{"gene":"SPG11","run_date":"2026-06-10T07:46:39","timeline":{"discoveries":[{"year":2013,"finding":"SPG11 (spatacsin) and SPG15 (spastizin) physically interact with all four subunits of the AP-5 adaptor protein complex in a ~1:1:1:1:1:1 stoichiometry, as shown by co-immunoprecipitation from both cytosol and detergent-extracted membranes. The N-terminal β-propeller-like domain of SPG11 interacts in vitro with AP-5. All six knockdowns (AP-5 subunits, SPG11, SPG15) phenocopy each other, causing cation-independent mannose-6-phosphate receptor trapping in early endosome clusters. AP-5, SPG11, and SPG15 co-localize on a late endosomal/lysosomal compartment, suggesting they form a coat-like complex involved in protein sorting.","method":"Co-immunoprecipitation (reciprocal, from cytosol and membranes), in vitro binding assay, siRNA knockdown with CI-M6PR localization readout, co-localization imaging, secondary structure prediction","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with stoichiometry determination, in vitro domain binding, knockdown epistasis, colocalization; multiple orthogonal methods in one study","pmids":["23825025"],"is_preprint":false},{"year":2015,"finding":"Loss of spatacsin (Spg11 knockout) in mice causes lysosome depletion: lysosome numbers are reduced in knockout MEFs and in cortical neurons and Purkinje cells in vivo. Recovery of lysosomes during sustained starvation is impaired, consistent with a defect in autophagic lysosome reformation (ALR). Lipidated LC3 levels are increased in knockout MEFs indicating a generalized autophagy defect. Degenerating neurons accumulate autofluorescent material positive for LAMP1 and p62. Cathepsin D processing and lysosomal pH are preserved, indicating the defect is specific to lysosome biogenesis/reformation rather than bulk lysosomal enzymatic function.","method":"Spg11 knockout mouse model; lysosome quantification by immunofluorescence in MEFs and neurons in vivo; LC3 lipidation western blot; cathepsin D processing assay; lysosomal pH measurement; starvation-recovery assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal cellular readouts in both primary cells and in vivo tissue; replicated across cell types","pmids":["26284655"],"is_preprint":false},{"year":2014,"finding":"Spatacsin localizes to axons and dendrites of human and mouse neurons, co-localizes with cytoskeletal and synaptic vesicle markers, and is present in synaptosomes. Loss of spatacsin (SPG11 patient-derived neurons or siRNA knockdown in mouse cortical neurons) leads to: downregulation of axonal genes, decreased neurite complexity, accumulation of membranous bodies in axonal processes, reduced acetylated tubulin (axonal instability), and reduced anterograde vesicle trafficking as shown by time-lapse imaging.","method":"iPSC-derived neurons from SPG11 patients; siRNA knockdown in mouse cortical neurons; immunofluorescence co-localization; synaptosome fractionation; time-lapse live imaging of vesicle trafficking; acetylated tubulin western blot","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in human patient neurons and mouse neurons with multiple orthogonal mechanistic readouts (localization, transport, cytoskeletal markers)","pmids":["24794856"],"is_preprint":false},{"year":2014,"finding":"Fibroblasts from SPG11 patients show selective enlargement of LAMP1-positive lysosomal structures. The stabilities of SPG15 (spastizin) and SPG11 (spatacsin) proteins are interdependent: loss of one destabilizes the other.","method":"Patient-derived fibroblast analysis; immunofluorescence for LAMP1; electron microscopy for lysosomal storage; western blot for protein stability in SPG11 and SPG15 patient cells","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells, two orthogonal methods (IF and EM), single lab","pmids":["24999486"],"is_preprint":false},{"year":2018,"finding":"SPG11 mutations cause a milder autophagy defect than SPG15 mutations. Both SPG11 and SPG15 interact with RAB5A and RAB11 (endosome trafficking regulators), but only SPG15 mutations affect RAB protein interactions and activation. SPG15 mutations disrupt fusion between autophagosomes and endosomes, while SPG11 mutations do not affect this step. Both proteins are required for autophagic lysosome reformation (ALR), but SPG15 additionally acts at the autophagy–endocytosis intersection.","method":"Patient-derived cells with SPG11 or SPG15 mutations; co-immunoprecipitation for RAB5A/RAB11 interactions; RAB activation assays; autophagosome–endosome fusion assays; ALR assays; constitutively active RAB5A rescue experiment","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient cells plus RAB interaction assays and functional rescue, single lab, multiple readouts","pmids":["30081747"],"is_preprint":false},{"year":2021,"finding":"Recruitment of the AP-5/SPG11/SPG15 complex to late endosomes/lysosomes requires coincidence detection of two signals: phosphatidylinositol 3-phosphate (PI3P, via the SPG15 FYVE domain) and Rag GTPases. GDP-locked RagC promotes complex recruitment while GTP-locked RagA prevents it. Recruitment is enhanced in starved cells, revealing an interplay between this complex and the mTORC1 pathway.","method":"Cell-based recruitment assays with dominant-negative/constitutively active Rag GTPase mutants; PI3P manipulation; localization imaging; starvation conditions","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic epistasis with Rag GTPase mutants and PI3P manipulation, multiple orthogonal approaches establishing coincidence detection mechanism","pmids":["33464297"],"is_preprint":false},{"year":2016,"finding":"SPG11 patient-derived neural progenitor cells (NPCs) show dysregulation of the GSK3β-signaling pathway. GSK3β hyperactivation in SPG11-NPCs impairs proliferation, reducing neural cell numbers. Pharmacological GSK3 modulation rescues the NPC proliferation defect. Gene expression profiling revealed alterations in cell-cycle, neurogenesis, cortical development, and autophagy pathways.","method":"iPSC-derived NPCs from 3 SPG11 patients; transcriptome profiling; proliferation assays; GSK3 inhibitor rescue (pharmacological modulation); pathway analysis","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient iPSC-derived NPCs with pharmacological rescue demonstrating GSK3β pathway, single lab, multiple methods","pmids":["26971897"],"is_preprint":false},{"year":2019,"finding":"SPG11 patient-derived cortical organoids are smaller than controls, with larger ventricles and thinner germinal walls, caused by increased asymmetric divisions of NPCs leading to premature neurogenesis. GSK3 inhibitors including FDA-approved tideglusib rescue organoid