{"gene":"ZFYVE26","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2008,"finding":"ZFYVE26 (spastizin) encodes a zinc-finger FYVE domain-containing protein that partially colocalizes with markers of endoplasmic reticulum and endosomes in cultured cells, suggesting a role in intracellular trafficking.","method":"Subcellular localization by immunofluorescence colocalization with organelle markers in cultured cells","journal":"American journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single colocalization experiment, single lab, no functional follow-up reported in this abstract","pmids":["18394578"],"is_preprint":false},{"year":2013,"finding":"AP-5 complex subunits coimmunoprecipitate with SPG15 (spastizin) and SPG11 (spatacsin) at ~1:1:1:1:1:1 stoichiometry from both cytosol and detergent-extracted membranes. Knockdown of SPG15 phenocopies AP-5 subunit knockdowns, causing cation-independent mannose 6-phosphate receptor trapping in early endosome clusters. AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment. The N-terminal β-propeller-like domain of SPG11 interacts in vitro with AP-5. SPG15 is proposed to dock the coat onto membranes via PI3P binding through its FYVE domain, and SPG11 forms a scaffold.","method":"Co-immunoprecipitation from cytosol and membranes; RNAi knockdown with endosomal trafficking phenotype readout; colocalization by immunofluorescence; in vitro binding assay (SPG11 domain vs AP-5)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with stoichiometry, RNAi epistasis with defined trafficking phenotype, in vitro binding, and colocalization; multiple orthogonal methods in single study","pmids":["23825025"],"is_preprint":false},{"year":2013,"finding":"In Zfyve26 knockout mice, ZFYVE26 associates with intracellular vesicles positive for early endosomal marker EEA1 and co-fractionates with a component of the AP-5 complex. Loss of Zfyve26 causes accumulation of large intraneuronal Lamp1-positive membrane deposits, increased density of Lamp1-positive compartments on density gradients, and elevated lysosomal enzyme levels, supporting a role in endolysosomal membrane trafficking.","method":"Zfyve26 knockout mouse model; subcellular fractionation/density gradient; immunofluorescence with EEA1 and Lamp1 markers; electron microscopy; enzymatic activity assay for lysosomal enzymes","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype, multiple orthogonal methods (fractionation, EM, IHC, enzyme assay) in a single rigorous study","pmids":["24367272"],"is_preprint":false},{"year":2014,"finding":"SPG15 patient-derived fibroblasts show selective enlargement of LAMP1-positive structures and abnormal lysosomal storage by electron microscopy. The stabilities of spastizin (ZFYVE26) and spatacsin (SPG11) are interdependent, indicating mutual stabilization of the two proteins.","method":"Patient-derived fibroblast analysis; immunofluorescence for LAMP1; electron microscopy; western blot for protein stability","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell lines with EM and immunofluorescence, mutual stability demonstrated, single lab with two orthogonal methods","pmids":["24999486"],"is_preprint":false},{"year":2013,"finding":"Patient-derived fibroblasts and lymphoblasts carrying ZFYVE26 mutations show accumulation of immature autophagosomes and increased MAP1LC3B-II and SQSTM1/p62 levels, establishing ZFYVE26 as a key determinant of autophagosome maturation. This defect was replicated in primary neurons.","method":"Patient-derived fibroblast/lymphoblast analysis; western blot for LC3B-II and p62; autophagosome quantification; replication in primary neurons","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells and primary neurons, multiple biochemical markers, single lab","pmids":["24284334"],"is_preprint":false},{"year":2018,"finding":"ZFYVE26 and SPG11 both interact with RAB5A and RAB11 (regulators of endosome trafficking and maturation), but only ZFYVE26 mutations affect RAB protein interactions and activation. ZFYVE26 mutations impair fusion between autophagosomes and endosomes, while SPG11 mutations do not affect this step. Expression of constitutively active RAB5A partially rescues the autophagy defect caused by ZFYVE26 mutations. ZFYVE26 and SPG11 are both required for autophagic lysosome reformation.","method":"Co-immunoprecipitation for RAB5A/RAB11 interactions; patient-derived cells with autophagosome-endosome fusion assay; rescue experiment with constitutively active RAB5A; autophagic lysosome reformation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, functional rescue with dominant-active construct, multiple orthogonal assays including fusion and lysosome reformation, single lab with strong evidence","pmids":["30081747"],"is_preprint":false},{"year":2021,"finding":"Recruitment of the AP-5/SPG11/SPG15 complex to late endosomes/lysosomes occurs by coincidence detection requiring both PI3P and Rag GTPases. The SPG15 FYVE domain alone localizes to early endosomes but PI3P binding cooperates with Rag GTPases for complex recruitment to late endosomes/lysosomes. GDP-locked RagC promotes recruitment, while GTP-locked RagA prevents it, linking the complex to the mTORC1 pathway and autophagic lysosome reformation.","method":"Live-cell imaging and subcellular localization