493]. Germline loss-of-function combined with a brain somatic second hit ('two-hit' model) in cortical progenitors causes focal cortical dysplasia with drug-resistant focal epilepsy [PMID:25623524, PMID:29708508, PMID:31353856], and excitatory-neuron-restricted loss drives generalized seizures and SUDEP that is preceded by ictal apnea rather than cardiac arrhythmia [PMID:37606181, PMID:34693554]. Beyond the nervous system, DEPDC5 restrains mTORC1 in hepatocytes (via PPARα-regulated fatty acid oxidation), in CD8+ T cells (limiting ATF4-driven xanthine oxidase/lipid ROS and ferroptosis), and in tumor cells where its loss alters proliferation and drug sensitivity [PMID:34267188, PMID:38763950, PMID:31636198].","teleology":[{"year":2013,"claim":"Established DEPDC5 as a disease gene before its molecular function was known, linking it to a neuronal signaling role through familial epilepsy genetics.","evidence":"Exome sequencing of affected families with immunostaining in human neurons","pmids":["23542697","23542701"],"confidence":"Medium","gaps":["No molecular pathway assigned at this stage","Homology-based inference of G-protein signaling role not biochemically tested"]},{"year":2014,"claim":"Resolved DEPDC5's molecular identity by placing it in the GATOR1 complex as a negative regulator of mTORC1, explaining how epilepsy variants act mechanistically.","evidence":"Cell-based mTORC1 signaling assays and GATOR1 complex-formation assessment with epilepsy variants; patient-tissue mTOR activation markers","pmids":["25366275","24585383"],"confidence":"High","gaps":["Did not define the amino acid sensing step DEPDC5 controls","Subcellular mechanism of mTORC1 inhibition unresolved"]},{"year":2015,"claim":"Demonstrated the two-hit mutational model for cortical lesion formation, connecting germline plus brain somatic DEPDC5 loss to focal cortical dysplasia with confirmed mTOR activation.","evidence":"Blood and brain DNA sequencing, histopathology, and mTOR activation immunostaining of resected tissue","pmids":["25623524","26000329"],"confidence":"Medium","gaps":["Causality of somatic second hit not yet shown experimentally","DEP domain functional requirement inferred, not dissected"]},{"year":2016,"claim":"Provided in vivo proof that DEPDC5 loss causes constitutive mTORC1 hyperactivation and that the phenotype is rapamycin-reversible, establishing the mTORopathy mechanism organismally.","evidence":"TALEN knockout rat with S6K1/rpS6 phosphorylation assays, prenatal rapamycin rescue, and neuropathology","pmids":["26873552"],"confidence":"High","gaps":["Embryonic lethality limited adult/neuronal analysis","Cell-autonomous vs systemic contributions not separated"]},{"year":2017,"claim":"Showed DEPDC5's mTORC1 repression is most critical during amino acid insufficiency and acts specifically in neurons to produce dysplasia and seizure susceptibility.","evidence":"Conditional (Synapsin1-Cre) and CRISPR germline knockout mice with phospho-S6, EEG, seizure threshold assays under nutrient deprivation; rapamycin rescue","pmids":["29274432","28974734"],"confidence":"High","gaps":["Synaptic-level mechanism not yet defined","Amino acid specificity not quantified"]},{"year":2018,"claim":"Causally linked somatic DEPDC5 loss to FCD-related epilepsy via in vivo mosaic models and established the cellular and morphological consequences of inactivation.","evidence":"Human tissue deep sequencing plus CRISPR-Cas9/in utero electroporation mosaic inactivation in mouse and rat; zebrafish loss-of-function with WT-but-not-mutant rescue; dendrite/spine morphology","pmids":["29708508","30080265","29761115"],"confidence":"High","gaps":["Molecular driver of synaptic hyperexcitability not yet identified","SUDEP mechanism not dissected"]},{"year":2018,"claim":"Defined the subcellular mechanism: DEPDC5 loss locks mTOR at the lysosome and selectively hyperactivates mTORC1, producing soma enlargement and membrane process changes.","evidence":"shRNA knockdown in neuroblastoma and neural progenitor cells with confocal mTOR localization and rapamycin rescue","pmids":["29481864"],"confidence":"High","gaps":["Direct biochemical interaction with Rag GTPases not shown here","Effect on inhibitory neurons untested"]},{"year":2018,"claim":"Extended DEPDC5-mTORC1 control beyond neurons to HIV-1 latency and hepatocellular carcinoma, broadening its role as a general mTORC1 restraint with metabolic/autophagic consequences.","evidence":"Genome-wide CRISPR screens and KO/overexpression in T-cell, monocyte, and HCC models with autophagy/ROS readouts and rapamycin antagonism","pmids":["30087333","29311600"],"confidence":"Medium","gaps":["RagA-specific mechanism vs TSC1/Rheb branch only partially dissected","Physiological relevance outside cell lines uncertain"]},{"year":2019,"claim":"Identified an upstream regulatory input: Pim1/AKT phosphorylation of DEPDC5 releases its mTORC1 inhibition, providing a signaling node exploitable in tumor drug resistance.","evidence":"Phospho-specific antibodies, phospho-inactive and phospho-mimic (S1530E) mutants, kinase assays, and in vivo tumor experiments","pmids":["31548394"],"confidence":"High","gaps":["Relevance of phosphorylation in neurons not tested","Structural basis of phospho-regulation unknown"]},{"year":2019,"claim":"Showed DEPDC5 loss destabilizes the GATOR1 complex (reduced NPRL2/NPRL3) and that downstream mTORC1, not GATOR1 levels, drives the rapamycin-rescuable phenotype.","evidence":"Conditional KO mice with video-EEG, behavior, and Western blot for NPRL2/NPRL3/phospho-S6; GIST tumor functional studies","pmids":["31174205","31636198","31353856"],"confidence":"High","gaps":["Mechanism of GATOR1 partner destabilization unresolved","Link between morphology and seizures incomplete"]},{"year":2020,"claim":"Defined the synaptic and human-cell mechanisms: DEPDC5 loss selectively augments excitatory transmission and recapitulates mTORC1 haploinsufficiency in human iPSC neurons.","evidence":"RNAi in primary cortical cultures with mEPSC recordings and glutamate receptor analysis; patient iPSC-derived neurons with phospho-S6 and rapamycin rescue; CRISPR Neuro2a cells with FRET 4E-BP1 biosensor and mTOR localization","pmids":["32113911","32574724","32781001"],"confidence":"High","gaps":["Molecular link from mTORC1 to glutamate receptors not yet established","Distinction from TSC2 mechanism mechanistically incomplete"]},{"year":2021,"claim":"Generalized DEPDC5-mTORC1 to peripheral metabolism, showing hepatocyte loss drives steatosis via PPARα suppression, and rigorously excluded a cardiac basis for SUDEP.","evidence":"Hepatocyte-specific