size and premature neurogenesis.","method":"3D brain organoids from SPG11 patient iPSCs; 2D NPC cultures; division mode quantification; GSK3 inhibitor (tideglusib) rescue","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient organoid model with pharmacological rescue, single lab, multiple readouts","pmids":["30476097"],"is_preprint":false},{"year":2018,"finding":"GSK3β inhibitor tideglusib rescues neurite pathology (shorter, less complex neurites), increased cell death, and membranous inclusions in SPG11 iPSC-derived cortical neurons and in a CRISPR-Cas9 SPG11 knockout line, confirming GSK3β/βCatenin pathway dysregulation as a mechanistic basis for neurodegeneration.","method":"SPG11 patient iPSC-derived cortical neurons; CRISPR-Cas9 SPG11 knockout iPSC line; tideglusib treatment; neurite morphometry; cell death assays; membrane inclusion quantification","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-edited KO plus patient neurons, pharmacological rescue, single lab","pmids":["30574063"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of the AP5-SPG11-SPG15 complex reveals: SPG11-SPG15 form a W-shaped intertwined head-to-head heterodimer; the N-terminal region of SPG11 is required for AP5 complex interaction and assembly; AP5 adopts a super-open conformation. The AP5-SPG11-SPG15 complex binds PI3P, senses membrane curvature, and drives membrane remodeling (tubulation initiation) in vitro.","method":"Cryo-electron microscopy; in silico structural prediction; PI3P binding assay; in vitro membrane remodeling/tubulation assay; domain deletion constructs","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus in vitro functional reconstitution of membrane remodeling; multiple orthogonal methods","pmids":["40175557"],"is_preprint":false},{"year":2024,"finding":"SPG11 loss of function causes accumulation of gangliosides in lysosomes of Spg11 knockout mouse neurons. Reducing ganglioside synthesis by AAV-mediated miRNA knockdown of St3gal5 or pharmacological inhibition of glucosylceramide synthase (venglustat) prevents ganglioside accumulation, delays motor and cognitive symptom onset, prevents neurofilament light chain elevation, and strongly reduces axonal spheroid formation. Venglustat also reduced axonal spheroids in cultured human SPG11 neurons, linking ganglioside trafficking to axonal pathology.","method":"Spg11 knockout mice; AAV-PHP.eB viral miRNA delivery targeting St3gal5; venglustat pharmacological treatment; ganglioside quantification; behavioral testing; serum NfL measurement; axonal spheroid counting in mouse and human SPG11 cultured neurons","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse with two independent intervention strategies (genetic and pharmacological) plus human neuron validation; multiple orthogonal readouts","pmids":["38876323"],"is_preprint":false},{"year":2023,"finding":"SPG11 deficiency in human cortical projection neurons (from hESC-derived knockdown and disease-mutation knock-in lines) causes cholesterol accumulation in lysosomes with reduction at the plasma membrane, indicating impaired cholesterol trafficking. LXR agonists restore cholesterol homeostasis and rescue axonal outgrowth defects, impaired axonal transport, and axonal swellings.","method":"hESC SPG11 knockdown; disease-mutation knock-in hESC cortical neurons; cholesterol subcellular distribution imaging; LXR agonist treatment; axonal outgrowth and transport assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent cell models (KD and KI), pharmacological rescue, multiple readouts; single lab","pmids":["37709208"],"is_preprint":false},{"year":2024,"finding":"Loss of SPG11 function in microglia/macrophages causes hyperactivation of the non-canonical inflammasome, resulting in stronger inflammatory responses. LPS challenge triggers markedly increased lethality and inflammatory response in Spg11 KO mice in vivo. Mass spectrometry of activated BMDMs from Spg11 KO mice reveals massive downregulation of AP5 subunits upon Spg11 disruption, linking spatacsin to AP5 stability in immune cells. STAT1 phosphorylation is increased as the molecular mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function; STAT1 inhibition decreases CXCL10 production and rescues toxic effects on SPG11 neurons.","method":"Spg11 KO mouse primary microglia and BMDMs; patient-derived MDMs; LPS challenge in vivo; mass spectrometry of activated BMDMs; STAT1 phosphorylation western blot; STAT1 inhibitor rescue; CXCL10 ELISA; IFNγ stimulation of patient iPSC-derived microglia-like cells","journal":"Acta neuropathologica","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse plus patient-derived cells, mass spectrometry, pathway-specific rescue, multiple orthogonal methods","pmids":["38305941"],"is_preprint":false},{"year":2025,"finding":"SPG11 mutations cause lysosomal calcium accumulation in neural progenitor cells (NPCs), which reduces NPC proliferation and diminishes apical tight junctions during cortical development. This is mechanistically linked to lysosomal recruitment of PI4K2A (phosphatidylinositol 4-kinase type 2 alpha), resulting in elevated PI(4)P levels that hypoactivate mTOR signaling. Pharmacological modulation of the lysosomal calcium channel TRPML1 corrects all developmental phenotypes in cortical organoids.","method":"Spg11 knockout mouse; iPSC-derived cortical organoids from SPG11 models; lysosomal calcium measurement; PI4K2A localization by imaging; PI(4)P quantification; mTOR activity assays; RNA sequencing; TRPML1 agonist/antagonist pharmacological rescue; tight junction imaging","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple models (KO mouse + organoids), mechanistic pathway elucidation (lysosomal Ca²⁺ → PI4K2A → PI(4)P → mTOR), pharmacological rescue, RNA-seq; multiple orthogonal methods","pmids":["42049147"],"is_preprint":false},{"year":2010,"finding":"Morpholino-mediated knockdown of spatacsin (spg11) in zebrafish embryos causes CNS developmental defects and an overall perturbation of neuronal differentiation with disruption of axon pathway formation, identifying a critical role for spatacsin in early neural development in vivo.","method":"Morpholino antisense oligonucleotide knockdown in zebrafish; whole-mount in situ hybridization for transcript distribution; axon pathway immunostaining","journal":"Neurogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — morpholino KD in zebrafish with defined axonal phenotype readout; single lab, single model organism approach","pmids":["20390432"],"is_preprint":false}],"current_model":"Spatacsin (SPG11) is a large scaffolding protein that forms a W-shaped head-to-head heterodimer with SPG15 (spastizin) and together associates with the AP-5 adaptor complex in a coat-like assembly on late endosomes/lysosomes; this AP5-SPG11-SPG15 complex is recruited by coincidence detection of PI3P (via the SPG15 FYVE domain) and Rag GTPases, senses membrane curvature, and drives lysosomal tubulation required for autophagic lysosome reformation (ALR), such that its loss causes lysosome depletion, ganglioside and cholesterol accumulation, impaired axonal transport and neurite maintenance, GSK3β-mediated neurodevelopmental defects in neural progenitors (via lysosomal calcium/PI4K2A/mTOR axis), and hyperactivation of the non-canonical inflammasome in microglia through increased STAT1 signaling."