{"gene":"RAB39B","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2002,"finding":"RAB39B was identified as a novel RAB GTPase encoded on the X chromosome (Xq28), expressed in a variety of human tissues, consisting of two exons spanning 3764 bp of genomic DNA, and showing 74.2% amino acid identity with RAB39A.","method":"cDNA library sequencing and genomic analysis","journal":"Cytogenetic and genome research","confidence":"Medium","confidence_rationale":"Tier 3 — original isolation/characterization paper, single lab, foundational characterization","pmids":["12438742"],"is_preprint":false},{"year":2010,"finding":"RAB39B is a neuronal-specific protein localized to the Golgi compartment; its downregulation leads to alterations in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, indicating a role in synapse formation and maintenance.","method":"shRNA-mediated knockdown in cultured neurons, immunofluorescence localization, morphological analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment combined with loss-of-function with defined cellular phenotypes, replicated across labs","pmids":["20159109"],"is_preprint":false},{"year":2014,"finding":"Loss of RAB39B results in dysregulation of α-synuclein homeostasis; shRNA-mediated knockdown of Rab39b in cultured neurons reduced steady-state levels of α-synuclein and the density of α-synuclein immunoreactive puncta in dendritic processes.","method":"shRNA knockdown in cultured neurons, immunofluorescence, western blot","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific molecular readout (α-synuclein levels), replicated in multiple cell models","pmids":["25434005"],"is_preprint":false},{"year":2015,"finding":"GTP-bound RAB39B directly interacts with PICK1 (protein interacting with C-kinase 1) as a downstream effector; the RAB39B–PICK1 complex controls trafficking from the endoplasmic reticulum to the Golgi and surface expression of the GluA2 AMPAR subunit. Downregulation of RAB39B skews AMPAR composition toward non-GluA2-containing Ca2+-permeable forms, altering synaptic activity in hippocampal neurons.","method":"Co-immunoprecipitation, pulldown with GTP-locked RAB39B mutant, shRNA knockdown in hippocampal neurons, electrophysiology, surface biotinylation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP identifying downstream effector, combined with functional knockdown and electrophysiological readout in multiple orthogonal assays","pmids":["25784538"],"is_preprint":false},{"year":2015,"finding":"A missense mutation (p.G192R) in the C-terminal hypervariable domain of RAB39B causes mislocalization of the mutant protein in PC12 and SK-N-BE(2)C cells, suggesting this domain mediates intracellular targeting of RAB39B.","method":"Transfection of wild-type and mutant constructs in cell lines, fluorescence microscopy","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP/localization experiment, single lab","pmids":["26399558"],"is_preprint":false},{"year":2019,"finding":"RAB39B localizes to the secretory network at the endoplasmic reticulum/cis-Golgi interface (distinct from RAB39A which localizes to late endocytic multivesicular bodies), and controls transport of sphingolipids biosynthesized at the ER-Golgi factory.","method":"Fluorescence microscopy, subcellular fractionation, lipid transport assays using fluorescent lipid analogs and Chlamydia trachomatis as a trafficking probe","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional lipid transport readout, multiple orthogonal methods in single lab","pmids":["30987349"],"is_preprint":false},{"year":2020,"finding":"RAB39B interacts with components of Class I PI3K; its deletion activates the PI3K-AKT-mTOR signaling pathway in neural progenitor cells (NPCs), promoting NPC overproliferation and impaired differentiation, leading to macrocephaly and ASD-like behaviors. AKT inhibition rescued enlarged organoid sizes and NPC overproliferation.","method":"Rab39b knockout mice and human cerebral organoids (CRISPR), Co-immunoprecipitation for PI3K interaction, phospho-AKT/mTOR western blot, pharmacological rescue with AKT inhibitor","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 — Co-IP establishing PI3K interaction combined with KO mouse and human organoid models, pathway rescue, multiple orthogonal methods","pmids":["32115408"],"is_preprint":false},{"year":2020,"finding":"RAB39B deficiency impairs autophagic flux at basal level in neurons; Rab39b knockout mice show impaired learning/memory and reduced NMDA receptors in the postsynaptic density. Rapamycin-induced autophagy activation partially rescued impaired memory and synaptic plasticity.","method":"Rab39b knockout mice, behavioral testing, autophagy flux assays (LC3-II accumulation with bafilomycin), synaptic fractionation, western blot for PSD proteins, pharmacological rescue","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype (autophagy, synaptic), pharmacological rescue, multiple orthogonal methods","pmids":["33364235"],"is_preprint":false},{"year":2020,"finding":"RAB39B localizes throughout cortical and hippocampal neurons and TH-positive dopaminergic neurons in the substantia nigra pars compacta in mice throughout postnatal life; it is enriched in MAP2-positive neurons.","method":"In situ hybridization, immunohistochemistry with novel monoclonal antibodies and Rab39b knockout controls, western blot on brain lysates","journal":"Molecular brain","confidence":"High","confidence_rationale":"Tier 