KO with Torin1/fenofibrate intervention; HA-tagged Depdc5 knock-in showing brain/heart/lung expression and simultaneous EEG-ECG with human cardiac investigations","pmids":["34267188","34693554"],"confidence":"High","gaps":["Tissue-specific determinants of mTORC1 output not defined","Non-cardiac SUDEP trigger not yet identified at this stage"]},{"year":2022,"claim":"Established DEPDC5 as the neuronal sensor of specific amino acids that underlies fasting-induced seizure protection, and revealed a non-cell-autonomous interneuron/PNN degradation route to hyperexcitability.","evidence":"Neuronal KO mice with brain amino acid metabolomics and fasting seizure assays; dorsal progenitor KO with PNN/PV+/microglia immunostaining and inhibitory synapse electrophysiology","pmids":["36044864","35580549"],"confidence":"High","gaps":["Mechanism coupling microglia activation to PNN degradation not fully defined","Relative contribution of excitatory vs inhibitory deficits unresolved"]},{"year":2023,"claim":"Pinpointed the SUDEP mechanism to excitatory-neuron-driven seizures producing ictal apnea and respiratory dysregulation rather than cardiac arrhythmia.","evidence":"Excitatory- vs inhibitory-neuron-specific conditional KO mice with simultaneous EEG, cardiac, and respiratory recording and respiratory challenge","pmids":["37606181"],"confidence":"High","gaps":["Brainstem circuit mediating apnea not mapped","Why excitatory but not inhibitory loss is fatal not fully explained"]},{"year":2024,"claim":"Revealed a ferroptosis-protective role in immune cells and confirmed human-organoid disease modeling, expanding the mTORC1-downstream consequences of DEPDC5 loss.","evidence":"T cell-specific KO mice with ROS/xanthine oxidase/ATF4 readouts and tumor immunity assays; human cortical organoids with two-hit inactivation, single-cell transcriptomics, electrophysiology, and rapamycin rescue","pmids":["38763950","41789478"],"confidence":"High","gaps":["ATF4/xanthine oxidase axis not tested in neurons","Notch/Wnt transcriptional changes not mechanistically connected to mTORC1"]},{"year":2024,"claim":"Identified chaperone-mediated autophagy as a route for DEPDC5 protein turnover, linking metabolic cues (lactate-GPR81) and SNX10 to mTORC1 activation.","evidence":"siRNA/Co-IP, lysosomal recruitment, glycolysis assays, and in vivo metastasis models defining GPR81/CMA and SNX10-DEPDC5 degradation","pmids":["38615493","41487148"],"confidence":"Medium","gaps":["CMA degradation of DEPDC5 not demonstrated in neurons","SNX10-DEPDC5 interaction relies on single-lab Co-IP"]},{"year":2025,"claim":"Defined the molecular effector of excitatory synaptic hyperexcitability: mTORC1-dependent USP46 upregulation deubiquitinates GluA1 and redistributes AMPA receptors to the surface.","evidence":"Conditional KO mice with Co-IP interaction network (USP46/WDR48/WDR20), mEPSC, GluA1 ubiquitination, surface biotinylation, and USP46-knockdown/rapamycin rescue","pmids":["40467011"],"confidence":"High","gaps":["Whether DEPDC5-USP46 binding is direct or mTORC1-mediated only partly resolved","WDR48/WDR20 functional role in this pathway untested"]},{"year":2025,"claim":"Separated developmental from postnatal disease mechanisms by showing postnatal focal DEPDC5 loss without lamination defects is sufficient for FCD pathology and seizures.","evidence":"AAV-Cre postnatal conditional KO mice with FCD-marker immunohistochemistry and seizure assays","pmids":["40996830"],"confidence":"High","gaps":["Critical postnatal time window not bounded","Reversibility after lesion establishment untested"]},{"year":2026,"claim":"Identified a downstream effector contributing to seizures, with ectopic SLC6A5/GlyT2 overexpression in excitatory neurons whose co-deletion mitigates seizures.","evidence":"CRISPR in utero electroporation double Depdc5/Slc6a5 KO with seizure monitoring and rat/human expression profiling","pmids":["41587632"],"confidence":"Medium","gaps":["Mechanism linking mTORC1 to Slc6a5 induction unknown","Single-lab functional rescue, mechanism not fully elucidated"]},{"year":null,"claim":"How DEPDC5/GATOR1 biochemically relays amino acid status to the Rag GTPases to control mTOR lysosomal localization, and how this is integrated with phosphorylation and CMA-mediated turnover across cell types, remains to be mechanistically unified.","evidence":"Not yet established in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of DEPDC5 within GATOR1 in the corpus","Direct enzymatic activity toward Rag GTPases not demonstrated","Cross-tissue regulation of DEPDC5 protein stability not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,11,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[21,7]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[18,11,33]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[17,28,23]}],"complexes":["GATOR1"],"partners":["NPRL2","NPRL3","USP46","WDR48","WDR20","SNX10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75140","full_name":"GATOR1 complex protein DEPDC5","aliases":["DEP domain-containing protein 5"],"length_aa":1603,"mass_kda":181.3,"function":"As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway (PubMed:23723238, PubMed:25457612, PubMed:29590090, PubMed:29769719, PubMed:31548394, PubMed:35338845). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling (PubMed:23723238, PubMed:25457612, PubMed:29590090, PubMed:29769719, PubMed:35338845). In the presence of abundant amino acids, the GATOR1 complex is negatively regulated by GATOR2, the other GATOR subcomplex, in this amino acid-sensing branch of the TORC1 pathway (PubMed:23723238, PubMed:25457612, PubMed:29769719). Within the GATOR1 complex, DEPDC5 mediates direct interaction with the nucleotide-binding pocket of small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) and coordinates their nucleotide loading states by promoting RagA/RRAGA or RagB/RRAGB into their GDP-binding state and RagC/RRAGC or RagD/RRAGD into their GTP-binding state (PubMed:29590090, PubMed:35338845). However, it does not execute the GAP activity, which is mediated by NPRL2 (PubMed:29590090)","subcellular_location":"Lysosome membrane; Cytoplasm, cytosol; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/O75140/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DEPDC5","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DEPDC5","total_profiled":1310},"omim":[{"mim_id":"620504","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 111; DEE111","url":"https://www.omim.org/entry/620504"},{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"618020","title":"KELCH-LIKE 22; KLHL22","url":"https://www.omim.org/entry/618020"},{"mim_id":"617418","title":"WD REPEAT-CONTAINING PROTEIN 59; WDR59","url":"https://www.omim.org/entry/617418"},{"mim_id":"616512","title":"RING FINGER PROTEIN 152; RNF152","url":"https://www.omim.org/entry/616512"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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the protein shares homology with G protein signaling molecules and localizes in human neurons, suggesting a role in neuronal signal transduction.