},"narrative":{"mechanistic_narrative":"Spatacsin (SPG11) is a large scaffolding protein that organizes a coat-like assembly on late endosomes/lysosomes to drive lysosome reformation, and its loss produces a spectrum of neurodevelopmental and neurodegenerative phenotypes [PMID:23825025, PMID:26284655]. Spatacsin and spastizin (SPG15) bind all four subunits of the AP-5 adaptor complex in fixed stoichiometry, with the N-terminal β-propeller-like domain of SPG11 mediating the AP-5 interaction; the two proteins are mutually stabilizing and co-localize with AP-5 on a late endosomal/lysosomal compartment [PMID:23825025, PMID:24999486]. Cryo-EM shows SPG11 and SPG15 form a W-shaped head-to-head heterodimer that holds AP-5 in a super-open conformation, binds PI3P, senses membrane curvature, and initiates membrane tubulation in vitro [PMID:40175557]. The complex is recruited to lysosomes by coincidence detection of PI3P (via the SPG15 FYVE domain) and GDP-locked RagC, an interplay with mTORC1 signaling that is enhanced upon starvation [PMID:33464297]. Functionally, this activity is required for autophagic lysosome reformation: Spg11 loss depletes lysosomes, impairs their recovery during starvation, and elevates lipidated LC3, while leaving lysosomal enzymatic function intact [PMID:26284655]. Loss of spatacsin disrupts neuronal homeostasis through multiple downstream routes — lysosomal accumulation of gangliosides and cholesterol with resulting axonal spheroids and impaired axonal transport [PMID:38876323, PMID:37709208], GSK3β hyperactivation impairing neural progenitor proliferation and driving premature neurogenesis [PMID:26971897, PMID:30476097, PMID:30574063], a lysosomal calcium–PI4K2A–mTOR axis that perturbs cortical development [PMID:42049147], and hyperactivation of the non-canonical inflammasome in microglia via increased STAT1 signaling [PMID:38305941]. SPG11 mutations underlie an autosomal recessive hereditary spastic paraplegia, modeled in patient-derived neurons and organoids [PMID:24794856, PMID:30476097].","teleology":[{"year":2010,"claim":"Established that spatacsin is required for early neural development in vivo, before any molecular function was known.","evidence":"Morpholino knockdown of spg11 in zebrafish embryos with axon pathway immunostaining","pmids":["20390432"],"confidence":"Medium","gaps":["No molecular mechanism for the developmental defect","Morpholino specificity not addressed by genetic rescue","Single model organism"]},{"year":2013,"claim":"Defined the core molecular identity of spatacsin as a stoichiometric partner of SPG15 and the AP-5 adaptor complex, establishing a coat-like sorting machinery on late endosomes/lysosomes.","evidence":"Reciprocal Co-IP with stoichiometry, in vitro domain binding of the SPG11 N-terminus to AP-5, knockdown epistasis on CI-M6PR sorting, and colocalization imaging","pmids":["23825025"],"confidence":"High","gaps":["Structural basis of the assembly not resolved","Functional consequence for lysosome biology not yet defined"]},{"year":2014,"claim":"Connected spatacsin loss to neuronal axonal pathology and to lysosomal enlargement, and showed SPG11/SPG15 protein stability is interdependent.","evidence":"iPSC patient neurons and mouse cortical neuron knockdown with vesicle trafficking imaging and cytoskeletal markers; patient fibroblast LAMP1 imaging, EM, and protein stability westerns","pmids":["24794856","24999486"],"confidence":"High","gaps":["Mechanism linking lysosomal defect to axonal transport not established","Cargo whose mistrafficking drives axonal instability unknown"]},{"year":2015,"claim":"Identified the cell-biological function of spatacsin as autophagic lysosome reformation, explaining lysosome depletion as the proximate consequence of its loss.","evidence":"Spg11 knockout mouse with lysosome quantification in MEFs and neurons, starvation-recovery assay, LC3 lipidation, and preserved cathepsin D processing/pH","pmids":["26284655"],"confidence":"High","gaps":["How the complex physically reforms lysosomes not yet shown","Recruitment signals to lysosomes undefined"]},{"year":2016,"claim":"Revealed that spatacsin loss impairs neural progenitor proliferation through GSK3β hyperactivation, a pharmacologically reversible mechanism.","evidence":"iPSC-derived NPCs from three SPG11 patients with transcriptome profiling, proliferation assays, and GSK3 inhibitor rescue","pmids":["26971897"],"confidence":"Medium","gaps":["Link between lysosomal dysfunction and GSK3β activation not mechanistically connected","Single lab"]},{"year":2018,"claim":"Distinguished SPG11 from SPG15 function, showing both are required for ALR but only SPG15 acts at the autophagy-endocytosis intersection via RAB regulation.","evidence":"Patient cells with SPG11 or SPG15 mutations, RAB5A/RAB11 Co-IP and activation assays, autophagosome-endosome fusion and ALR assays with RAB5A rescue","pmids":["30081747"],"confidence":"Medium","gaps":["Why SPG11 produces a milder defect than its partner unclear","Single lab"]},{"year":2018,"claim":"Confirmed GSK3β/β-catenin dysregulation as a driver of neuronal pathology in mature neurons using both patient and isogenic knockout lines.","evidence":"SPG11 patient iPSC cortical neurons and a CRISPR-Cas9 knockout line with tideglusib rescue of neurite, death, and inclusion phenotypes","pmids":["30574063"],"confidence":"Medium","gaps":["Upstream trigger of GSK3β hyperactivation still not identified"]},{"year":2019,"claim":"Demonstrated that GSK3β dysregulation causes a developmental phenotype — premature neurogenesis from altered NPC division mode — reversible by an FDA-approved GSK3 inhibitor.","evidence":"SPG11 patient iPSC cortical organoids with division mode quantification and tideglusib rescue","pmids":["30476097"],"confidence":"Medium","gaps":["Molecular path from spatacsin to division asymmetry not resolved"]},{"year":2021,"claim":"Solved how the complex is targeted to lysosomes, defining coincidence detection of PI3P and