2 — direct localization with validated antibodies and KO controls, functional relevance to disease-affected brain regions","pmids":["32228644"],"is_preprint":false},{"year":2020,"finding":"RAB39B co-localizes with beta-amyloid plaques in post-mortem human brain tissue from DLB and AD cases, and is present in a subpopulation of Lewy bodies in DLB. Subcellular fractionation revealed reduced cytoplasmic RAB39B in DLB, indicating sequestration of RAB39B into pathological aggregates impairs its normal vesicular trafficking function.","method":"Immunohistochemistry on tissue microarrays from post-mortem brains, subcellular fractionation, western blot","journal":"Brain pathology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct co-localization in human tissue with biochemical fractionation, but no direct functional rescue experiment","pmids":["32762091"],"is_preprint":false},{"year":2021,"finding":"RAB39B controls GluA2/GluA3 AMPAR trafficking and dendritic spine refinement; loss of RAB39B in knockout mice results in increased Ca2+-permeable AMPAR composition, hypermobile immature spines, and cognitive/behavioral alterations. The Ca2+-permeable AMPAR antagonist NASPM restored spine hypermobility.","method":"Rab39b knockout mice, two-photon live imaging of spine dynamics, electrophysiology, NASPM pharmacological rescue, behavioral testing","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1–2 — KO mouse with live imaging and electrophysiology, pharmacological rescue confirming mechanism, multiple orthogonal methods","pmids":["34035473"],"is_preprint":false},{"year":2023,"finding":"RAB39B deficiency impairs macroautophagy (reducing Atg3, Atg5, Atg7, Atg12, Atg16L1), which leads to accumulation of α-synuclein in the ER and mitochondria of SH-SY5Y dopaminergic cells, activating ER stress pro-apoptotic cascades, mitochondrial dysfunction, and oxidative stress. PD-associated mutant RAB39B (T168K, W186X, G192R) failed to prevent these effects.","method":"shRNA knockdown and mutant overexpression in SH-SY5Y cells, western blot for autophagy markers and α-synuclein, mitochondrial membrane potential assay, ER stress markers, apoptosis assays","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function and mutant rescue in cell model with multiple molecular pathway readouts, single lab","pmids":["36715921"],"is_preprint":false},{"year":2022,"finding":"A RAB39B nonstop mutation causes protein instability and increased degradation. In a Rab39b knockdown mouse model, downregulation of RAB39B increases Ca2+-permeable (GluA2-lacking) AMPAR composition at hippocampal neuronal surfaces and increases dendritic spine density in an immature filopodia-like state, affecting social behavior and memory.","method":"Heterologous cell expression of nonstop mutant, western blot for protein stability, Rab39b KD mouse model, surface biotinylation of AMPARs, Golgi staining for spine morphology, behavioral testing","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — protein stability assay with mutant, KD mouse with AMPAR trafficking and spine morphology readouts, multiple orthogonal methods","pmids":["34761259"],"is_preprint":false},{"year":2023,"finding":"Neuronal overexpression of RAB39B decreases dendritic arborization of primary neurons in vitro, reduces synaptic transmission, impairs recognition and working memory, and alters autophagy in mice, demonstrating that both loss and gain of RAB39B function are detrimental to neuronal development.","method":"AAV-mediated overexpression in neonatal mouse brain, primary neuron morphology analysis, electrophysiology, autophagy assays, behavioral testing","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function in vivo with cellular and behavioral phenotypes, single lab","pmids":["36977207"],"is_preprint":false},{"year":2025,"finding":"Rab39b knockout mice develop PD motor impairment, degeneration of substantia nigra dopaminergic neurons, and Lewy bodies. RAB39B deficiency impairs macroautophagy via reduction of autophagy proteins (Atg3, Atg5, Atg7, Atg12, Atg16L1), elevating α-synuclein and activating ER stress apoptotic signaling, mitochondrial dysfunction, microglial activation, NLRP3 inflammasome, and necroptotic pathways. Rapamycin reversed autophagy dysfunction, reduced α-synuclein, and ameliorated motor deficits.","method":"Rab39b knockout mice, western blot for autophagy and apoptosis markers, immunohistochemistry for dopaminergic neurons and α-synuclein, rapamycin pharmacological rescue, behavioral testing","journal":"Life sciences","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO model with multiple molecular pathway readouts and pharmacological rescue, comprehensive mechanistic characterization","pmids":["40473068"],"is_preprint":false}],"current_model":"RAB39B is a neuronal-enriched small GTPase that localizes to the ER/cis-Golgi interface, where in its GTP-bound state it interacts with PICK1 to control GluA2-containing AMPAR trafficking from the ER to the Golgi and to the neuronal surface (determining Ca2+-permeable vs. Ca2+-impermeable AMPAR composition at synapses), and also interacts with PI3K components to suppress PI3K-AKT-mTOR signaling in neural progenitor cells; additionally, RAB39B is required for basal macroautophagic flux to maintain α-synuclein homeostasis in dopaminergic neurons, such that its loss causes autophagy impairment, α-synuclein accumulation, ER stress, mitochondrial dysfunction, and dopaminergic neuron degeneration."