assays; dominant-active/dominant-negative Rag GTPase constructs; PI3P binding assays via FYVE domain; starvation conditions","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with dominant Rag GTPase mutants, PI3P binding via FYVE domain, starvation-dependent recruitment assays; multiple orthogonal methods in one rigorous study","pmids":["33464297"],"is_preprint":false},{"year":2022,"finding":"Loss of SPG15 protein in patient fibroblasts and SPG15 KO primary cortical neurons causes defective anterograde transport, impaired neurite outgrowth, axonal swelling, reduced autophagic flux, lipid accumulation within the lysosomal compartment, and synaptic dysfunction with augmented vulnerability to glutamate-induced excitotoxicity.","method":"Patient fibroblasts and SPG15 KO mouse primary cortical neurons; live imaging of axonal transport; neurite outgrowth assays; autophagic flux assays; lipid staining; electrophysiology for synaptic function; glutamate excitotoxicity assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO neurons with multiple defined cellular phenotypes, single lab, several orthogonal assays","pmids":["35313342"],"is_preprint":false},{"year":2023,"finding":"SPG15-related ZFYVE26 mutations cause autophagic lysosome reformation defects with lysosome enlargement, free lysosome depletion, and autophagosome accumulation. Pharmacological rescue with compounds modulating intracellular calcium, the calcium-calpain pathway, or lysosomal function (including SMER28, verapamil, Bay K8644, 2',5'-dideoxyadenosine, trehalose, trifluoperazine) improves lysosome biogenesis and function in a Drosophila SPG15 loss-of-function model and in patient-derived cells, validating lysosomes as a key pharmacological target.","method":"Patient-derived cell compound library screen; SPG15 loss-of-function Drosophila model; autophagosome and lysosome quantification; locomotor deficit readout in Drosophila","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila model plus patient-derived cells, multiple compounds validated, single lab","pmids":["36029068"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of SPG11-SPG15 reveals a W-shaped complex intertwined in a head-to-head fashion. The N-terminal region of SPG11 is required for AP-5 complex interaction and assembly. The AP-5 complex adopts a super-open conformation. The AP5-SPG11-SPG15 complex binds PI3P molecules, senses membrane curvature, and drives membrane remodeling in vitro, including initiation of autolysosome tubulation.","method":"Cryo-electron microscopy; in silico structural predictions; in vitro membrane remodeling assay; PI3P binding assay; domain deletion/mutagenesis for AP5 interaction","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus in vitro reconstitution of membrane remodeling activity and PI3P binding, with domain mutagenesis validating AP5 interaction","pmids":["40175557"],"is_preprint":false},{"year":2025,"finding":"Spastizin partially localizes to mitochondria in SPG15 patient iPSC-derived cortical neurons. SPG15 neurons exhibit reduced ATP production and increased mitochondrial fragmentation. Inhibition of mitochondrial fission protein DRP1 with peptide P110 restores mitochondrial morphology, reduces oxidative stress, and suppresses axonal swellings and apoptosis in SPG15 neurons.","method":"iPSC-derived cortical neurons from SPG15 patients; ATP production assay; mitochondrial morphology imaging; DRP1 inhibitor (P110) treatment; axonal swelling quantification; oxidative stress assay; apoptosis assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient iPSC-derived neurons with multiple biochemical and imaging readouts, pharmacological rescue, single lab","pmids":["41192643"],"is_preprint":false}],"current_model":"ZFYVE26/spastizin forms a stable ~1:1:1:1:1:1 coat-like complex with SPG11/spatacsin and the AP-5 adaptor complex on late endosomes/lysosomes; the SPG15 FYVE domain binds PI3P while Rag GTPases (GDP-RagC promotes, GTP-RagA inhibits) mediate coincidence detection for membrane recruitment; cryo-EM shows the SPG11-SPG15 heterodimer adopts a W-shaped head-to-head architecture that, together with AP-5 in a super-open conformation, binds PI3P, senses membrane curvature, and drives membrane remodeling to initiate autolysosome tubulation; loss of spastizin disrupts autophagosome-endosome fusion (via RAB5A/RAB11 interactions), blocks autophagic lysosome reformation causing lysosome enlargement and autophagosome accumulation, and additionally leads to defective anterograde axonal transport, lipid accumulation, mitochondrial fragmentation/dysfunction, and synaptic vulnerability."