Rag GTPase state as the recruitment switch and linking it to mTORC1.","evidence":"Cell-based recruitment assays with Rag GTPase mutants, PI3P manipulation, and starvation conditions","pmids":["33464297"],"confidence":"High","gaps":["Direct contact between the complex and Rag GTPases not structurally defined"]},{"year":2023,"claim":"Identified impaired cholesterol trafficking as a distinct lysosomal consequence of SPG11 loss, with axonal phenotypes rescuable by LXR agonists.","evidence":"hESC SPG11 knockdown and disease-mutation knock-in cortical neurons with cholesterol distribution imaging, LXR agonist treatment, axonal outgrowth and transport assays","pmids":["37709208"],"confidence":"Medium","gaps":["Whether cholesterol and ganglioside accumulation share a common upstream lysosomal defect unclear","Single lab"]},{"year":2024,"claim":"Showed ganglioside accumulation in lysosomes is a causal driver of axonal pathology in vivo, reversible by reducing glycosphingolipid synthesis.","evidence":"Spg11 knockout mice with AAV miRNA knockdown of St3gal5 and venglustat treatment, ganglioside quantification, behavior, serum NfL, and axonal spheroid counts plus human neuron validation","pmids":["38876323"],"confidence":"High","gaps":["Mechanism by which ganglioside buildup generates spheroids not detailed"]},{"year":2024,"claim":"Extended spatacsin function to innate immunity, showing its loss destabilizes AP5 in immune cells and hyperactivates the non-canonical inflammasome through increased STAT1 signaling.","evidence":"Spg11 KO mouse microglia/BMDMs and patient MDMs, LPS challenge in vivo, mass spectrometry, STAT1 phospho westerns, STAT1 inhibitor rescue of neuronal toxicity","pmids":["38305941"],"confidence":"High","gaps":["How lysosomal/AP5 dysfunction mechanistically elevates STAT1 phosphorylation not resolved"]},{"year":2025,"claim":"Provided the structural basis for the complex and reconstituted its membrane-remodeling activity, unifying the recruitment and ALR observations into a physical mechanism.","evidence":"Cryo-EM of AP5-SPG11-SPG15, PI3P binding and in vitro membrane tubulation assays, and domain deletion constructs","pmids":["40175557"],"confidence":"High","gaps":["Structure of the membrane-engaged, curvature-sensing state not captured","In vivo tubulation dynamics not visualized"]},{"year":2025,"claim":"Defined a lysosomal calcium–PI4K2A–PI(4)P–mTOR axis through which spatacsin loss disrupts cortical development, with TRPML1 modulation as a corrective intervention.","evidence":"Spg11 KO mouse and iPSC cortical organoids with lysosomal calcium measurement, PI4K2A localization, PI(4)P and mTOR assays, RNA-seq, and TRPML1 pharmacological rescue","pmids":["42049147"],"confidence":"High","gaps":["Relationship between this axis and the GSK3β pathway in NPCs not integrated"]},{"year":null,"claim":"How a single lysosomal reformation defect bifurcates into distinct downstream cascades — GSK3β, lysosomal Ca2+/PI4K2A/mTOR, lipid accumulation, and STAT1-driven inflammation — and whether they converge on a common proximal lesion remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model linking the four downstream pathways","Cell-type specificity of each cascade not systematically compared","Cargo whose mistrafficking initiates each cascade unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,9]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1,3,5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2]}],"complexes":["AP5-SPG11-SPG15 complex"],"partners":["SPG15","AP5Z1","AP5M1","AP5B1","AP5S1","RAB5A","RAB11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JI7","full_name":"Spatacsin","aliases":["Colorectal carcinoma-associated protein","Spastic paraplegia 11 protein"],"length_aa":2443,"mass_kda":278.9,"function":"May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport","subcellular_location":"Cytoplasm, cytosol; Nucleus; Cell projection, axon; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q96JI7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPG11","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPG11","total_profiled":1310},"omim":[{"mim_id":"616668","title":"CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2X; CMT2X","url":"https://www.omim.org/entry/616668"},{"mim_id":"614824","title":"ADAPTOR-RELATED PROTEIN COMPLEX 5, SIGMA-1 SUBUNIT; AP5S1","url":"https://www.omim.org/entry/614824"},{"mim_id":"614409","title":"SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE; SPG46","url":"https://www.omim.org/entry/614409"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPG11"},"hgnc":{"alias_symbol":["FLJ21439"],"prev_symbol":["KIAA1840","ALS5"]},"alphafold":{"accession":"Q96JI7","domains":[{"cath_id":"-","chopping":"30-193","consensus_level":"medium","plddt":69.8041,"start":30,"end":193},{"cath_id":"-","chopping":"1033-1133","consensus_level":"medium","plddt":67.226,"start":1033,"end":1133},{"cath_id":"-","chopping":"1669-1700","consensus_level":"medium","plddt":67.7769,"start":1669,"end":1700},{"cath_id":"-","chopping":"1849-1935_1972-2014","consensus_level":"medium","plddt":72.1677,"start":1849,"end":2014},{"cath_id":"-","chopping":"2227-2315","consensus_level":"medium","plddt":81.1449,"start":2227,"end":2315}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JI7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JI7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JI7-F1-predicted_aligned_error_v6.png","plddt_mean":66.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPG11","jax_strain_url":"https://www.jax.org/strain/search?query=SPG11"},"sequence":{"accession":"Q96JI7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JI7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JI7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JI7"}},"corpus_meta":[{"pmid":"17322883","id":"PMC_17322883","title":"Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17322883","citation_count":263,"is_preprint":false},{"pmid":"18079167","id":"PMC_18079167","title":"Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.","date":"2007","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/18079167","citation_count":189,"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":"26284655","id":"PMC_26284655","title":"In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary 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A case-control study.","date":"2025","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40498122","citation_count":1,"is_preprint":false},{"pmid":"34479069","id":"PMC_34479069","title":"Generation and characterization of an endogenously tagged SPG11-human iPSC line by CRISPR/Cas9 mediated knock-in.