{"gene":"ATL1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2003,"finding":"ATL1 (atlastin-1) is an integral membrane protein with two transmembrane domains, both N-terminal GTP-binding and C-terminal domains exposed to the cytoplasm. It self-associates to form oligomers (likely tetramers) in vivo, as demonstrated by yeast two-hybrid, co-immunoprecipitation, gel-exclusion chromatography, and chemical cross-linking. It localizes predominantly to the cis-Golgi in cultured cortical neurons, as shown by co-localization with Golgi markers and immunogold electron microscopy.","method":"Co-immunoprecipitation, yeast two-hybrid, gel-exclusion chromatography, chemical cross-linking, membrane fractionation, protease protection assay, immunogold electron microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, yeast two-hybrid, chromatography, cross-linking, EM) in a single study with rigorous controls","pmids":["14506257"],"is_preprint":false},{"year":2006,"finding":"ATL1 is highly enriched in vesicular structures within axonal growth cones, varicosities, and axonal branch points in cultured cortical neurons. Knockdown of ATL1 by shRNA reduces the number of neuronal processes and impairs axon formation and elongation during development. Several SPG3A missense mutations have impaired GTPase activity, and may act in a dominant-negative manner by forming mixed oligomers with wild-type atlastin-1.","method":"shRNA knockdown, confocal microscopy, electron microscopy, GTPase activity assay, dominant-negative oligomerization analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined cellular phenotype (axon elongation), localization by EM, enzymatic activity assay, multiple orthogonal methods","pmids":["16537571"],"is_preprint":false},{"year":2007,"finding":"ATL1 mutations in the GTPase domain interfere with Golgi maturation by preventing ER-derived vesicle budding, while mutations in other regions disrupt fission of ER-derived vesicles or their migration to Golgi targets. ATL1 co-immunoprecipitates p24 (a member of the p24/emp/gp25L family that regulates vesicle budding), suggesting a functional relationship in the early secretory pathway.","method":"Cell culture expression of wild-type and mutant ATL1, co-immunoprecipitation, vesicle transport assays","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus cell-based vesicle trafficking assays, single lab, two methods","pmids":["17321752"],"is_preprint":false},{"year":2009,"finding":"Purified ATL1 transforms phosphatidylserine liposomes into branched tubules and polygonal networks of tubules and vesicles in vitro, an activity inhibited by GDP and the dynamin inhibitor dynasore. GTPase domain mutations T162P and R217C decrease but do not completely prevent this membrane remodeling activity. ATL1 is incorporated into ER microsome-derived vesicles, implicating it in vesicle formation.","method":"In vitro liposome tubulation assay with purified ATL1, pharmacological inhibition (GDP, dynasore), microsome vesicle incorporation assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified protein and mutagenesis, single lab","pmids":["19573020"],"is_preprint":false},{"year":2011,"finding":"Crystal structures of ATL1 comprising the G and middle domains were solved in two different conformations, both revealing dimeric assemblies with a common GDP-bound G domain dimer. Dimer formation in solution occurs only in the presence of GTP and transition state analogs (not GDP alone), consistent with nucleotide-dependent dimerization. Solution scattering data indicate the protein adopts an extended dimeric conformation upon nucleotide binding. Several HSP-associated mutations affect this nucleotide-dependent dimerization mechanism.","method":"X-ray crystallography, small-angle X-ray scattering (SAXS), solution dimerization assays with GTP/GDP/transition state analogs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures in two conformations plus SAXS solution analysis, multiple orthogonal structural and biochemical methods, rigorous controls","pmids":["21220294"],"is_preprint":false},{"year":2010,"finding":"ATL1 and NIPA1 are direct binding partners, demonstrated by co-immunoprecipitation and confocal co-localization. Their endogenous expression and trafficking are mutually dependent on coexpression. HSP-causing mutations in atlastin-1 (R239C, R495W) cause sequestration of atlastin-1:NIPA1 complexes in the Golgi complex, while NIPA1 mutations (T45R, G106R) cause sequestration in the ER. Both atlastin-1 and NIPA1 mutations reduce axonal and dendritic sprouting in cultured rat cortical neurons.","method":"Co-immunoprecipitation, confocal microscopy, flow cytometry, loss-of-function in primary neurons","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, confocal, neuronal phenotype; single lab, multiple orthogonal methods","pmids":["20816793"],"is_preprint":false},{"year":2014,"finding":"ATL1 mediates homotypic fusion of ER tubules to form the polygonal ER network. A disease-associated mutation (P342S) in the hinge region between the GTPase and assembly domains impairs this function. SPG3A patient iPSC-derived neurons show impaired axon growth, and this defect can be rescued by microtubule-binding agents, establishing that tubular ER interactions with the microtubule cytoskeleton are important for axon growth in SPG3A.","method":"iPSC-derived human neurons, axon growth assays, microtubule-binding drug rescue, mitochondrial motility assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC disease model with pharmacologic rescue, single lab, multiple readouts","pmids":["24908668"],"is_preprint":false},{"year":2015,"finding":"ATL1 is sufficient to catalyze membrane fusion and required for ER