},"narrative":{"teleology":[{"year":2002,"claim":"Identification of RAB39B as a novel X-linked RAB GTPase established a new member of the RAB family with unknown neuronal function.","evidence":"cDNA library sequencing and genomic characterization","pmids":["12438742"],"confidence":"Medium","gaps":["no functional data","expression pattern not fully resolved at single-cell level","no effector or interaction partners identified"]},{"year":2010,"claim":"Demonstrating that RAB39B is neuron-specific and localizes to the Golgi, and that its knockdown impairs neurite growth cones and presynaptic button number, established a direct role in synapse formation.","evidence":"shRNA knockdown in cultured neurons with immunofluorescence and morphological analysis","pmids":["20159109"],"confidence":"High","gaps":["effector proteins mediating synaptic effects unknown","no in vivo confirmation","no link to specific cargo"]},{"year":2015,"claim":"Discovery that GTP-bound RAB39B binds PICK1 and that this complex controls ER-to-Golgi trafficking and surface expression of GluA2 AMPARs resolved the molecular mechanism by which RAB39B determines synaptic AMPAR composition and Ca²⁺ permeability.","evidence":"Reciprocal co-immunoprecipitation with GTP-locked mutant, shRNA knockdown in hippocampal neurons, surface biotinylation, electrophysiology","pmids":["25784538"],"confidence":"High","gaps":["structural basis of RAB39B–PICK1 interaction unresolved","whether other RAB39B effectors exist at this trafficking step unknown","GEF and GAP for RAB39B not identified"]},{"year":2014,"claim":"Linking RAB39B loss to dysregulated α-synuclein homeostasis in neurons opened the connection between this trafficking GTPase and Parkinson disease-relevant pathology.","evidence":"shRNA knockdown in cultured neurons with western blot and immunofluorescence for α-synuclein","pmids":["25434005"],"confidence":"High","gaps":["mechanism linking RAB39B to α-synuclein regulation not determined at this stage","no in vivo PD model","directionality of α-synuclein change (reduced vs. accumulated) required reconciliation with later studies"]},{"year":2019,"claim":"Precise localization of RAB39B to the ER/cis-Golgi interface (distinct from RAB39A at late endosomes) and demonstration of its role in sphingolipid transport refined the subcellular site of action.","evidence":"Fluorescence microscopy, subcellular fractionation, fluorescent lipid analog transport assays","pmids":["30987349"],"confidence":"Medium","gaps":["sphingolipid cargo specificity not fully defined","functional relationship between lipid transport and AMPAR trafficking not tested","single-lab observation"]},{"year":2020,"claim":"Identification of RAB39B interaction with class I PI3K and demonstration that its loss activates PI3K–AKT–mTOR signaling, causing NPC overproliferation and macrocephaly rescued by AKT inhibition, revealed a second major signaling axis controlled by RAB39B in neural development.","evidence":"Rab39b knockout mice, human cerebral organoids (CRISPR), co-immunoprecipitation, phospho-AKT/mTOR western blot, pharmacological rescue","pmids":["32115408"],"confidence":"High","gaps":["whether RAB39B directly suppresses PI3K catalytic activity or acts via membrane trafficking not distinguished","relationship between PI3K axis and AMPAR trafficking axis not explored","specific PI3K subunit(s) bound not fully characterized"]},{"year":2020,"claim":"Demonstrating that Rab39b knockout mice have impaired basal autophagic flux with reduced NMDA receptor levels at postsynaptic densities, rescued by rapamycin, established autophagy as a key downstream pathway mediating RAB39B's synaptic effects.","evidence":"Rab39b knockout mice, LC3-II flux assays with bafilomycin, synaptic fractionation, behavioral testing, rapamycin rescue","pmids":["33364235"],"confidence":"High","gaps":["how RAB39B mechanistically promotes autophagy initiation not defined","whether autophagy and AMPAR trafficking phenotypes are causally linked unknown"]},{"year":2021,"claim":"In vivo confirmation that RAB39B loss increases Ca²⁺-permeable AMPAR composition and produces hypermobile immature spines, rescued by NASPM, validated the PICK1–GluA2 trafficking model in intact circuits and linked it to cognitive deficits.","evidence":"Rab39b knockout mice, two-photon live imaging, electrophysiology, NASPM pharmacological rescue, behavioral testing","pmids":["34035473"],"confidence":"High","gaps":["no structural data on RAB39B–PICK1–GluA2 complex","spine maturation mechanism downstream of AMPAR switch not resolved"]},{"year":2023,"claim":"Mechanistic dissection in dopaminergic cells showed that RAB39B deficiency reduces core ATG proteins, causing α-synuclein accumulation in ER and mitochondria with consequent ER stress and mitochondrial dysfunction; PD-associated mutants failed to rescue, linking patient mutations to autophagy failure.","evidence":"shRNA knockdown and mutant overexpression in SH-SY5Y cells, western blot for ATG proteins, ER stress and mitochondrial assays","pmids":["36715921"],"confidence":"Medium","gaps":["single cell-line model","how RAB39B regulates ATG protein levels (transcriptional vs. post-translational) not resolved","no in vivo validation of mutant rescue at this point"]},{"year":2025,"claim":"Full PD modeling in Rab39b knockout mice—demonstrating dopaminergic neuron degeneration, Lewy body formation, microglial activation, NLRP3 inflammasome