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34479069","citation_count":1,"is_preprint":false},{"pmid":"37510225","id":"PMC_37510225","title":"Upregulation of Heat-Shock Protein (hsp)-27 in a Patient with Heterozygous SPG11 c.1951C>T and SYNJ1 c.2614G>T Mutations Causing Clinical Spastic Paraplegia.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37510225","citation_count":1,"is_preprint":false},{"pmid":"41228418","id":"PMC_41228418","title":"Nutritional Approaches in Neurodegenerative Disorders: A Mini Scoping Review with Emphasis on SPG11-Related Conditions.","date":"2025","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/41228418","citation_count":1,"is_preprint":false},{"pmid":"35036589","id":"PMC_35036589","title":"A complex form of hereditary spastic paraplegia harboring a novel variant, p.W1515*, in the SPG11 gene.","date":"2022","source":"eNeurologicalSci","url":"https://pubmed.ncbi.nlm.nih.gov/35036589","citation_count":1,"is_preprint":false},{"pmid":"41138668","id":"PMC_41138668","title":"Hyperactivity of the non-canonical inflammasome in SPG11 and SPG48.","date":"2025","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41138668","citation_count":0,"is_preprint":false},{"pmid":"33222977","id":"PMC_33222977","title":"Homozygous frameshift mutation of SPG11 as a cause of progressive flaccid paralysis, ataxia and dysphagia.","date":"2020","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/33222977","citation_count":0,"is_preprint":false},{"pmid":"42049147","id":"PMC_42049147","title":"SPG11 models reveal lysosomal calcium regulation of neural progenitor proliferation.","date":"2026","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/42049147","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.21.665525","title":"SPG11 models reveal lysosomal calcium as a regulator of neural progenitor proliferation","date":"2025-07-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.21.665525","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47017,"output_tokens":4590,"usd":0.104951,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12841,"output_tokens":4796,"usd":0.092052,"stage2_stop_reason":"end_turn"},"total_usd":0.197003,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"SPG11 (spatacsin) and SPG15 (spastizin) physically interact with all four subunits of the AP-5 adaptor protein complex in a ~1:1:1:1:1:1 stoichiometry, as shown by co-immunoprecipitation from both cytosol and detergent-extracted membranes. The N-terminal β-propeller-like domain of SPG11 interacts in vitro with AP-5. All six knockdowns (AP-5 subunits, SPG11, SPG15) phenocopy each other, causing cation-independent mannose-6-phosphate receptor trapping in early endosome clusters. AP-5, SPG11, and SPG15 co-localize on a late endosomal/lysosomal compartment, suggesting they form a coat-like complex involved in protein sorting.\",\n      \"method\": \"Co-immunoprecipitation (reciprocal, from cytosol and membranes), in vitro binding assay, siRNA knockdown with CI-M6PR localization readout, co-localization imaging, secondary structure prediction\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with stoichiometry determination, in vitro domain binding, knockdown epistasis, colocalization; multiple orthogonal methods in one study\",\n      \"pmids\": [\"23825025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of spatacsin (Spg11 knockout) in mice causes lysosome depletion: lysosome numbers are reduced in knockout MEFs and in cortical neurons and Purkinje cells in vivo. Recovery of lysosomes during sustained starvation is impaired, consistent with a defect in autophagic lysosome reformation (ALR). Lipidated LC3 levels are increased in knockout MEFs indicating a generalized autophagy defect. Degenerating neurons accumulate autofluorescent material positive for LAMP1 and p62. Cathepsin D processing and lysosomal pH are preserved, indicating the defect is specific to lysosome biogenesis/reformation rather than bulk lysosomal enzymatic function.\",\n      \"method\": \"Spg11 knockout mouse model; lysosome quantification by immunofluorescence in MEFs and neurons in vivo; LC3 lipidation western blot; cathepsin D processing assay; lysosomal pH measurement; starvation-recovery assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal cellular readouts in both primary cells and in vivo tissue; replicated across cell types\",\n      \"pmids\": [\"26284655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Spatacsin localizes to axons and dendrites of human and mouse neurons, co-localizes with cytoskeletal and synaptic vesicle markers, and is present in synaptosomes. Loss of spatacsin (SPG11 patient-derived neurons or siRNA knockdown in mouse cortical neurons) leads to: downregulation of axonal genes, decreased neurite complexity, accumulation of membranous bodies in axonal processes, reduced acetylated tubulin (axonal instability), and reduced anterograde vesicle trafficking as shown by time-lapse imaging.\",\n      \"method\": \"iPSC-derived neurons from SPG11 patients; siRNA knockdown in mouse cortical neurons; immunofluorescence co-localization; synaptosome fractionation; time-lapse live imaging of vesicle trafficking; acetylated tubulin western blot\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in human patient neurons and mouse neurons with multiple orthogonal mechanistic readouts (localization, transport, cytoskeletal markers)\",\n      \"pmids\": [\"24794856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fibroblasts from SPG11 patients show selective enlargement of LAMP1-positive lysosomal structures. The stabilities of SPG15 (spastizin) and SPG11 (spatacsin) proteins are interdependent: loss of one destabilizes the other.\",\n      \"method\": \"Patient-derived fibroblast analysis; immunofluorescence for LAMP1; electron microscopy for lysosomal storage; western blot for protein stability in SPG11 and SPG15 patient cells\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells, two orthogonal methods (IF and EM), single lab\",\n      \"pmids\": [\"24999486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPG11 mutations cause a milder autophagy defect than SPG15 mutations. Both SPG11 and SPG15 interact with RAB5A and RAB11 (endosome trafficking regulators), but only SPG15 mutations affect RAB protein interactions and activation. SPG15 mutations disrupt fusion between autophagosomes and endosomes, while SPG11 mutations do not affect this step. Both proteins are required for autophagic lysosome reformation (ALR), but SPG15 additionally acts at the autophagy–endocytosis intersection.