\",\n      \"method\": \"Exome sequencing of affected families; localization by immunostaining in human neurons\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization in neurons reported but without detailed functional follow-up; replicated across two simultaneous papers\",\n      \"pmids\": [\"23542697\", \"23542701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPDC5 is a component of the GATOR1 complex and functions as a negative regulator of mTORC1 in the amino acid-sensing branch; variants disrupt DEPDC5-dependent inhibition of mTORC1 and GATOR1 complex formation.\",\n      \"method\": \"Functional assays of TORC1 signaling in cells transfected with epilepsy-associated DEPDC5 variants; assessment of GATOR1 complex formation\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay of mTORC1 inhibition and complex assembly tested for multiple variants in cell-based system; single lab but multiple variants and two orthogonal readouts\",\n      \"pmids\": [\"25366275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPDC5 negatively regulates the mTOR pathway; loss-of-function mutations are associated with mTOR pathway hyperactivation (mTORopathy), and clinicoradiological phenotypes overlap with tuberous sclerosis.\",\n      \"method\": \"Genetic mutation analysis combined with mTOR pathway activation markers in patient tissue\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement via patient tissue analysis; replicated across multiple papers\",\n      \"pmids\": [\"24585383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Germline, germline mosaic, and brain somatic DEPDC5 mutations can cause focal cortical dysplasia, with a 'two-hit' mutational model (similar to other mTORopathies) proposed for cortical lesion formation; mTOR activation confirmed by immunostaining of resected brain tissue.\",\n      \"method\": \"Sequencing of blood and brain DNA from patients; histopathological analysis; mTOR activation markers in brain tissue\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent methods (DNA sequencing + tissue immunostaining); single lab but replicated in subsequent studies\",\n      \"pmids\": [\"25623524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Germline nonsense DEPDC5 mutation (p.Arg555*) causes extensive focal cortical dysplasia IIa with mTOR activation confirmed by immunostaining of resected brain tissue; the DEP domain is critical for DEPDC5 function.\",\n      \"method\": \"Whole-exome sequencing; immunostaining of resected brain tissue for mTOR activation markers\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct tissue-level mTOR activation measurement + genetic identification; single case series\",\n      \"pmids\": [\"26000329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Homozygous Depdc5 knockout rat embryos die from embryonic day 14.5 with global growth delay and constitutive mTORC1 hyperactivation in brain and fibroblasts (measured by enhanced phosphorylation of S6K1 and rpS6); prenatal rapamycin treatment rescues the lethal phenotype. Heterozygous rats show cortical cytomegalic neurons and balloon-like cells with phosphorylated rpS6, abolished by prenatal rapamycin.\",\n      \"method\": \"TALEN-generated knockout rat; phosphorylation assays for S6K1/rpS6; rapamycin rescue experiment; neuropathological analysis\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vivo genetic KO with biochemical readout, pharmacological rescue, and neuropathology; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26873552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Neuron-specific Depdc5 conditional knockout mice (Synapsin1-Cre) develop mTORC1 hyperactivation exclusively in neurons (increased phospho-S6), dysplastic and ectopic neurons, reactive astrogliosis, and seizure susceptibility; rapamycin inhibition rescues mTORC1 activity and partially rescues phenotype.\",\n      \"method\": \"Conditional KO mouse (Cre-lox); phospho-S6 immunostaining; EEG recording; chemoconvulsant seizure threshold assays; rapamycin treatment\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype, biochemical readout, and pharmacological rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29274432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRISPR-generated germline Depdc5 knockout mouse embryos show mTORC1 hyperactivity in brain and in fibroblasts/neurospheres under nutrient-deprived conditions, supporting DEPDC5 as a negative regulator of mTORC1 that is particularly important during amino acid insufficiency.\",\n      \"method\": \"CRISPR mutagenesis mouse model; mTORC1 activity assays in fibroblasts and neurospheres under nutrient deprivation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vivo genetic KO with in vitro biochemical validation under nutrient deprivation; single lab, multiple cell types tested\",\n      \"pmids\": [\"28974734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biallelic two-hit (germline + brain somatic) DEPDC5 mutations cause focal cortical dysplasia with focal epilepsy; somatic second-hit mutation load is higher in seizure-onset zone than surrounding epileptogenic zone. CRISPR-Cas9 + in utero electroporation mosaic Depdc5 inactivation in mice recapitulates focal epilepsy with FCD and SUDEP-like events. Depdc5 inactivation shapes dendrite and spine morphology of excitatory neurons.\",\n      \"method\": \"Deep sequencing of postoperative human tissue; CRISPR-Cas9 + in utero electroporation mouse model; morphological analysis of dendrites and spines\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — human tissue sequencing + in vivo CRISPR mouse model; multiple orthogonal methods; independently supported by other studies\",\n      \"pmids\": [\"29708508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DEPDC5 knockdown in zebrafish causes mTOR-dependent motor hyperactivity and neuronal hyperexcitability; rescue by WT human DEPDC5 but not by epilepsy-associated mutants (p.Arg487* and p.Arg485Gln) confirms loss-of-function mechanism; rapamycin treatment rescues phenotype.