},"narrative":{"mechanistic_narrative":"ZFYVE26/spastizin is a FYVE-domain protein that, together with spatacsin (SPG11) and the AP-5 adaptor complex, forms a coat-like assembly governing endolysosomal membrane trafficking and autophagic lysosome reformation [PMID:23825025]. The three proteins coimmunoprecipitate at ~1:1:1:1:1:1 stoichiometry and colocalize on a late endosomal/lysosomal compartment, where SPG15 docks the coat onto membranes through PI3P binding by its FYVE domain while SPG11 forms the scaffold [PMID:23825025]; cryo-EM resolves the SPG11-SPG15 heterodimer as a head-to-head W-shaped complex that, with AP-5 in a super-open conformation, binds PI3P, senses membrane curvature, and drives membrane remodeling including autolysosome tubulation in vitro [PMID:40175557]. Membrane recruitment depends on coincidence detection of PI3P and Rag GTPases, with GDP-locked RagC promoting and GTP-locked RagA preventing recruitment, linking the complex to the mTORC1 pathway and autophagic lysosome reformation [PMID:33464297]. Loss of spastizin blocks autophagosome maturation and autophagosome-endosome fusion—the latter via its interactions with RAB5A and RAB11, with constitutively active RAB5A partially rescuing the defect—producing accumulation of immature autophagosomes, enlarged LAMP1-positive lysosomes, and depletion of free lysosomes [PMID:24284334, PMID:30081747, PMID:24367272]. Spastizin and spatacsin mutually stabilize one another [PMID:24999486]. In neurons, deficiency causes defective anterograde axonal transport, lipid accumulation, mitochondrial fragmentation with reduced ATP production, and synaptic vulnerability to excitotoxicity [PMID:35313342, PMID:41192643], establishing ZFYVE26 as a determinant of neuronal lysosomal and mitochondrial homeostasis.","teleology":[{"year":2008,"claim":"Established the first cellular context for an uncharacterized FYVE-domain protein by placing it at ER/endosomal compartments, implicating it in intracellular trafficking.","evidence":"Immunofluorescence colocalization with organelle markers in cultured cells","pmids":["18394578"],"confidence":"Low","gaps":["Single colocalization experiment with no functional follow-up","No interaction partners or molecular activity defined","Did not distinguish ER from endosomal residence functionally"]},{"year":2013,"claim":"Defined spastizin as a stoichiometric subunit of an AP-5/SPG11/SPG15 coat complex on late endosomes/lysosomes, assigning it a membrane-docking role via PI3P binding and establishing a shared trafficking phenotype with AP-5.","evidence":"Reciprocal Co-IP with stoichiometry, RNAi epistasis with mannose 6-phosphate receptor trapping, colocalization, and in vitro SPG11-AP-5 binding","pmids":["23825025"],"confidence":"High","gaps":["FYVE-PI3P docking proposed but not directly demonstrated in this study","Mechanism of cargo handling by the coat unresolved","No in vivo validation"]},{"year":2013,"claim":"Confirmed the endolysosomal trafficking role in vivo, showing genetic loss produces intraneuronal LAMP1-positive deposits and lysosomal dysregulation.","evidence":"Zfyve26 knockout mouse with fractionation, EM, EEA1/Lamp1 immunostaining, and lysosomal enzyme assays","pmids":["24367272"],"confidence":"High","gaps":["Did not resolve the molecular step disrupted","Link to autophagy not yet established here","Mechanism connecting deposits to neurodegeneration unknown"]},{"year":2013,"claim":"Identified spastizin as a determinant of autophagosome maturation, extending its role from endosomal trafficking to autophagy.","evidence":"Patient fibroblasts/lymphoblasts and primary neurons with LC3B-II and p62 western blots and autophagosome quantification","pmids":["24284334"],"confidence":"Medium","gaps":["Did not define which fusion or maturation step is blocked","No structural or interaction mechanism","Single lab"]},{"year":2014,"claim":"Showed spastizin and spatacsin are interdependently stabilized and that patient cells exhibit lysosomal enlargement and storage, reinforcing an obligate heterodimer with a lysosomal phenotype.","evidence":"Patient-derived fibroblasts with LAMP1 immunofluorescence, EM, and western blot stability analysis","pmids":["24999486"],"confidence":"Medium","gaps":["Mechanism of mutual stabilization not structurally defined","Lysosomal storage cargo not identified"]},{"year":2018,"claim":"Distinguished spastizin's specific function from spatacsin by showing only ZFYVE26 controls RAB5A/RAB11 activation and autophagosome-endosome fusion, with RAB5A rescue pinpointing the defective step.","evidence":"Co-IP for RAB5A/RAB11, autophagosome-endosome fusion assay, constitutively active RAB5A rescue, and autophagic lysosome reformation assay in patient cells","pmids":["30081747"],"confidence":"High","gaps":["How spastizin regulates RAB activation mechanistically unresolved","Direct vs indirect RAB interaction not separated","Relationship between fusion defect and ALR defect not fully ordered"]},{"year":2021,"claim":"Resolved how the coat is recruited to membranes, showing PI3P–Rag GTPase coincidence detection and linking complex localization to mTORC1-coupled autophagic lysosome reformation.","evidence":"Live-cell imaging with dominant Rag GTPase mutants, FYVE-domain PI3P binding assays, and starvation-dependent recruitment","pmids":["33464297"],"confidence":"High","gaps":["Direct physical Rag-complex contact not structurally mapped","How GDP-RagC vs GTP-RagA states are sensed unresolved"]},{"year":2022,"claim":"Mapped the neuronal consequences of spastizin loss, connecting lysosomal/autophagy dysfunction to axonal transport, lipid handling, and synaptic vulnerability.","evidence":"Patient fibroblasts and KO mouse cortical neurons with axonal transport imaging, autophagic flux, lipid staining, electrophysiology, and excitotoxicity assays","pmids":["35313342"],"confidence":"Medium","gaps":["Causal chain from lysosomal defect to transport failure not established","Single lab","Lipid species not identified"]},{"year":2023,"claim":"Validated