\",\n      \"method\": \"Patient-derived cells with SPG11 or SPG15 mutations; co-immunoprecipitation for RAB5A/RAB11 interactions; RAB activation assays; autophagosome–endosome fusion assays; ALR assays; constitutively active RAB5A rescue experiment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient cells plus RAB interaction assays and functional rescue, single lab, multiple readouts\",\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 requires coincidence detection of two signals: phosphatidylinositol 3-phosphate (PI3P, via the SPG15 FYVE domain) and Rag GTPases. GDP-locked RagC promotes complex recruitment while GTP-locked RagA prevents it. Recruitment is enhanced in starved cells, revealing an interplay between this complex and the mTORC1 pathway.\",\n      \"method\": \"Cell-based recruitment assays with dominant-negative/constitutively active Rag GTPase mutants; PI3P manipulation; localization imaging; starvation conditions\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic epistasis with Rag GTPase mutants and PI3P manipulation, multiple orthogonal approaches establishing coincidence detection mechanism\",\n      \"pmids\": [\"33464297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SPG11 patient-derived neural progenitor cells (NPCs) show dysregulation of the GSK3β-signaling pathway. GSK3β hyperactivation in SPG11-NPCs impairs proliferation, reducing neural cell numbers. Pharmacological GSK3 modulation rescues the NPC proliferation defect. Gene expression profiling revealed alterations in cell-cycle, neurogenesis, cortical development, and autophagy pathways.\",\n      \"method\": \"iPSC-derived NPCs from 3 SPG11 patients; transcriptome profiling; proliferation assays; GSK3 inhibitor rescue (pharmacological modulation); pathway analysis\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient iPSC-derived NPCs with pharmacological rescue demonstrating GSK3β pathway, single lab, multiple methods\",\n      \"pmids\": [\"26971897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPG11 patient-derived cortical organoids are smaller than controls, with larger ventricles and thinner germinal walls, caused by increased asymmetric divisions of NPCs leading to premature neurogenesis. GSK3 inhibitors including FDA-approved tideglusib rescue organoid size and premature neurogenesis.\",\n      \"method\": \"3D brain organoids from SPG11 patient iPSCs; 2D NPC cultures; division mode quantification; GSK3 inhibitor (tideglusib) rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient organoid model with pharmacological rescue, single lab, multiple readouts\",\n      \"pmids\": [\"30476097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GSK3β inhibitor tideglusib rescues neurite pathology (shorter, less complex neurites), increased cell death, and membranous inclusions in SPG11 iPSC-derived cortical neurons and in a CRISPR-Cas9 SPG11 knockout line, confirming GSK3β/βCatenin pathway dysregulation as a mechanistic basis for neurodegeneration.\",\n      \"method\": \"SPG11 patient iPSC-derived cortical neurons; CRISPR-Cas9 SPG11 knockout iPSC line; tideglusib treatment; neurite morphometry; cell death assays; membrane inclusion quantification\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-edited KO plus patient neurons, pharmacological rescue, single lab\",\n      \"pmids\": [\"30574063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of the AP5-SPG11-SPG15 complex reveals: SPG11-SPG15 form a W-shaped intertwined head-to-head heterodimer; the N-terminal region of SPG11 is required for AP5 complex interaction and assembly; AP5 adopts a super-open conformation. The AP5-SPG11-SPG15 complex binds PI3P, senses membrane curvature, and drives membrane remodeling (tubulation initiation) in vitro.\",\n      \"method\": \"Cryo-electron microscopy; in silico structural prediction; PI3P binding assay; in vitro membrane remodeling/tubulation assay; domain deletion constructs\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus in vitro functional reconstitution of membrane remodeling; multiple orthogonal methods\",\n      \"pmids\": [\"40175557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPG11 loss of function causes accumulation of gangliosides in lysosomes of Spg11 knockout mouse neurons. Reducing ganglioside synthesis by AAV-mediated miRNA knockdown of St3gal5 or pharmacological inhibition of glucosylceramide synthase (venglustat) prevents ganglioside accumulation, delays motor and cognitive symptom onset, prevents neurofilament light chain elevation, and strongly reduces axonal spheroid formation. Venglustat also reduced axonal spheroids in cultured human SPG11 neurons, linking ganglioside trafficking to axonal pathology.\",\n      \"method\": \"Spg11 knockout mice; AAV-PHP.eB viral miRNA delivery targeting St3gal5; venglustat pharmacological treatment; ganglioside quantification; behavioral testing; serum NfL measurement; axonal spheroid counting in mouse and human SPG11 cultured neurons\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse with two independent intervention strategies (genetic and pharmacological) plus human neuron validation; multiple orthogonal readouts\",\n      \"pmids\": [\"38876323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPG11 deficiency in human cortical projection neurons (from hESC-derived knockdown and disease-mutation knock-in lines) causes cholesterol accumulation in lysosomes with reduction at the plasma membrane, indicating impaired cholesterol trafficking. LXR agonists restore cholesterol homeostasis and rescue axonal outgrowth defects, impaired axonal transport, and axonal swellings.\",\n      \"method\": \"hESC SPG11 knockdown; disease-mutation knock-in hESC cortical neurons; cholesterol subcellular distribution imaging; LXR agonist treatment; axonal outgrowth and transport assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent cell models (KD and KI), pharmacological rescue, multiple readouts; single lab\",\n      \"pmids\": [\"37709208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of SPG11 function in microglia/macrophages causes hyperactivation of the non-canonical inflammasome, resulting in stronger inflammatory responses. LPS challenge triggers markedly increased lethality and inflammatory response in Spg11 KO mice in vivo. Mass spectrometry of activated BMDMs from Spg11 KO mice reveals massive downregulation of AP5 subunits upon Spg11 disruption, linking spatacsin to AP5 stability in immune cells. STAT1 phosphorylation is increased as the molecular mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function; STAT1 inhibition decreases CXCL10 production and rescues toxic effects on SPG11 neurons.