\",\n      \"method\": \"Zebrafish Depdc5 knockdown model; behavioral assays; overexpression of WT and mutant DEPDC5; rapamycin treatment\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo vertebrate model with WT rescue, mutant non-rescue, and pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"29761115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Somatic focal Depdc5 deletion via CRISPR + in utero electroporation in rat brain produces spontaneous seizures with electroclinical features of focal cortical dysplasia type IIA, establishing a causal link between somatic DEPDC5 loss and FCD-related epilepsy.\",\n      \"method\": \"In utero electroporation with CRISPR gene deletion in rat; EEG recording; histopathological analysis\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo somatic KO model with defined electroclinical phenotype; single lab but rigorous animal model\",\n      \"pmids\": [\"30080265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DEPDC5 knockdown in neural progenitor cells and neurons causes mTORC1 (but not mTORC2) hyperactivation, soma enlargement, increased filopodia, and inappropriate localization of mTOR at the lysosome during amino acid starvation; these effects are reversed by rapamycin.\",\n      \"method\": \"shRNA knockdown in neuroblastoma cells and mouse neural progenitor cells; mTOR subcellular localization by confocal imaging; rapamycin rescue\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization experiment tied to functional consequence; multiple cell types; pharmacological rescue\",\n      \"pmids\": [\"29481864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DEPDC5 maintains HIV-1 latency by suppressing the mTORC1 pathway through RagA (distinct from TSC1 which acts via Rheb); knockout of DEPDC5 leads to enhanced HIV-1 reactivation antagonized by rapamycin.\",\n      \"method\": \"Genome-wide CRISPR screening; DEPDC5 KO in T-cell and monocyte latency models; rapamycin antagonism assay\",\n      \"journal\": \"Emerging microbes & infections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional CRISPR KO in two cell line models with mechanistic pathway dissection; single lab\",\n      \"pmids\": [\"30087333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DEPDC5 is phosphorylated by Pim1 and AKT kinases; phosphorylation of DEPDC5 releases inhibition of mTORC1. A phospho-mimic S1530E DEPDC5 confers resistance to Pim and AKT inhibitors in tumor cells in vitro and in vivo.\",\n      \"method\": \"Phospho-specific antibodies; transfection of phospho-inactive DEPDC5 mutants; kinase assays; knock-in phospho-mimic glutamic acid substitution; in vivo tumor experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phospho-specific antibodies + mutagenesis + in vivo knock-in; multiple orthogonal methods in single study\",\n      \"pmids\": [\"31548394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DEPDC5 inactivation mutations in GISTs promote tumor growth via the mTORC1 signaling pathway, leading to cell-cycle arrest when DEPDC5 is present; DEPDC5 loss reduces cell proliferation and modulates sensitivity to KIT inhibitors.\",\n      \"method\": \"Whole exome sequencing; in vitro and nude mouse in vivo DEPDC5 inactivation experiments; mTORC1 pathway assays; cell proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro and in vivo validation of DEPDC5 loss with mTORC1 readout; multiple methods\",\n      \"pmids\": [\"31636198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Neuronal Depdc5 knockout (Depdc5cc+) mice exhibit mTORC1 hyperactivation, hyperactivity, enlarged brain and neuronal soma, and rare seizures; rapamycin treatment prolongs survival, partially rescues hyperactivity, and reduces brain/neuronal size by suppressing downstream mTORC1 (phospho-S6) but not GATOR1 protein levels. Loss of Depdc5 leads to decreased levels of other GATOR1 proteins NPRL2 and NPRL3.\",\n      \"method\": \"Conditional KO mouse; video-EEG monitoring; open-field and elevated-plus maze testing; rapamycin treatment; Western blot for NPRL2, NPRL3, phospho-S6\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with behavioral, EEG, biochemical phenotyping; pharmacological rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31174205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Second-hit DEPDC5 somatic mutation is limited to dysmorphic neurons in focal cortical dysplasia type IIA, and the somatic mutation load correlates with dysmorphic neuron density and the epileptogenic zone.\",\n      \"method\": \"Deep sequencing of surgical tissue; correlation of variant allele frequency with cell-type-specific histopathology\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular measurement in identified cell types; single lab, single case\",\n      \"pmids\": [\"31353856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Acute Depdc5 knockdown (~80%) in cortical neurons causes dose-dependent mTOR hyperactivation, soma enlargement, increased dendritic arborization, increased excitatory (but not inhibitory) synaptic transmission, and increased intrinsic excitability; the synaptic phenotype is driven specifically by excitatory synapses, with increased mEPSC frequency/amplitude, excitatory synapse density, and glutamate receptor expression.\",\n      \"method\": \"RNA interference in primary cortical cultures; mEPSC recording; synapse density analysis; glutamate receptor expression; comparison with heterozygous Depdc5+/- neurons\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiology + molecular characterization of synaptic mechanism; dose-response established; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32113911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Depdc5 KO (but not Tsc2 KO) cells fail to respond to amino acid withdrawal by moving mTOR off the lysosome; Depdc5 KO cells maintain mTOR lysosomal localization and 4E-BP1 phosphorylation even under amino acid-free conditions, whereas Tsc2 KO cells show partial reduction under amino acid starvation.\",\n      \"method\": \"CRISPR-edited Neuro2a cells; FRET-biosensor for 4E-BP1 phosphorylation in living cells; confocal imaging of mTOR lysosomal localization\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — live-cell FRET biosensor + confocal localization; direct mechanistic comparison of two KO genotypes; single lab\",\n      \"pmids\": [\"32781001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DEPDC5 haploinsufficiency in human iPSC-derived cortical neurons causes increased phosphorylation of ribosomal protein S6, increased iPSC proliferation rate, and enlarged soma in neurons; rapamycin rescues soma size, demonstrating mTORC1 haploinsufficiency in human cells.