lysosomes as a tractable therapeutic node by showing calcium/calpain- and lysosome-modulating compounds rescue ALR defects across patient cells and a Drosophila model.","evidence":"Compound library screen in patient cells, Drosophila SPG15 loss-of-function model with lysosome quantification and locomotor readouts","pmids":["36029068"],"confidence":"Medium","gaps":["Molecular targets of rescue compounds not all defined","Whether rescue restores neuronal function long-term unknown"]},{"year":2025,"claim":"Provided the structural mechanism, showing the W-shaped SPG11-SPG15 heterodimer with super-open AP-5 binds PI3P, senses curvature, and remodels membranes to initiate autolysosome tubulation.","evidence":"Cryo-EM structure, in vitro membrane remodeling and PI3P binding reconstitution, and domain mutagenesis validating SPG11 N-terminal AP-5 contact","pmids":["40175557"],"confidence":"High","gaps":["In-cell relevance of curvature sensing not directly tested","Conformational coupling to Rag/PI3P recruitment not resolved structurally"]},{"year":2025,"claim":"Extended spastizin function beyond endolysosomal trafficking by linking it to mitochondrial integrity, with DRP1 inhibition rescuing fragmentation and downstream neuronal pathology.","evidence":"Patient iPSC-derived cortical neurons with ATP, mitochondrial morphology, oxidative stress and apoptosis assays plus DRP1 inhibitor P110 rescue","pmids":["41192643"],"confidence":"Medium","gaps":["Whether mitochondrial defect is primary or secondary to lysosomal dysfunction unresolved","Mechanism of spastizin mitochondrial localization unknown","Single lab"]},{"year":null,"claim":"How the structurally defined coat coordinates PI3P/Rag coincidence detection, RAB-dependent fusion, and membrane remodeling into a single ordered ALR cycle in neurons remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking recruitment, fusion, and tubulation in time","Causal hierarchy among lysosomal, transport, and mitochondrial defects unestablished","No structure of the membrane-bound holocomplex with Rag GTPases"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,6,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,5,6,8]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2,9]}],"complexes":["AP-5/SPG11/SPG15 coat complex"],"partners":["SPG11","AP5Z1","RAB5A","RAB11","RAGC","RAGA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q68DK2","full_name":"Zinc finger FYVE domain-containing protein 26","aliases":["FYVE domain-containing centrosomal protein","FYVE-CENT","Spastizin"],"length_aa":2539,"mass_kda":284.6,"function":"Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission. May also be required for efficient homologous recombination DNA double-strand break repair","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Midbody","url":"https://www.uniprot.org/uniprotkb/Q68DK2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZFYVE26","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZFYVE26","total_profiled":1310},"omim":[{"mim_id":"619870","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 82; CCDC82","url":"https://www.omim.org/entry/619870"},{"mim_id":"614824","title":"ADAPTOR-RELATED PROTEIN COMPLEX 5, SIGMA-1 SUBUNIT; AP5S1","url":"https://www.omim.org/entry/614824"},{"mim_id":"613653","title":"ADAPTOR-RELATED PROTEIN COMPLEX 5, ZETA-1 SUBUNIT; AP5Z1","url":"https://www.omim.org/entry/613653"},{"mim_id":"613647","title":"SPASTIC PARAPLEGIA 48, AUTOSOMAL RECESSIVE; SPG48","url":"https://www.omim.org/entry/613647"},{"mim_id":"612012","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 26; ZFYVE26","url":"https://www.omim.org/entry/612012"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZFYVE26"},"hgnc":{"alias_symbol":["KIAA0321"],"prev_symbol":["SPG15"]},"alphafold":{"accession":"Q68DK2","domains":[{"cath_id":"-","chopping":"872-890_916-1011_1023-1035","consensus_level":"medium","plddt":73.092,"start":872,"end":1035},{"cath_id":"-","chopping":"1070-1097_1106-1136_1155-1222","consensus_level":"medium","plddt":72.938,"start":1070,"end":1222},{"cath_id":"-","chopping":"1242-1267_1304-1324_1348-1376_1388-1470","consensus_level":"medium","plddt":75.2542,"start":1242,"end":1470},{"cath_id":"3.30.40.10","chopping":"1817-1871","consensus_level":"medium","plddt":82.0153,"start":1817,"end":1871}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68DK2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q68DK2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q68DK2-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZFYVE26","jax_strain_url":"https://www.jax.org/strain/search?query=ZFYVE26"},"sequence":{"accession":"Q68DK2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q68DK2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q68DK2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68DK2"}},"corpus_meta":[{"pmid":"18394578","id":"PMC_18394578","title":"Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18394578","citation_count":165,"is_preprint":false},{"pmid":"24833714","id":"PMC_24833714","title":"Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24833714","citation_count":132,"is_preprint":false},{"pmid":"23825025","id":"PMC_23825025","title":"Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23825025","citation_count":98,"is_preprint":false},{"pmid":"24999486","id":"PMC_24999486","title":"Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11.","date":"2014","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24999486","citation_count":92,"is_preprint":false},{"pmid":"24367272","id":"PMC_24367272","title":"A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24367272","citation_count":79,"is_preprint":false},{"pmid":"19805727","id":"PMC_19805727","title":"SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum.","date":"2009","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19805727","citation_count":77,"is_preprint":false},{"pmid":"19917823","id":"PMC_19917823","title":"Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia.","date":"2009","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/19917823","citation_count":60,"is_preprint":false},{"pmid":"30606727","id":"PMC_30606727","title":"\"Ears of the Lynx\" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia.","date":"2019","source":"AJNR. 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mutation in ZFYVE26 (SPG15) gene in a patient with hereditary spastic paraparesis.","date":"2018","source":"Journal of genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30555096","citation_count":2,"is_preprint":false},{"pmid":"37681008","id":"PMC_37681008","title":"Case report: Hereditary spastic paraplegia with a novel homozygous mutation in ZFYVE26.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37681008","citation_count":1,"is_preprint":false},{"pmid":"41192643","id":"PMC_41192643","title":"Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.","date":"2025","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/41192643","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.02.610538","title":"Disease-associated microglia and activation of CD8  <sup>+</sup>  T cells precede neuronal cell loss in a model of hereditary spastic paraplegia","date":"2024-09-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.02.610538","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15919,"output_tokens":3357,"usd":0.049056,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10860,"output_tokens":3939,"usd":0.076387,"stage2_stop_reason":"end_turn"},"total_usd":0.125443,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"ZFYVE26 (spastizin) encodes a zinc-finger FYVE domain-containing protein that partially colocalizes with markers of endoplasmic reticulum and endosomes in cultured cells, suggesting a role in intracellular trafficking.\",\n      \"method\": \"Subcellular localization by immunofluorescence colocalization with organelle markers in cultured cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single colocalization experiment, single lab, no functional follow-up reported in this abstract\",\n      \"pmids\": [\"18394578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AP-5 complex subunits coimmunoprecipitate with SPG15 (spastizin) and SPG11 (spatacsin) at ~1:1:1:1:1:1 stoichiometry from both cytosol and detergent-extracted membranes. Knockdown of SPG15 phenocopies AP-5 subunit knockdowns, causing cation-independent mannose 6-phosphate receptor trapping in early endosome clusters. AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment. The N-terminal β-propeller-like domain of SPG11 interacts in vitro with AP-5. SPG15 is proposed to dock the coat onto membranes via PI3P binding through its FYVE domain, and SPG11 forms a scaffold.\",\n      \"method\": \"Co-immunoprecipitation from cytosol and membranes; RNAi knockdown with endosomal trafficking phenotype readout; colocalization by immunofluorescence; in vitro binding assay (SPG11 domain vs AP-5)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with stoichiometry, RNAi epistasis with defined trafficking phenotype, in vitro binding, and colocalization; multiple orthogonal methods in single study\",\n      \"pmids\": [\"23825025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Zfyve26 knockout mice, ZFYVE26 associates with intracellular vesicles positive for early endosomal marker EEA1 and co-fractionates with a component of the AP-5 complex. Loss of Zfyve26 causes accumulation of large intraneuronal Lamp1-positive membrane deposits, increased density of Lamp1-positive compartments on density gradients, and elevated lysosomal enzyme levels, supporting a role in endolysosomal membrane trafficking.\",\n      \"method\": \"Zfyve26 knockout mouse model; subcellular fractionation/density gradient; immunofluorescence with EEA1 and Lamp1 markers; electron microscopy; enzymatic activity assay for lysosomal enzymes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype, multiple orthogonal methods (fractionation, EM, IHC, enzyme assay) in a single rigorous study\",\n      \"pmids\": [\"24367272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SPG15 patient-derived fibroblasts show selective enlargement of LAMP1-positive structures and abnormal lysosomal storage by electron microscopy. The stabilities of spastizin (ZFYVE26) and spatacsin (SPG11) are interdependent, indicating mutual stabilization of the two proteins.