\",\n      \"method\": \"Spg11 KO mouse primary microglia and BMDMs; patient-derived MDMs; LPS challenge in vivo; mass spectrometry of activated BMDMs; STAT1 phosphorylation western blot; STAT1 inhibitor rescue; CXCL10 ELISA; IFNγ stimulation of patient iPSC-derived microglia-like cells\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse plus patient-derived cells, mass spectrometry, pathway-specific rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38305941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPG11 mutations cause lysosomal calcium accumulation in neural progenitor cells (NPCs), which reduces NPC proliferation and diminishes apical tight junctions during cortical development. This is mechanistically linked to lysosomal recruitment of PI4K2A (phosphatidylinositol 4-kinase type 2 alpha), resulting in elevated PI(4)P levels that hypoactivate mTOR signaling. Pharmacological modulation of the lysosomal calcium channel TRPML1 corrects all developmental phenotypes in cortical organoids.\",\n      \"method\": \"Spg11 knockout mouse; iPSC-derived cortical organoids from SPG11 models; lysosomal calcium measurement; PI4K2A localization by imaging; PI(4)P quantification; mTOR activity assays; RNA sequencing; TRPML1 agonist/antagonist pharmacological rescue; tight junction imaging\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple models (KO mouse + organoids), mechanistic pathway elucidation (lysosomal Ca²⁺ → PI4K2A → PI(4)P → mTOR), pharmacological rescue, RNA-seq; multiple orthogonal methods\",\n      \"pmids\": [\"42049147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Morpholino-mediated knockdown of spatacsin (spg11) in zebrafish embryos causes CNS developmental defects and an overall perturbation of neuronal differentiation with disruption of axon pathway formation, identifying a critical role for spatacsin in early neural development in vivo.\",\n      \"method\": \"Morpholino antisense oligonucleotide knockdown in zebrafish; whole-mount in situ hybridization for transcript distribution; axon pathway immunostaining\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — morpholino KD in zebrafish with defined axonal phenotype readout; single lab, single model organism approach\",\n      \"pmids\": [\"20390432\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Spatacsin (SPG11) is a large scaffolding protein that forms a W-shaped head-to-head heterodimer with SPG15 (spastizin) and together associates with the AP-5 adaptor complex in a coat-like assembly on late endosomes/lysosomes; this AP5-SPG11-SPG15 complex is recruited by coincidence detection of PI3P (via the SPG15 FYVE domain) and Rag GTPases, senses membrane curvature, and drives lysosomal tubulation required for autophagic lysosome reformation (ALR), such that its loss causes lysosome depletion, ganglioside and cholesterol accumulation, impaired axonal transport and neurite maintenance, GSK3β-mediated neurodevelopmental defects in neural progenitors (via lysosomal calcium/PI4K2A/mTOR axis), and hyperactivation of the non-canonical inflammasome in microglia through increased STAT1 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Spatacsin (SPG11) is a large scaffolding protein that organizes a coat-like assembly on late endosomes/lysosomes to drive lysosome reformation, and its loss produces a spectrum of neurodevelopmental and neurodegenerative phenotypes [#0, #1]. Spatacsin and spastizin (SPG15) bind all four subunits of the AP-5 adaptor complex in fixed stoichiometry, with the N-terminal \\u03b2-propeller-like domain of SPG11 mediating the AP-5 interaction; the two proteins are mutually stabilizing and co-localize with AP-5 on a late endosomal/lysosomal compartment [#0, #3]. Cryo-EM shows SPG11 and SPG15 form a W-shaped head-to-head heterodimer that holds AP-5 in a super-open conformation, binds PI3P, senses membrane curvature, and initiates membrane tubulation in vitro [#9]. The complex is recruited to lysosomes by coincidence detection of PI3P (via the SPG15 FYVE domain) and GDP-locked RagC, an interplay with mTORC1 signaling that is enhanced upon starvation [#5]. Functionally, this activity is required for autophagic lysosome reformation: Spg11 loss depletes lysosomes, impairs their recovery during starvation, and elevates lipidated LC3, while leaving lysosomal enzymatic function intact [#1]. Loss of spatacsin disrupts neuronal homeostasis through multiple downstream routes \\u2014 lysosomal accumulation of gangliosides and cholesterol with resulting axonal spheroids and impaired axonal transport [#10, #11], GSK3\\u03b2 hyperactivation impairing neural progenitor proliferation and driving premature neurogenesis [#6, #7, #8], a lysosomal calcium\\u2013PI4K2A\\u2013mTOR axis that perturbs cortical development [#13], and hyperactivation of the non-canonical inflammasome in microglia via increased STAT1 signaling [#12]. SPG11 mutations underlie an autosomal recessive hereditary spastic paraplegia, modeled in patient-derived neurons and organoids [#2, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that spatacsin is required for early neural development in vivo, before any molecular function was known.\",\n      \"evidence\": \"Morpholino knockdown of spg11 in zebrafish embryos with axon pathway immunostaining\",\n      \"pmids\": [\"20390432\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular mechanism for the developmental defect\", \"Morpholino specificity not addressed by genetic rescue\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the core molecular identity of spatacsin as a stoichiometric partner of SPG15 and the AP-5 adaptor complex, establishing a coat-like sorting machinery on late endosomes/lysosomes.\",\n      \"evidence\": \"Reciprocal Co-IP with stoichiometry, in vitro domain binding of the SPG11 N-terminus to AP-5, knockdown epistasis on CI-M6PR sorting, and colocalization imaging\",\n      \"pmids\": [\"23825025\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of the assembly not resolved\", \"Functional consequence for lysosome biology not yet defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected spatacsin loss to neuronal axonal pathology and to lysosomal enlargement, and showed SPG11/SPG15 protein stability is interdependent.\",\n      \"evidence\": \"iPSC patient neurons and mouse cortical neuron knockdown with vesicle trafficking imaging and cytoskeletal markers; patient fibroblast LAMP1 imaging, EM, and protein stability westerns\",\n      \"pmids\": [\"24794856\", \"24999486\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking lysosomal defect to axonal transport not established\", \"Cargo whose mistrafficking drives axonal instability unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the cell-biological function of spatacsin as autophagic lysosome reformation, explaining lysosome depletion as the proximate consequence of its loss.