\",\n      \"method\": \"Patient iPSC-derived cortical neurons; phospho-S6 Western blot; soma size measurement; rapamycin rescue\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC model with pharmacological rescue; single lab; limited to heterozygous haploinsufficiency\",\n      \"pmids\": [\"32574724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatocyte-specific Depdc5 knockout activates mTORC1 constitutively; in ethanol-fed Depdc5-LKO mice, severe hepatic steatosis and inflammation develop via suppression of PPARα (master regulator of fatty acid oxidation); fenofibrate (PPARα agonist) reverses the steatosis, linking DEPDC5-mTORC1 to PPARα-mediated fatty acid oxidation.\",\n      \"method\": \"Hepatocyte-specific conditional KO mouse; Torin1 and fenofibrate pharmacological intervention; mTORC1 and PPARα pathway assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular mechanism (mTORC1→PPARα suppression) and two pharmacological rescues; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"34267188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Brain mTORC1 signaling is reduced after acute fasting; neuronal mTORC1 integrates GATOR1 (amino acid sensing via DEPDC5) and TSC (growth factor sensing). Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine in a DEPDC5-dependent manner. Depdc5 neuronal-specific KO mice are resistant to changes in brain amino acid levels after fasting and do not benefit from fasting-induced seizure protection.\",\n      \"method\": \"Neuronal-specific Depdc5 KO mice; metabolomic analysis of brain amino acids; seizure susceptibility assays with fasting; comparison with amino acid withdrawal\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with metabolomics and functional seizure assay; mechanistic dissection of amino acid sensing specificity; single lab but multiple methods\",\n      \"pmids\": [\"36044864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Long before seizure onset in a mouse model of DEPDC5-related epilepsy with cortical dysplasia (dorsal progenitor-specific Depdc5 deletion), microglia inflammation and proteolytic enzyme activity degrade perineuronal nets (PNNs) in malformed cortex, resulting in parvalbumin interneuron loss and impaired presynaptic inhibition.\",\n      \"method\": \"Forebrain dorsal progenitor-specific conditional KO mouse; immunostaining for PNNs, PV+ interneurons, microglia markers; electrophysiology of inhibitory synapses\",\n      \"journal\": \"Developmental neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — non-cell-autonomous interneuron loss mechanism identified with direct histological and functional readouts; single lab, single study\",\n      \"pmids\": [\"35580549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Depdc5 deletion in excitatory (but not inhibitory) cortical neurons causes frequent generalized tonic-clonic seizures and SUDEP; SUDEP is preceded by ictal apnea and respiratory dysregulation rather than cardiac arrhythmia, with EEG suppression at ictal offset and loss of theta activity only in fatal seizures.\",\n      \"method\": \"Neuron subtype-specific conditional KO mice (excitatory vs inhibitory); EEG, cardiac, and respiratory recording; respiratory challenge assays\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with simultaneous multi-modal physiological recording; mechanistic dissection of SUDEP mechanism; single lab but rigorous experimental design\",\n      \"pmids\": [\"37606181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cardiac investigations in DEPDC5/NPRL2/NPRL3 patients and novel Depdc5 mouse strains reveal no structural or functional cardiac damage; HA-tagged Depdc5 mouse shows Depdc5 expression in brain, heart, and lungs; simultaneous EEG-ECG in Depdc5c/- mice shows seizure-induced SUDEP-like events are not preceded by cardiac arrhythmia.\",\n      \"method\": \"HA-tagged Depdc5 knock-in mouse; neuron-specific second-allele deletion mouse; simultaneous EEG-ECG recording; human cardiac investigations (Holter, Echo, ECG); autopsy\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multi-modal approach in both mouse and human; negative cardiac finding rigorously established; HA-tagging confirmed tissue-level expression\",\n      \"pmids\": [\"34693554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DEPDC5 deficiency in CD8+ T cells causes hyper-mTORC1-induced ATF4 expression, leading to elevated xanthine oxidase and lipid ROS production, spontaneous ferroptosis, and reduced peripheral CD8+ T cell numbers; T cell-specific Depdc5 KO mice confirm impaired anti-tumor immunity.\",\n      \"method\": \"T cell-specific Depdc5 conditional KO mouse; ROS measurement; xanthine oxidase assay; ATF4 expression analysis; tumor immunity assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular cascade (mTORC1→ATF4→xanthine oxidase/lipid ROS→ferroptosis); multiple biochemical readouts; single lab\",\n      \"pmids\": [\"38763950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic inactivation of DEPDC5 in mosaic human cortical organoids (two-hit model) increases mTOR activity rescued by rapamycin, produces dysmorphic-like neurons and enhanced neuronal excitability, disrupts neuronal differentiation, and alters expression of Notch/Wnt signaling pathway genes and synaptic/epilepsy-associated genes.\",\n      \"method\": \"Patient-derived human cortical organoids with CRISPR-based two-hit DEPDC5 inactivation; single-cell transcriptomics; mTOR activity assays; electrophysiology; rapamycin rescue\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — human organoid model with single-cell transcriptomics + electrophysiology + pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"41789478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic inactivation of Depdc5 in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability with other mTORC1 repressor gene knockouts, but different changes in excitatory synaptic transmission compared to Tsc1 or Pten loss, indicating gene-specific synaptic mechanisms.\",\n      \"method\": \"In utero electroporation-based biallelic inactivation; electrophysiology; morphological analysis; comparison across mTORC1 pathway genes\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo comparison across multiple mTOR pathway genes with electrophysiology; single lab\",\n      \"pmids\": [\"38411613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DEPDC5 interacts with USP46 (ubiquitin-specific protease that regulates GluA1), WDR48, and WDR20 as binding partners. In Depdc5 cKO neurons, loss of DEPDC5 leads to mTORC1-dependent USP46 upregulation, decreased ubiquitination of GluA1, and surface redistribution of GluA1-containing AMPA receptors, increasing excitatory quantal size. USP46 knockdown or rapamycin rescues the increased glutamate quantal size and USP46 elevation.