engagement, and motor deficits all rescued by rapamycin—consolidated the autophagy-α-synuclein axis as the primary mechanism of RAB39B-linked parkinsonism.","evidence":"Rab39b knockout mice, immunohistochemistry, western blot for autophagy/apoptosis/inflammasome markers, rapamycin pharmacological rescue, behavioral testing","pmids":["40473068"],"confidence":"High","gaps":["GEF and GAP for RAB39B remain unidentified","direct molecular step by which RAB39B maintains ATG protein levels still unknown","whether neuroinflammatory cascade is cell-autonomous or involves non-neuronal contributions not fully dissected"]},{"year":null,"claim":"The GEF and GAP regulating RAB39B nucleotide cycling, the structural basis of RAB39B–PICK1 and RAB39B–PI3K interactions, and the direct molecular mechanism by which RAB39B sustains core autophagy protein levels remain unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["no GEF or GAP identified","no crystal or cryo-EM structure of RAB39B or its effector complexes","mechanistic link between ER/Golgi trafficking function and autophagy regulation not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3,5,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,11,14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,10,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,14]}],"complexes":[],"partners":["PICK1","PIK3CA","GRIA2","GRIA3","SNCA"],"other_free_text":[]},"mechanistic_narrative":"RAB39B is a neuron-enriched small GTPase that operates at the endoplasmic reticulum/cis-Golgi interface to regulate vesicular trafficking and macroautophagy, with dosage-sensitive roles in synaptogenesis, synaptic composition, and neuronal survival [PMID:20159109, PMID:25784538, PMID:33364235, PMID:36977207]. In its GTP-bound state, RAB39B binds PICK1 to control ER-to-Golgi trafficking and surface delivery of GluA2-containing AMPARs; its loss shifts synaptic AMPAR composition toward Ca²⁺-permeable (GluA2-lacking) forms, producing immature dendritic spines and cognitive deficits rescued by the Ca²⁺-permeable AMPAR antagonist NASPM [PMID:25784538, PMID:34761259, PMID:34035473]. RAB39B also interacts with class I PI3K components to suppress PI3K–AKT–mTOR signaling in neural progenitor cells, and its deletion causes NPC overproliferation, macrocephaly, and ASD-like phenotypes reversible by AKT inhibition [PMID:32115408]. Loss of RAB39B impairs basal macroautophagy by reducing core ATG proteins (Atg3, Atg5, Atg7, Atg12, Atg16L1), leading to α-synuclein accumulation, ER stress, mitochondrial dysfunction, dopaminergic neuron degeneration, and Parkinson disease-like pathology in knockout mice—phenotypes partially rescued by rapamycin [PMID:36715921, PMID:40473068]."},"prefetch_data":{"uniprot":{"accession":"Q96DA2","full_name":"Ras-related protein Rab-39B","aliases":[],"length_aa":213,"mass_kda":24.6,"function":"The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:27103069). RAB39B is involved in autophagy and may function in autophagosome formation (PubMed:27103069, PubMed:37821429). Binds downstream effector PICK1 to ensure selectively GRIA2 exit from the endoplasmic reticulum to the Golgi and to regulate AMPAR composition at the post-synapses and thus synaptic transmission (By similarity). May regulate the homeostasis of SNCA/alpha-synuclein (By similarity)","subcellular_location":"Cell membrane; Cytoplasmic vesicle membrane; Golgi apparatus; Cytoplasmic vesicle, autophagosome membrane; Autolysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q96DA2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB39B","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":[{"gene":"PIP4P1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAB39B","total_profiled":1310},"omim":[{"mim_id":"619558","title":"RAB39A, MEMBER RAS ONCOGENE FAMILY; RAB39A","url":"https://www.omim.org/entry/619558"},{"mim_id":"617279","title":"DENN DOMAIN-CONTAINING PROTEIN 5B; DENND5B","url":"https://www.omim.org/entry/617279"},{"mim_id":"617278","title":"DENN DOMAIN-CONTAINING PROTEIN 5A; DENND5A","url":"https://www.omim.org/entry/617278"},{"mim_id":"617074","title":"SMITH-MAGENIS SYNDROME CHROMOSOME REGION, CANDIDATE GENE 8; SMCR8","url":"https://www.omim.org/entry/617074"},{"mim_id":"614260","title":"CHROMOSOME 9 OPEN READING FRAME 72; C9ORF72","url":"https://www.omim.org/entry/614260"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":11.2},{"tissue":"retina","ntpm":9.2}],"url":"https://www.proteinatlas.org/search/RAB39B"},"hgnc":{"alias_symbol":[],"prev_symbol":["MRX72","WSN"]},"alphafold":{"accession":"Q96DA2","domains":[{"cath_id":"3.40.50.300","chopping":"6-190","consensus_level":"high","plddt":93.9981,"start":6,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DA2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DA2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DA2-F1-predicted_aligned_error_v6.png","plddt_mean":88.