\",\n      \"evidence\": \"Spg11 knockout mouse with lysosome quantification in MEFs and neurons, starvation-recovery assay, LC3 lipidation, and preserved cathepsin D processing/pH\",\n      \"pmids\": [\"26284655\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How the complex physically reforms lysosomes not yet shown\", \"Recruitment signals to lysosomes undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed that spatacsin loss impairs neural progenitor proliferation through GSK3\\u03b2 hyperactivation, a pharmacologically reversible mechanism.\",\n      \"evidence\": \"iPSC-derived NPCs from three SPG11 patients with transcriptome profiling, proliferation assays, and GSK3 inhibitor rescue\",\n      \"pmids\": [\"26971897\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Link between lysosomal dysfunction and GSK3\\u03b2 activation not mechanistically connected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished SPG11 from SPG15 function, showing both are required for ALR but only SPG15 acts at the autophagy-endocytosis intersection via RAB regulation.\",\n      \"evidence\": \"Patient cells with SPG11 or SPG15 mutations, RAB5A/RAB11 Co-IP and activation assays, autophagosome-endosome fusion and ALR assays with RAB5A rescue\",\n      \"pmids\": [\"30081747\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Why SPG11 produces a milder defect than its partner unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed GSK3\\u03b2/\\u03b2-catenin dysregulation as a driver of neuronal pathology in mature neurons using both patient and isogenic knockout lines.\",\n      \"evidence\": \"SPG11 patient iPSC cortical neurons and a CRISPR-Cas9 knockout line with tideglusib rescue of neurite, death, and inclusion phenotypes\",\n      \"pmids\": [\"30574063\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Upstream trigger of GSK3\\u03b2 hyperactivation still not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that GSK3\\u03b2 dysregulation causes a developmental phenotype \\u2014 premature neurogenesis from altered NPC division mode \\u2014 reversible by an FDA-approved GSK3 inhibitor.\",\n      \"evidence\": \"SPG11 patient iPSC cortical organoids with division mode quantification and tideglusib rescue\",\n      \"pmids\": [\"30476097\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular path from spatacsin to division asymmetry not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Solved how the complex is targeted to lysosomes, defining coincidence detection of PI3P and Rag GTPase state as the recruitment switch and linking it to mTORC1.\",\n      \"evidence\": \"Cell-based recruitment assays with Rag GTPase mutants, PI3P manipulation, and starvation conditions\",\n      \"pmids\": [\"33464297\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct contact between the complex and Rag GTPases not structurally defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified impaired cholesterol trafficking as a distinct lysosomal consequence of SPG11 loss, with axonal phenotypes rescuable by LXR agonists.\",\n      \"evidence\": \"hESC SPG11 knockdown and disease-mutation knock-in cortical neurons with cholesterol distribution imaging, LXR agonist treatment, axonal outgrowth and transport assays\",\n      \"pmids\": [\"37709208\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether cholesterol and ganglioside accumulation share a common upstream lysosomal defect unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed ganglioside accumulation in lysosomes is a causal driver of axonal pathology in vivo, reversible by reducing glycosphingolipid synthesis.\",\n      \"evidence\": \"Spg11 knockout mice with AAV miRNA knockdown of St3gal5 and venglustat treatment, ganglioside quantification, behavior, serum NfL, and axonal spheroid counts plus human neuron validation\",\n      \"pmids\": [\"38876323\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which ganglioside buildup generates spheroids not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended spatacsin function to innate immunity, showing its loss destabilizes AP5 in immune cells and hyperactivates the non-canonical inflammasome through increased STAT1 signaling.\",\n      \"evidence\": \"Spg11 KO mouse microglia/BMDMs and patient MDMs, LPS challenge in vivo, mass spectrometry, STAT1 phospho westerns, STAT1 inhibitor rescue of neuronal toxicity\",\n      \"pmids\": [\"38305941\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How lysosomal/AP5 dysfunction mechanistically elevates STAT1 phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural basis for the complex and reconstituted its membrane-remodeling activity, unifying the recruitment and ALR observations into a physical mechanism.\",\n      \"evidence\": \"Cryo-EM of AP5-SPG11-SPG15, PI3P binding and in vitro membrane tubulation assays, and domain deletion constructs\",\n      \"pmids\": [\"40175557\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structure of the membrane-engaged, curvature-sensing state not captured\", \"In vivo tubulation dynamics not visualized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a lysosomal calcium\\u2013PI4K2A\\u2013PI(4)P\\u2013mTOR axis through which spatacsin loss disrupts cortical development, with TRPML1 modulation as a corrective intervention.\",\n      \"evidence\": \"Spg11 KO mouse and iPSC cortical organoids with lysosomal calcium measurement, PI4K2A localization, PI(4)P and mTOR assays, RNA-seq, and TRPML1 pharmacological rescue\",\n      \"pmids\": [\"42049147\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Relationship between this axis and the GSK3\\u03b2 pathway in NPCs not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single lysosomal reformation defect bifurcates into distinct downstream cascades \\u2014 GSK3\\u03b2, lysosomal Ca2+/PI4K2A/mTOR, lipid accumulation, and STAT1-driven inflammation \\u2014 and whether they converge on a common proximal lesion remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unifying model linking the four downstream pathways\", \"Cell-type specificity of each cascade not systematically compared\", \"Cargo whose mistrafficking initiates each cascade unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"AP5-SPG11-SPG15 complex\"\n    ],\n    \"partners\": [\n      \"SPG15\",\n      \"AP5Z1\",\n      \"AP5M1\",\n      \"AP5B1\",\n      \"AP5S1\",\n      \"RAB5A\",\n      \"RAB11\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}