\",\n      \"method\": \"Conditional KO mouse; co-immunoprecipitation/protein interaction network; electrophysiology (mEPSC); GluA1 ubiquitination assay; surface biotinylation; USP46 knockdown; rapamycin rescue\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal IP for binding partners + electrophysiology + ubiquitination assay + two independent rescue strategies; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40467011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Postnatal focal cortical DEPDC5 loss (AAV-Cre injection in postnatal day 0-1 mice) without disruption to cortical lamination is sufficient to cause mTOR hyperactivation, FCD pathological hallmarks (SMI-311 neurofilament staining, hypomyelination, astrogliosis, microglial activation), lower seizure thresholds, increased focal seizures, and seizure-induced death.\",\n      \"method\": \"AAV-Cre postnatal conditional KO mouse; immunohistochemistry for FCD markers; seizure threshold assays; seizure monitoring\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — postnatal focal KO separating developmental from postnatal mechanisms; multiple histological and functional readouts; single lab\",\n      \"pmids\": [\"40996830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DEPDC5 knockout in hepatocellular carcinoma cells causes resistance to leucine starvation; DEPDC5-KO reduces LC3-II and accumulates p62, inducing ROS tolerance. DEPDC5 overexpression suppresses cell proliferation and tumorigenicity in immunocompromised mice and triggers p62 degradation with increased ROS susceptibility.\",\n      \"method\": \"CRISPR/Cas9 DEPDC5 KO in HCC cells; overexpression in immunocompromised mice; autophagy markers (LC3-II, p62); ROS measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo; multiple molecular readouts; single lab\",\n      \"pmids\": [\"29311600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DEPDC5 downregulation in hepatic stellate cells (LX-2) increases β-catenin expression and production of MMP2 (matrix metallopeptidase 2), a secreted enzyme involved in fibrosis progression, linking DEPDC5 to the β-catenin pathway in liver fibrosis.\",\n      \"method\": \"In vitro DEPDC5 downregulation in LX-2 cells; β-catenin and MMP2 expression assays\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro experiment in cell line; single lab; limited mechanistic depth\",\n      \"pmids\": [\"26517016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPR81 activation by lactate promotes chaperone-mediated autophagy (CMA)-mediated degradation of DEPDC5 protein, activating mTOR signaling and promoting EMT/metastasis in colorectal cancer; gentisic acid inhibits GPR81 and blocks DEPDC5 degradation.\",\n      \"method\": \"siRNA knockdown; Western blotting; immunofluorescence; in vivo lung metastasis mouse model; CMA pathway analysis\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments linking GPR81→CMA→DEPDC5 degradation→mTOR; single lab; mechanistic pathway established\",\n      \"pmids\": [\"38615493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 interacts directly with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation; SNX10 knockdown accelerates DEPDC5 degradation, activates mTORC1, and elevates glycolysis; α-hederin binds the SNX10-DEPDC5 complex and impairs the SNX10-DEPDC5 interaction to inhibit CMA-mediated DEPDC5 degradation.\",\n      \"method\": \"Co-immunoprecipitation (SNX10-DEPDC5 interaction); lysosomal recruitment assay; siRNA knockdown; Western blotting; glycolysis measurement\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct Co-IP of interaction + functional assays of degradation and downstream signaling; single lab\",\n      \"pmids\": [\"41487148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In excitatory neurons of the malformed cortex of a DEPDC5-related epilepsy rat model and human patient tissue, Slc6a5 (glycine transporter GlyT2) is ectopically overexpressed. Simultaneous CRISPR KO of Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration.\",\n      \"method\": \"CRISPR in utero electroporation for simultaneous Depdc5/Slc6a5 KO; seizure monitoring; expression profiling in rat and human tissue\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional rescue by double KO establishes SLC6A5 as downstream effector; single lab, mechanism not fully elucidated per abstract\",\n      \"pmids\": [\"41587632\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DEPDC5 is a component of the GATOR1 complex (with NPRL2 and NPRL3) that functions as a negative regulator of mTORC1 in the amino acid-sensing branch; it prevents constitutive mTOR lysosomal localization and activation under amino acid-poor conditions, and its loss causes mTORC1 hyperactivation leading to neuronal soma enlargement, dysplastic morphology, increased excitatory synaptic strength (via mTORC1→USP46→GluA1 deubiquitination and surface redistribution), dendritic/spine abnormalities, and cortical hyperexcitability; DEPDC5 phosphorylation by Pim1/AKT kinases releases its mTORC1 inhibition, while chaperone-mediated autophagy via SNX10 or GPR81/CMA can degrade DEPDC5 protein; in excitatory neurons it also protects against ferroptosis by limiting mTORC1-induced ATF4/xanthine oxidase/lipid ROS, and biallelic loss-of-function (germline plus somatic second-hit) in cortical progenitors causes focal cortical dysplasia with drug-resistant epilepsy and SUDEP risk predominantly driven by ictal apnea.