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB39B","jax_strain_url":"https://www.jax.org/strain/search?query=RAB39B"},"sequence":{"accession":"Q96DA2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DA2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DA2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DA2"}},"corpus_meta":[{"pmid":"25434005","id":"PMC_25434005","title":"Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25434005","citation_count":202,"is_preprint":false},{"pmid":"20159109","id":"PMC_20159109","title":"Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20159109","citation_count":198,"is_preprint":false},{"pmid":"8411368","id":"PMC_8411368","title":"Glycosylation of neuraminidase determines the neurovirulence of influenza A/WSN/33 virus.","date":"1993","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8411368","citation_count":131,"is_preprint":false},{"pmid":"32115408","id":"PMC_32115408","title":"Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes.","date":"2020","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/32115408","citation_count":121,"is_preprint":false},{"pmid":"1165595","id":"PMC_1165595","title":"Temperature-sensitive mutants of influenza WSN virus defective in virus-specific RNA synthesis.","date":"1975","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/1165595","citation_count":114,"is_preprint":false},{"pmid":"2196448","id":"PMC_2196448","title":"Function of two discrete regions is required for nuclear localization of polymerase basic protein 1 of A/WSN/33 influenza virus (H1 N1).","date":"1990","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2196448","citation_count":113,"is_preprint":false},{"pmid":"1985200","id":"PMC_1985200","title":"Two signals mediate nuclear localization of influenza virus (A/WSN/33) polymerase basic protein 2.","date":"1991","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/1985200","citation_count":111,"is_preprint":false},{"pmid":"26399558","id":"PMC_26399558","title":"The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.","date":"2015","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/26399558","citation_count":87,"is_preprint":false},{"pmid":"25784538","id":"PMC_25784538","title":"The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25784538","citation_count":78,"is_preprint":false},{"pmid":"27066548","id":"PMC_27066548","title":"Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease.","date":"2015","source":"Neurology. 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of two exons spanning 3764 bp of genomic DNA, and showing 74.2% amino acid identity with RAB39A.\",\n      \"method\": \"cDNA library sequencing and genomic analysis\",\n      \"journal\": \"Cytogenetic and genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — original isolation/characterization paper, single lab, foundational characterization\",\n      \"pmids\": [\"12438742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RAB39B is a neuronal-specific protein localized to the Golgi compartment; its downregulation leads to alterations in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, indicating a role in synapse formation and maintenance.\",\n      \"method\": \"shRNA-mediated knockdown in cultured neurons, immunofluorescence localization, morphological analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment combined with loss-of-function with defined cellular phenotypes, replicated across labs\",\n      \"pmids\": [\"20159109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of RAB39B results in dysregulation of α-synuclein homeostasis; shRNA-mediated knockdown of Rab39b in cultured neurons reduced steady-state levels of α-synuclein and the density of α-synuclein immunoreactive puncta in dendritic processes.\",\n      \"method\": \"shRNA knockdown in cultured neurons, immunofluorescence, western blot\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific molecular readout (α-synuclein levels), replicated in multiple cell models\",\n      \"pmids\": [\"25434005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GTP-bound RAB39B directly interacts with PICK1 (protein interacting with C-kinase 1) as a downstream effector; the RAB39B–PICK1 complex controls trafficking from the endoplasmic reticulum to the Golgi and surface expression of the GluA2 AMPAR subunit. Downregulation of RAB39B skews AMPAR composition toward non-GluA2-containing Ca2+-permeable forms, altering synaptic activity in hippocampal neurons.\",\n      \"method\": \"Co-immunoprecipitation, pulldown with GTP-locked RAB39B mutant, shRNA knockdown in hippocampal neurons, electrophysiology, surface biotinylation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP identifying downstream effector, combined with functional knockdown and electrophysiological readout in multiple orthogonal assays\",\n      \"pmids\": [\"25784538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A missense mutation (p.G192R) in the C-terminal hypervariable domain of RAB39B causes mislocalization of the mutant protein in PC12 and SK-N-BE(2)C cells, suggesting this domain mediates intracellular targeting of RAB39B.\",\n      \"method\": \"Transfection of wild-type and mutant constructs in cell lines, fluorescence microscopy\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/localization experiment, single lab\",\n      \"pmids\": [\"26399558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAB39B localizes to the secretory network at the endoplasmic reticulum/cis-Golgi interface (distinct from RAB39A which localizes to late endocytic multivesicular bodies), and controls transport of sphingolipids biosynthesized at the ER-Golgi factory.