\",\n      \"method\": \"Patient-derived fibroblast analysis; immunofluorescence for LAMP1; electron microscopy; western blot for protein stability\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell lines with EM and immunofluorescence, mutual stability demonstrated, single lab with two orthogonal methods\",\n      \"pmids\": [\"24999486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Patient-derived fibroblasts and lymphoblasts carrying ZFYVE26 mutations show accumulation of immature autophagosomes and increased MAP1LC3B-II and SQSTM1/p62 levels, establishing ZFYVE26 as a key determinant of autophagosome maturation. This defect was replicated in primary neurons.\",\n      \"method\": \"Patient-derived fibroblast/lymphoblast analysis; western blot for LC3B-II and p62; autophagosome quantification; replication in primary neurons\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells and primary neurons, multiple biochemical markers, single lab\",\n      \"pmids\": [\"24284334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZFYVE26 and SPG11 both interact with RAB5A and RAB11 (regulators of endosome trafficking and maturation), but only ZFYVE26 mutations affect RAB protein interactions and activation. ZFYVE26 mutations impair fusion between autophagosomes and endosomes, while SPG11 mutations do not affect this step. Expression of constitutively active RAB5A partially rescues the autophagy defect caused by ZFYVE26 mutations. ZFYVE26 and SPG11 are both required for autophagic lysosome reformation.\",\n      \"method\": \"Co-immunoprecipitation for RAB5A/RAB11 interactions; patient-derived cells with autophagosome-endosome fusion assay; rescue experiment with constitutively active RAB5A; autophagic lysosome reformation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, functional rescue with dominant-active construct, multiple orthogonal assays including fusion and lysosome reformation, single lab with strong evidence\",\n      \"pmids\": [\"30081747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Recruitment of the AP-5/SPG11/SPG15 complex to late endosomes/lysosomes occurs by coincidence detection requiring both PI3P and Rag GTPases. The SPG15 FYVE domain alone localizes to early endosomes but PI3P binding cooperates with Rag GTPases for complex recruitment to late endosomes/lysosomes. GDP-locked RagC promotes recruitment, while GTP-locked RagA prevents it, linking the complex to the mTORC1 pathway and autophagic lysosome reformation.\",\n      \"method\": \"Live-cell imaging and subcellular localization assays; dominant-active/dominant-negative Rag GTPase constructs; PI3P binding assays via FYVE domain; starvation conditions\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with dominant Rag GTPase mutants, PI3P binding via FYVE domain, starvation-dependent recruitment assays; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"33464297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of SPG15 protein in patient fibroblasts and SPG15 KO primary cortical neurons causes defective anterograde transport, impaired neurite outgrowth, axonal swelling, reduced autophagic flux, lipid accumulation within the lysosomal compartment, and synaptic dysfunction with augmented vulnerability to glutamate-induced excitotoxicity.\",\n      \"method\": \"Patient fibroblasts and SPG15 KO mouse primary cortical neurons; live imaging of axonal transport; neurite outgrowth assays; autophagic flux assays; lipid staining; electrophysiology for synaptic function; glutamate excitotoxicity assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO neurons with multiple defined cellular phenotypes, single lab, several orthogonal assays\",\n      \"pmids\": [\"35313342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPG15-related ZFYVE26 mutations cause autophagic lysosome reformation defects with lysosome enlargement, free lysosome depletion, and autophagosome accumulation. Pharmacological rescue with compounds modulating intracellular calcium, the calcium-calpain pathway, or lysosomal function (including SMER28, verapamil, Bay K8644, 2',5'-dideoxyadenosine, trehalose, trifluoperazine) improves lysosome biogenesis and function in a Drosophila SPG15 loss-of-function model and in patient-derived cells, validating lysosomes as a key pharmacological target.\",\n      \"method\": \"Patient-derived cell compound library screen; SPG15 loss-of-function Drosophila model; autophagosome and lysosome quantification; locomotor deficit readout in Drosophila\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila model plus patient-derived cells, multiple compounds validated, single lab\",\n      \"pmids\": [\"36029068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of SPG11-SPG15 reveals a W-shaped complex intertwined in a head-to-head fashion. The N-terminal region of SPG11 is required for AP-5 complex interaction and assembly. The AP-5 complex adopts a super-open conformation. The AP5-SPG11-SPG15 complex binds PI3P molecules, senses membrane curvature, and drives membrane remodeling in vitro, including initiation of autolysosome tubulation.\",\n      \"method\": \"Cryo-electron microscopy; in silico structural predictions; in vitro membrane remodeling assay; PI3P binding assay; domain deletion/mutagenesis for AP5 interaction\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus in vitro reconstitution of membrane remodeling activity and PI3P binding, with domain mutagenesis validating AP5 interaction\",\n      \"pmids\": [\"40175557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Spastizin partially localizes to mitochondria in SPG15 patient iPSC-derived cortical neurons. SPG15 neurons exhibit reduced ATP production and increased mitochondrial fragmentation. Inhibition of mitochondrial fission protein DRP1 with peptide P110 restores mitochondrial morphology, reduces oxidative stress, and suppresses axonal swellings and apoptosis in SPG15 neurons.