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DEPDC5 is a component of the GATOR1 complex (with NPRL2 and NPRL3) that acts as a negative regulator of mTORC1 within the amino acid-sensing branch of the pathway [#1, #15]. Mechanistically, DEPDC5 prevents constitutive mTOR retention at the lysosome under amino acid-poor conditions; its loss leaves mTOR lysosomally localized and signaling active even during amino acid withdrawal, distinguishing it from TSC2-dependent growth-factor sensing [#18, #11]. Loss-of-function causes cell-autonomous mTORC1 (but not mTORC2) hyperactivation, neuronal soma enlargement, dysplastic and ectopic neurons, increased dendritic arborization, and a selective increase in excitatory synaptic transmission and intrinsic excitability [#11, #17, #6]; the excitatory synaptic phenotype is driven by an mTORC1-dependent rise in USP46, which deubiquitinates GluA1 and redistributes AMPA receptors to the neuronal surface, an effect reversed by USP46 knockdown or rapamycin [#28]. In neurons, DEPDC5 integrates amino acid availability (leucine, arginine, glutamine) into mTORC1 tone and mediates fasting-induced seizure protection [#21]. DEPDC5 inhibition of mTORC1 is released by Pim1/AKT phosphorylation [#13], and DEPDC5 protein is degraded through chaperone-mediated autophagy via SNX10 or lactate-GPR81 signaling [#33, #32]. Germline loss-of-function combined with a brain somatic second hit ('two-hit' model) in cortical progenitors causes focal cortical dysplasia with drug-resistant focal epilepsy [#3, #8, #16], and excitatory-neuron-restricted loss drives generalized seizures and SUDEP that is preceded by ictal apnea rather than cardiac arrhythmia [#23, #24]. Beyond the nervous system, DEPDC5 restrains mTORC1 in hepatocytes (via PPARα-regulated fatty acid oxidation), in CD8+ T cells (limiting ATF4-driven xanthine oxidase/lipid ROS and ferroptosis), and in tumor cells where its loss alters proliferation and drug sensitivity [#20, #25, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established DEPDC5 as a disease gene before its molecular function was known, linking it to a neuronal signaling role through familial epilepsy genetics.\",\n      \"evidence\": \"Exome sequencing of affected families with immunostaining in human neurons\",\n      \"pmids\": [\"23542697\", \"23542701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular pathway assigned at this stage\", \"Homology-based inference of G-protein signaling role not biochemically tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved DEPDC5's molecular identity by placing it in the GATOR1 complex as a negative regulator of mTORC1, explaining how epilepsy variants act mechanistically.\",\n      \"evidence\": \"Cell-based mTORC1 signaling assays and GATOR1 complex-formation assessment with epilepsy variants; patient-tissue mTOR activation markers\",\n      \"pmids\": [\"25366275\", \"24585383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the amino acid sensing step DEPDC5 controls\", \"Subcellular mechanism of mTORC1 inhibition unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated the two-hit mutational model for cortical lesion formation, connecting germline plus brain somatic DEPDC5 loss to focal cortical dysplasia with confirmed mTOR activation.\",\n      \"evidence\": \"Blood and brain DNA sequencing, histopathology, and mTOR activation immunostaining of resected tissue\",\n      \"pmids\": [\"25623524\", \"26000329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of somatic second hit not yet shown experimentally\", \"DEP domain functional requirement inferred, not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided in vivo proof that DEPDC5 loss causes constitutive mTORC1 hyperactivation and that the phenotype is rapamycin-reversible, establishing the mTORopathy mechanism organismally.\",\n      \"evidence\": \"TALEN knockout rat with S6K1/rpS6 phosphorylation assays, prenatal rapamycin rescue, and neuropathology\",\n      \"pmids\": [\"26873552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Embryonic lethality limited adult/neuronal analysis\", \"Cell-autonomous vs systemic contributions not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed DEPDC5's mTORC1 repression is most critical during amino acid insufficiency and acts specifically in neurons to produce dysplasia and seizure susceptibility.\",\n      \"evidence\": \"Conditional (Synapsin1-Cre) and CRISPR germline knockout mice with phospho-S6, EEG, seizure threshold assays under nutrient deprivation; rapamycin rescue\",\n      \"pmids\": [\"29274432\", \"28974734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic-level mechanism not yet defined\", \"Amino acid specificity not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Causally linked somatic DEPDC5 loss to FCD-related epilepsy via in vivo mosaic models and established the cellular and morphological consequences of inactivation.\",\n      \"evidence\": \"Human tissue deep sequencing plus CRISPR-Cas9/in utero electroporation mosaic inactivation in mouse and rat; zebrafish loss-of-function with WT-but-not-mutant rescue; dendrite/spine morphology\",\n      \"pmids\": [\"29708508\", \"30080265\", \"29761115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular driver of synaptic hyperexcitability not yet identified\", \"SUDEP mechanism not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the subcellular mechanism: DEPDC5 loss locks mTOR at the lysosome and selectively hyperactivates mTORC1, producing soma enlargement and membrane process changes.\",\n      \"evidence\": \"shRNA knockdown in neuroblastoma and neural progenitor cells with confocal mTOR localization and rapamycin rescue\",\n      \"pmids\": [\"29481864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical interaction with Rag GTPases not shown here\", \"Effect on inhibitory neurons untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended DEPDC5-mTORC1 control beyond neurons to HIV-1 latency and hepatocellular carcinoma, broadening its role as a general mTORC1 restraint with metabolic/autophagic consequences.\",\n      \"evidence\": \"Genome-wide CRISPR screens and KO/overexpression in T-cell, monocyte, and HCC models with autophagy/ROS readouts and rapamycin antagonism\",\n      \"pmids\": [\"30087333\", \"29311600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RagA-specific mechanism vs TSC1/Rheb branch only partially dissected\", \"Physiological relevance outside cell lines uncertain\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an upstream regulatory input: Pim1/AKT phosphorylation of DEPDC5 releases its mTORC1 inhibition, providing a signaling node exploitable in tumor drug resistance.\",\n      \"evidence\": \"Phospho-specific antibodies, phospho-inactive and phospho-mimic (S1530E) mutants, kinase assays, and in vivo tumor experiments\",\n      \"pmids\": [\"31548394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance of phosphorylation in neurons not tested\", \"Structural basis of phospho-regulation unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed DEPDC5 loss destabilizes the GATOR1 complex (reduced NPRL2/NPRL3) and that downstream mTORC1, not GATOR1 levels, drives the rapamycin-rescuable phenotype.