\",\n      \"method\": \"Fluorescence microscopy, subcellular fractionation, lipid transport assays using fluorescent lipid analogs and Chlamydia trachomatis as a trafficking probe\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional lipid transport readout, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30987349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB39B interacts with components of Class I PI3K; its deletion activates the PI3K-AKT-mTOR signaling pathway in neural progenitor cells (NPCs), promoting NPC overproliferation and impaired differentiation, leading to macrocephaly and ASD-like behaviors. AKT inhibition rescued enlarged organoid sizes and NPC overproliferation.\",\n      \"method\": \"Rab39b knockout mice and human cerebral organoids (CRISPR), Co-immunoprecipitation for PI3K interaction, phospho-AKT/mTOR western blot, pharmacological rescue with AKT inhibitor\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Co-IP establishing PI3K interaction combined with KO mouse and human organoid models, pathway rescue, multiple orthogonal methods\",\n      \"pmids\": [\"32115408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB39B deficiency impairs autophagic flux at basal level in neurons; Rab39b knockout mice show impaired learning/memory and reduced NMDA receptors in the postsynaptic density. Rapamycin-induced autophagy activation partially rescued impaired memory and synaptic plasticity.\",\n      \"method\": \"Rab39b knockout mice, behavioral testing, autophagy flux assays (LC3-II accumulation with bafilomycin), synaptic fractionation, western blot for PSD proteins, pharmacological rescue\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype (autophagy, synaptic), pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33364235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB39B localizes throughout cortical and hippocampal neurons and TH-positive dopaminergic neurons in the substantia nigra pars compacta in mice throughout postnatal life; it is enriched in MAP2-positive neurons.\",\n      \"method\": \"In situ hybridization, immunohistochemistry with novel monoclonal antibodies and Rab39b knockout controls, western blot on brain lysates\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with validated antibodies and KO controls, functional relevance to disease-affected brain regions\",\n      \"pmids\": [\"32228644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB39B co-localizes with beta-amyloid plaques in post-mortem human brain tissue from DLB and AD cases, and is present in a subpopulation of Lewy bodies in DLB. Subcellular fractionation revealed reduced cytoplasmic RAB39B in DLB, indicating sequestration of RAB39B into pathological aggregates impairs its normal vesicular trafficking function.\",\n      \"method\": \"Immunohistochemistry on tissue microarrays from post-mortem brains, subcellular fractionation, western blot\",\n      \"journal\": \"Brain pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct co-localization in human tissue with biochemical fractionation, but no direct functional rescue experiment\",\n      \"pmids\": [\"32762091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB39B controls GluA2/GluA3 AMPAR trafficking and dendritic spine refinement; loss of RAB39B in knockout mice results in increased Ca2+-permeable AMPAR composition, hypermobile immature spines, and cognitive/behavioral alterations. The Ca2+-permeable AMPAR antagonist NASPM restored spine hypermobility.\",\n      \"method\": \"Rab39b knockout mice, two-photon live imaging of spine dynamics, electrophysiology, NASPM pharmacological rescue, behavioral testing\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO mouse with live imaging and electrophysiology, pharmacological rescue confirming mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"34035473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAB39B deficiency impairs macroautophagy (reducing Atg3, Atg5, Atg7, Atg12, Atg16L1), which leads to accumulation of α-synuclein in the ER and mitochondria of SH-SY5Y dopaminergic cells, activating ER stress pro-apoptotic cascades, mitochondrial dysfunction, and oxidative stress. PD-associated mutant RAB39B (T168K, W186X, G192R) failed to prevent these effects.\",\n      \"method\": \"shRNA knockdown and mutant overexpression in SH-SY5Y cells, western blot for autophagy markers and α-synuclein, mitochondrial membrane potential assay, ER stress markers, apoptosis assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and mutant rescue in cell model with multiple molecular pathway readouts, single lab\",\n      \"pmids\": [\"36715921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A RAB39B nonstop mutation causes protein instability and increased degradation. In a Rab39b knockdown mouse model, downregulation of RAB39B increases Ca2+-permeable (GluA2-lacking) AMPAR composition at hippocampal neuronal surfaces and increases dendritic spine density in an immature filopodia-like state, affecting social behavior and memory.\",\n      \"method\": \"Heterologous cell expression of nonstop mutant, western blot for protein stability, Rab39b KD mouse model, surface biotinylation of AMPARs, Golgi staining for spine morphology, behavioral testing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — protein stability assay with mutant, KD mouse with AMPAR trafficking and spine morphology readouts, multiple orthogonal methods\",\n      \"pmids\": [\"34761259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Neuronal overexpression of RAB39B decreases dendritic arborization of primary neurons in vitro, reduces synaptic transmission, impairs recognition and working memory, and alters autophagy in mice, demonstrating that both loss and gain of RAB39B function are detrimental to neuronal development.