\",\n      \"method\": \"iPSC-derived cortical neurons from SPG15 patients; ATP production assay; mitochondrial morphology imaging; DRP1 inhibitor (P110) treatment; axonal swelling quantification; oxidative stress assay; apoptosis assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient iPSC-derived neurons with multiple biochemical and imaging readouts, pharmacological rescue, single lab\",\n      \"pmids\": [\"41192643\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZFYVE26/spastizin forms a stable ~1:1:1:1:1:1 coat-like complex with SPG11/spatacsin and the AP-5 adaptor complex on late endosomes/lysosomes; the SPG15 FYVE domain binds PI3P while Rag GTPases (GDP-RagC promotes, GTP-RagA inhibits) mediate coincidence detection for membrane recruitment; cryo-EM shows the SPG11-SPG15 heterodimer adopts a W-shaped head-to-head architecture that, together with AP-5 in a super-open conformation, binds PI3P, senses membrane curvature, and drives membrane remodeling to initiate autolysosome tubulation; loss of spastizin disrupts autophagosome-endosome fusion (via RAB5A/RAB11 interactions), blocks autophagic lysosome reformation causing lysosome enlargement and autophagosome accumulation, and additionally leads to defective anterograde axonal transport, lipid accumulation, mitochondrial fragmentation/dysfunction, and synaptic vulnerability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZFYVE26/spastizin is a FYVE-domain protein that, together with spatacsin (SPG11) and the AP-5 adaptor complex, forms a coat-like assembly governing endolysosomal membrane trafficking and autophagic lysosome reformation [#1]. The three proteins coimmunoprecipitate at ~1:1:1:1:1:1 stoichiometry and colocalize on a late endosomal/lysosomal compartment, where SPG15 docks the coat onto membranes through PI3P binding by its FYVE domain while SPG11 forms the scaffold [#1]; cryo-EM resolves the SPG11-SPG15 heterodimer as a head-to-head W-shaped complex that, with AP-5 in a super-open conformation, binds PI3P, senses membrane curvature, and drives membrane remodeling including autolysosome tubulation in vitro [#9]. Membrane recruitment depends on coincidence detection of PI3P and Rag GTPases, with GDP-locked RagC promoting and GTP-locked RagA preventing recruitment, linking the complex to the mTORC1 pathway and autophagic lysosome reformation [#6]. Loss of spastizin blocks autophagosome maturation and autophagosome-endosome fusion—the latter via its interactions with RAB5A and RAB11, with constitutively active RAB5A partially rescuing the defect—producing accumulation of immature autophagosomes, enlarged LAMP1-positive lysosomes, and depletion of free lysosomes [#4, #5, #2]. Spastizin and spatacsin mutually stabilize one another [#3]. In neurons, deficiency causes defective anterograde axonal transport, lipid accumulation, mitochondrial fragmentation with reduced ATP production, and synaptic vulnerability to excitotoxicity [#7, #10], establishing ZFYVE26 as a determinant of neuronal lysosomal and mitochondrial homeostasis.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the first cellular context for an uncharacterized FYVE-domain protein by placing it at ER/endosomal compartments, implicating it in intracellular trafficking.\",\n      \"evidence\": \"Immunofluorescence colocalization with organelle markers in cultured cells\",\n      \"pmids\": [\"18394578\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single colocalization experiment with no functional follow-up\", \"No interaction partners or molecular activity defined\", \"Did not distinguish ER from endosomal residence functionally\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined spastizin as a stoichiometric subunit of an AP-5/SPG11/SPG15 coat complex on late endosomes/lysosomes, assigning it a membrane-docking role via PI3P binding and establishing a shared trafficking phenotype with AP-5.\",\n      \"evidence\": \"Reciprocal Co-IP with stoichiometry, RNAi epistasis with mannose 6-phosphate receptor trapping, colocalization, and in vitro SPG11-AP-5 binding\",\n      \"pmids\": [\"23825025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FYVE-PI3P docking proposed but not directly demonstrated in this study\", \"Mechanism of cargo handling by the coat unresolved\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Confirmed the endolysosomal trafficking role in vivo, showing genetic loss produces intraneuronal LAMP1-positive deposits and lysosomal dysregulation.\",\n      \"evidence\": \"Zfyve26 knockout mouse with fractionation, EM, EEA1/Lamp1 immunostaining, and lysosomal enzyme assays\",\n      \"pmids\": [\"24367272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular step disrupted\", \"Link to autophagy not yet established here\", \"Mechanism connecting deposits to neurodegeneration unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified spastizin as a determinant of autophagosome maturation, extending its role from endosomal trafficking to autophagy.