\",\n      \"evidence\": \"Conditional KO mice with video-EEG, behavior, and Western blot for NPRL2/NPRL3/phospho-S6; GIST tumor functional studies\",\n      \"pmids\": [\"31174205\", \"31636198\", \"31353856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of GATOR1 partner destabilization unresolved\", \"Link between morphology and seizures incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the synaptic and human-cell mechanisms: DEPDC5 loss selectively augments excitatory transmission and recapitulates mTORC1 haploinsufficiency in human iPSC neurons.\",\n      \"evidence\": \"RNAi in primary cortical cultures with mEPSC recordings and glutamate receptor analysis; patient iPSC-derived neurons with phospho-S6 and rapamycin rescue; CRISPR Neuro2a cells with FRET 4E-BP1 biosensor and mTOR localization\",\n      \"pmids\": [\"32113911\", \"32574724\", \"32781001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from mTORC1 to glutamate receptors not yet established\", \"Distinction from TSC2 mechanism mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized DEPDC5-mTORC1 to peripheral metabolism, showing hepatocyte loss drives steatosis via PPARα suppression, and rigorously excluded a cardiac basis for SUDEP.\",\n      \"evidence\": \"Hepatocyte-specific KO with Torin1/fenofibrate intervention; HA-tagged Depdc5 knock-in showing brain/heart/lung expression and simultaneous EEG-ECG with human cardiac investigations\",\n      \"pmids\": [\"34267188\", \"34693554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific determinants of mTORC1 output not defined\", \"Non-cardiac SUDEP trigger not yet identified at this stage\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established DEPDC5 as the neuronal sensor of specific amino acids that underlies fasting-induced seizure protection, and revealed a non-cell-autonomous interneuron/PNN degradation route to hyperexcitability.\",\n      \"evidence\": \"Neuronal KO mice with brain amino acid metabolomics and fasting seizure assays; dorsal progenitor KO with PNN/PV+/microglia immunostaining and inhibitory synapse electrophysiology\",\n      \"pmids\": [\"36044864\", \"35580549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling microglia activation to PNN degradation not fully defined\", \"Relative contribution of excitatory vs inhibitory deficits unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Pinpointed the SUDEP mechanism to excitatory-neuron-driven seizures producing ictal apnea and respiratory dysregulation rather than cardiac arrhythmia.\",\n      \"evidence\": \"Excitatory- vs inhibitory-neuron-specific conditional KO mice with simultaneous EEG, cardiac, and respiratory recording and respiratory challenge\",\n      \"pmids\": [\"37606181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brainstem circuit mediating apnea not mapped\", \"Why excitatory but not inhibitory loss is fatal not fully explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a ferroptosis-protective role in immune cells and confirmed human-organoid disease modeling, expanding the mTORC1-downstream consequences of DEPDC5 loss.\",\n      \"evidence\": \"T cell-specific KO mice with ROS/xanthine oxidase/ATF4 readouts and tumor immunity assays; human cortical organoids with two-hit inactivation, single-cell transcriptomics, electrophysiology, and rapamycin rescue\",\n      \"pmids\": [\"38763950\", \"41789478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATF4/xanthine oxidase axis not tested in neurons\", \"Notch/Wnt transcriptional changes not mechanistically connected to mTORC1\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified chaperone-mediated autophagy as a route for DEPDC5 protein turnover, linking metabolic cues (lactate-GPR81) and SNX10 to mTORC1 activation.\",\n      \"evidence\": \"siRNA/Co-IP, lysosomal recruitment, glycolysis assays, and in vivo metastasis models defining GPR81/CMA and SNX10-DEPDC5 degradation\",\n      \"pmids\": [\"38615493\", \"41487148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CMA degradation of DEPDC5 not demonstrated in neurons\", \"SNX10-DEPDC5 interaction relies on single-lab Co-IP\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the molecular effector of excitatory synaptic hyperexcitability: mTORC1-dependent USP46 upregulation deubiquitinates GluA1 and redistributes AMPA receptors to the surface.\",\n      \"evidence\": \"Conditional KO mice with Co-IP interaction network (USP46/WDR48/WDR20), mEPSC, GluA1 ubiquitination, surface biotinylation, and USP46-knockdown/rapamycin rescue\",\n      \"pmids\": [\"40467011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DEPDC5-USP46 binding is direct or mTORC1-mediated only partly resolved\", \"WDR48/WDR20 functional role in this pathway untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Separated developmental from postnatal disease mechanisms by showing postnatal focal DEPDC5 loss without lamination defects is sufficient for FCD pathology and seizures.\",\n      \"evidence\": \"AAV-Cre postnatal conditional KO mice with FCD-marker immunohistochemistry and seizure assays\",\n      \"pmids\": [\"40996830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Critical postnatal time window not bounded\", \"Reversibility after lesion establishment untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a downstream effector contributing to seizures, with ectopic SLC6A5/GlyT2 overexpression in excitatory neurons whose co-deletion mitigates seizures.\",\n      \"evidence\": \"CRISPR in utero electroporation double Depdc5/Slc6a5 KO with seizure monitoring and rat/human expression profiling\",\n      \"pmids\": [\"41587632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking mTORC1 to Slc6a5 induction unknown\", \"Single-lab functional rescue, mechanism not fully elucidated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DEPDC5/GATOR1 biochemically relays amino acid status to the Rag GTPases to control mTOR lysosomal localization, and how this is integrated with phosphorylation and CMA-mediated turnover across cell types, remains to be mechanistically unified.\",\n      \"evidence\": \"Not yet established in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of DEPDC5 within GATOR1 in the corpus\", \"Direct enzymatic activity toward Rag GTPases not demonstrated\", \"Cross-tissue regulation of DEPDC5 protein stability not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 11, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [21, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [18, 11, 33]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-165159\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [17, 28, 23]}\n    ],\n    \"complexes\": [\"GATOR1\"],\n    \"partners\": [\"NPRL2\", \"NPRL3\", \"USP46\", \"WDR48\", \"WDR20\", \"SNX10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}