\",\n      \"method\": \"AAV-mediated overexpression in neonatal mouse brain, primary neuron morphology analysis, electrophysiology, autophagy assays, behavioral testing\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function in vivo with cellular and behavioral phenotypes, single lab\",\n      \"pmids\": [\"36977207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rab39b knockout mice develop PD motor impairment, degeneration of substantia nigra dopaminergic neurons, and Lewy bodies. RAB39B deficiency impairs macroautophagy via reduction of autophagy proteins (Atg3, Atg5, Atg7, Atg12, Atg16L1), elevating α-synuclein and activating ER stress apoptotic signaling, mitochondrial dysfunction, microglial activation, NLRP3 inflammasome, and necroptotic pathways. Rapamycin reversed autophagy dysfunction, reduced α-synuclein, and ameliorated motor deficits.\",\n      \"method\": \"Rab39b knockout mice, western blot for autophagy and apoptosis markers, immunohistochemistry for dopaminergic neurons and α-synuclein, rapamycin pharmacological rescue, behavioral testing\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO model with multiple molecular pathway readouts and pharmacological rescue, comprehensive mechanistic characterization\",\n      \"pmids\": [\"40473068\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB39B is a neuronal-enriched small GTPase that localizes to the ER/cis-Golgi interface, where in its GTP-bound state it interacts with PICK1 to control GluA2-containing AMPAR trafficking from the ER to the Golgi and to the neuronal surface (determining Ca2+-permeable vs. Ca2+-impermeable AMPAR composition at synapses), and also interacts with PI3K components to suppress PI3K-AKT-mTOR signaling in neural progenitor cells; additionally, RAB39B is required for basal macroautophagic flux to maintain α-synuclein homeostasis in dopaminergic neurons, such that its loss causes autophagy impairment, α-synuclein accumulation, ER stress, mitochondrial dysfunction, and dopaminergic neuron degeneration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RAB39B is a neuron-enriched small GTPase that operates at the endoplasmic reticulum/cis-Golgi interface to regulate vesicular trafficking and macroautophagy, with dosage-sensitive roles in synaptogenesis, synaptic composition, and neuronal survival [PMID:20159109, PMID:25784538, PMID:33364235, PMID:36977207]. In its GTP-bound state, RAB39B binds PICK1 to control ER-to-Golgi trafficking and surface delivery of GluA2-containing AMPARs; its loss shifts synaptic AMPAR composition toward Ca²⁺-permeable (GluA2-lacking) forms, producing immature dendritic spines and cognitive deficits rescued by the Ca²⁺-permeable AMPAR antagonist NASPM [PMID:25784538, PMID:34761259, PMID:34035473]. RAB39B also interacts with class I PI3K components to suppress PI3K–AKT–mTOR signaling in neural progenitor cells, and its deletion causes NPC overproliferation, macrocephaly, and ASD-like phenotypes reversible by AKT inhibition [PMID:32115408]. Loss of RAB39B impairs basal macroautophagy by reducing core ATG proteins (Atg3, Atg5, Atg7, Atg12, Atg16L1), leading to α-synuclein accumulation, ER stress, mitochondrial dysfunction, dopaminergic neuron degeneration, and Parkinson disease-like pathology in knockout mice—phenotypes partially rescued by rapamycin [PMID:36715921, PMID:40473068].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of RAB39B as a novel X-linked RAB GTPase established a new member of the RAB family with unknown neuronal function.\",\n      \"evidence\": \"cDNA library sequencing and genomic characterization\",\n      \"pmids\": [\"12438742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no functional data\", \"expression pattern not fully resolved at single-cell level\", \"no effector or interaction partners identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that RAB39B is neuron-specific and localizes to the Golgi, and that its knockdown impairs neurite growth cones and presynaptic button number, established a direct role in synapse formation.\",\n      \"evidence\": \"shRNA knockdown in cultured neurons with immunofluorescence and morphological analysis\",\n      \"pmids\": [\"20159109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"effector proteins mediating synaptic effects unknown\", \"no in vivo confirmation\", \"no link to specific cargo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that GTP-bound RAB39B binds PICK1 and that this complex controls ER-to-Golgi trafficking and surface expression of GluA2 AMPARs resolved the molecular mechanism by which RAB39B determines synaptic AMPAR composition and Ca²⁺ permeability.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation with GTP-locked mutant, shRNA knockdown in hippocampal neurons, surface biotinylation, electrophysiology\",\n      \"pmids\": [\"25784538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of RAB39B–PICK1 interaction unresolved\", \"whether other RAB39B effectors exist at this trafficking step unknown\", \"GEF and GAP for RAB39B not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking RAB39B loss to dysregulated α-synuclein homeostasis in neurons opened the connection between this trafficking GTPase and Parkinson disease-relevant pathology.