\",\n      \"evidence\": \"Patient fibroblasts/lymphoblasts and primary neurons with LC3B-II and p62 western blots and autophagosome quantification\",\n      \"pmids\": [\"24284334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which fusion or maturation step is blocked\", \"No structural or interaction mechanism\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed spastizin and spatacsin are interdependently stabilized and that patient cells exhibit lysosomal enlargement and storage, reinforcing an obligate heterodimer with a lysosomal phenotype.\",\n      \"evidence\": \"Patient-derived fibroblasts with LAMP1 immunofluorescence, EM, and western blot stability analysis\",\n      \"pmids\": [\"24999486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mutual stabilization not structurally defined\", \"Lysosomal storage cargo not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished spastizin's specific function from spatacsin by showing only ZFYVE26 controls RAB5A/RAB11 activation and autophagosome-endosome fusion, with RAB5A rescue pinpointing the defective step.\",\n      \"evidence\": \"Co-IP for RAB5A/RAB11, autophagosome-endosome fusion assay, constitutively active RAB5A rescue, and autophagic lysosome reformation assay in patient cells\",\n      \"pmids\": [\"30081747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How spastizin regulates RAB activation mechanistically unresolved\", \"Direct vs indirect RAB interaction not separated\", \"Relationship between fusion defect and ALR defect not fully ordered\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how the coat is recruited to membranes, showing PI3P–Rag GTPase coincidence detection and linking complex localization to mTORC1-coupled autophagic lysosome reformation.\",\n      \"evidence\": \"Live-cell imaging with dominant Rag GTPase mutants, FYVE-domain PI3P binding assays, and starvation-dependent recruitment\",\n      \"pmids\": [\"33464297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical Rag-complex contact not structurally mapped\", \"How GDP-RagC vs GTP-RagA states are sensed unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the neuronal consequences of spastizin loss, connecting lysosomal/autophagy dysfunction to axonal transport, lipid handling, and synaptic vulnerability.\",\n      \"evidence\": \"Patient fibroblasts and KO mouse cortical neurons with axonal transport imaging, autophagic flux, lipid staining, electrophysiology, and excitotoxicity assays\",\n      \"pmids\": [\"35313342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from lysosomal defect to transport failure not established\", \"Single lab\", \"Lipid species not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated lysosomes as a tractable therapeutic node by showing calcium/calpain- and lysosome-modulating compounds rescue ALR defects across patient cells and a Drosophila model.\",\n      \"evidence\": \"Compound library screen in patient cells, Drosophila SPG15 loss-of-function model with lysosome quantification and locomotor readouts\",\n      \"pmids\": [\"36029068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets of rescue compounds not all defined\", \"Whether rescue restores neuronal function long-term unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural mechanism, showing the W-shaped SPG11-SPG15 heterodimer with super-open AP-5 binds PI3P, senses curvature, and remodels membranes to initiate autolysosome tubulation.\",\n      \"evidence\": \"Cryo-EM structure, in vitro membrane remodeling and PI3P binding reconstitution, and domain mutagenesis validating SPG11 N-terminal AP-5 contact\",\n      \"pmids\": [\"40175557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of curvature sensing not directly tested\", \"Conformational coupling to Rag/PI3P recruitment not resolved structurally\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended spastizin function beyond endolysosomal trafficking by linking it to mitochondrial integrity, with DRP1 inhibition rescuing fragmentation and downstream neuronal pathology.\",\n      \"evidence\": \"Patient iPSC-derived cortical neurons with ATP, mitochondrial morphology, oxidative stress and apoptosis assays plus DRP1 inhibitor P110 rescue\",\n      \"pmids\": [\"41192643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mitochondrial defect is primary or secondary to lysosomal dysfunction unresolved\", \"Mechanism of spastizin mitochondrial localization unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structurally defined coat coordinates PI3P/Rag coincidence detection, RAB-dependent fusion, and membrane remodeling into a single ordered ALR cycle in neurons remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking recruitment, fusion, and tubulation in time\", \"Causal hierarchy among lysosomal, transport, and mitochondrial defects unestablished\", \"No structure of the membrane-bound holocomplex with Rag GTPases\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 6, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"complexes\": [\"AP-5/SPG11/SPG15 coat complex\"],\n    \"partners\": [\"SPG11\", \"AP5Z1\", \"RAB5A\", \"RAB11\", \"RagC\", \"RagA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}