\",\n      \"evidence\": \"shRNA knockdown in cultured neurons with western blot and immunofluorescence for α-synuclein\",\n      \"pmids\": [\"25434005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking RAB39B to α-synuclein regulation not determined at this stage\", \"no in vivo PD model\", \"directionality of α-synuclein change (reduced vs. accumulated) required reconciliation with later studies\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Precise localization of RAB39B to the ER/cis-Golgi interface (distinct from RAB39A at late endosomes) and demonstration of its role in sphingolipid transport refined the subcellular site of action.\",\n      \"evidence\": \"Fluorescence microscopy, subcellular fractionation, fluorescent lipid analog transport assays\",\n      \"pmids\": [\"30987349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"sphingolipid cargo specificity not fully defined\", \"functional relationship between lipid transport and AMPAR trafficking not tested\", \"single-lab observation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of RAB39B interaction with class I PI3K and demonstration that its loss activates PI3K–AKT–mTOR signaling, causing NPC overproliferation and macrocephaly rescued by AKT inhibition, revealed a second major signaling axis controlled by RAB39B in neural development.\",\n      \"evidence\": \"Rab39b knockout mice, human cerebral organoids (CRISPR), co-immunoprecipitation, phospho-AKT/mTOR western blot, pharmacological rescue\",\n      \"pmids\": [\"32115408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether RAB39B directly suppresses PI3K catalytic activity or acts via membrane trafficking not distinguished\", \"relationship between PI3K axis and AMPAR trafficking axis not explored\", \"specific PI3K subunit(s) bound not fully characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that Rab39b knockout mice have impaired basal autophagic flux with reduced NMDA receptor levels at postsynaptic densities, rescued by rapamycin, established autophagy as a key downstream pathway mediating RAB39B's synaptic effects.\",\n      \"evidence\": \"Rab39b knockout mice, LC3-II flux assays with bafilomycin, synaptic fractionation, behavioral testing, rapamycin rescue\",\n      \"pmids\": [\"33364235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how RAB39B mechanistically promotes autophagy initiation not defined\", \"whether autophagy and AMPAR trafficking phenotypes are causally linked unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In vivo confirmation that RAB39B loss increases Ca²⁺-permeable AMPAR composition and produces hypermobile immature spines, rescued by NASPM, validated the PICK1–GluA2 trafficking model in intact circuits and linked it to cognitive deficits.\",\n      \"evidence\": \"Rab39b knockout mice, two-photon live imaging, electrophysiology, NASPM pharmacological rescue, behavioral testing\",\n      \"pmids\": [\"34035473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no structural data on RAB39B–PICK1–GluA2 complex\", \"spine maturation mechanism downstream of AMPAR switch not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistic dissection in dopaminergic cells showed that RAB39B deficiency reduces core ATG proteins, causing α-synuclein accumulation in ER and mitochondria with consequent ER stress and mitochondrial dysfunction; PD-associated mutants failed to rescue, linking patient mutations to autophagy failure.\",\n      \"evidence\": \"shRNA knockdown and mutant overexpression in SH-SY5Y cells, western blot for ATG proteins, ER stress and mitochondrial assays\",\n      \"pmids\": [\"36715921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single cell-line model\", \"how RAB39B regulates ATG protein levels (transcriptional vs. post-translational) not resolved\", \"no in vivo validation of mutant rescue at this point\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Full PD modeling in Rab39b knockout mice—demonstrating dopaminergic neuron degeneration, Lewy body formation, microglial activation, NLRP3 inflammasome engagement, and motor deficits all rescued by rapamycin—consolidated the autophagy-α-synuclein axis as the primary mechanism of RAB39B-linked parkinsonism.\",\n      \"evidence\": \"Rab39b knockout mice, immunohistochemistry, western blot for autophagy/apoptosis/inflammasome markers, rapamycin pharmacological rescue, behavioral testing\",\n      \"pmids\": [\"40473068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEF and GAP for RAB39B remain unidentified\", \"direct molecular step by which RAB39B maintains ATG protein levels still unknown\", \"whether neuroinflammatory cascade is cell-autonomous or involves non-neuronal contributions not fully dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The GEF and GAP regulating RAB39B nucleotide cycling, the structural basis of RAB39B–PICK1 and RAB39B–PI3K interactions, and the direct molecular mechanism by which RAB39B sustains core autophagy protein levels remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no GEF or GAP identified\", \"no crystal or cryo-EM structure of RAB39B or its effector complexes\", \"mechanistic link between ER/Golgi trafficking function and autophagy regulation not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3, 5, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 11, 14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 10, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PICK1\",\n      \"PIK3CA\",\n      \"GRIA2\",\n      \"GRIA3\",\n      \"SNCA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}