network formation. Biochemical analysis of SPG3A disease variants showed that some variants have clear deficits in GTP hydrolysis, dimer formation, and membrane fusion, but at least two disease variants (including the most frequently identified in SPG3A HSP patients) displayed wild-type levels of activity in all assays, including co-redistribution of ER-localized REEP1. This indicates that a deficit in membrane fusion activity of ATL1 is a key contributor but is not required for HSP causation.","method":"Cell-based ER network formation assays, in vitro GTP hydrolysis assay, biochemical dimer formation assay, in vitro membrane fusion assay, REEP1 co-redistribution assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro and cell-based functional assays across a panel of disease variants, rigorous controls","pmids":["25761634"],"is_preprint":false},{"year":2016,"finding":"ATL1 cooperates with VCP (valosin-containing protein) and its cofactor p47 to regulate tubular ER formation, which in turn influences the efficiency of protein synthesis and controls dendritic spine formation in neurons. Knockdown or disease-mutation knockin of ATL1 reduces dendritic spine density. Augmenting protein synthesis (via leucine supplementation) ameliorates dendritic spine defects caused by ATL1 deficiency, placing ATL1 upstream of ER morphology and protein synthesis in dendritic spinogenesis.","method":"Knockdown, disease mutation knockin mice, leucine supplementation rescue, dendritic spine density quantification, ER morphology analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockin mouse model plus knockdown plus pharmacologic rescue, multiple orthogonal methods, replication across conditions","pmids":["26984393"],"is_preprint":false},{"year":2007,"finding":"An in-frame deletion (p.del436N) in ATL1 does not affect GTPase activity or interactions between atlastin and spastin, but causes a significant reduction in ATL1 protein levels in patient lymphoblasts, supporting a loss-of-function mechanism for this HSP mutation.","method":"GTPase activity assay, co-immunoprecipitation (atlastin-spastin interaction), immunoblot of patient lymphoblasts","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic assay, Co-IP, and patient material immunoblot, single lab, multiple methods","pmids":["17427918"],"is_preprint":false},{"year":2025,"finding":"ATL-mediated ER fusion activity is essential for sustained lipid synthesis (phosphatidylcholine and cholesterol). In ATL-deleted mice, reduced ER membrane area correlates with decreased phosphatidylcholine and cholesterol synthesis. At calyx-type synapses in ATL-deleted mice, a reduced membrane reservoir (fewer presynaptic vesicles) leads to defective synaptic function and deafness, linking ATL1/ATL2 ER-shaping activity to synaptic vesicle pool maintenance.","method":"ATL2-knockout mice, lipid synthesis measurements, electron microscopy of synaptic vesicles, electrophysiology at calyx synapses","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with biochemical (lipid) and functional (electrophysiology, EM) readouts; preprint, single lab","pmids":["bio_10.1101_2025.04.12.648519"],"is_preprint":true},{"year":2022,"finding":"ATL1 inhibits proliferation, migration, and invasion of trophoblast (HTR-8/SVneo) cells through inhibition of the mTOR signaling pathway. Downregulation of ATL1 increased p-p70S6K and p-mTOR levels, while upregulation decreased them. Rapamycin (mTOR inhibitor) reversed the promotive effect of ATL1 knockdown on proliferation and invasion.","method":"siRNA knockdown, overexpression, cell viability/proliferation/migration/invasion assays, western blot for p-p70S6K and p-mTOR, pharmacologic rescue with rapamycin","journal":"Journal of biochemical and molecular toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, mechanistic follow-up limited to pathway marker levels, no direct enzymatic or structural evidence","pmids":["36193555"],"is_preprint":false},{"year":2025,"finding":"SPG3A patient iPSC-derived cortical projection neurons show significant reductions in synaptic genes and proteins (compared to controls), reduced calcium activity, and axonal degeneration. Treatment with LXR623 (an LXR agonist) rescues synaptic protein levels, calcium activity, and axonal degeneration, and restores lipid and synaptic gene expression patterns, implicating lipid metabolism and synaptic dysfunction as downstream consequences of ATL1 loss.","method":"Patient iPSC-derived cortical neurons, RNA-sequencing, calcium imaging, western blot for synaptic proteins, LXR623 pharmacologic rescue","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient iPSC model with RNA-seq, functional calcium imaging, and pharmacologic rescue; single lab, multiple orthogonal methods","pmids":["41250225"],"is_preprint":false}],"current_model":"ATL1 (atlastin-1) is an oligomeric, integral membrane GTPase that undergoes nucleotide-dependent dimerization to mediate homotypic fusion of ER tubules, forming the polygonal ER network; it localizes to the cis-Golgi and axonal growth cones in neurons, where it promotes axon elongation, and together with VCP regulates tubular ER morphology to support efficient protein synthesis and dendritic spine formation, with disease-causing mutations impairing GTPase activity, ER network formation, membrane fusion, or protein stability to cause the length-dependent axonopathy of SPG3A hereditary spastic paraplegia."},"narrative":{"mechanistic_narrative":"ATL1 (atlastin-1) is an oligomeric integral-membrane GTPase that catalyzes homotypic fusion of endoplasmic reticulum tubules to build and maintain the polygonal ER network, with a dedicated role in neuronal process formation [PMID:14506257, PMID:24908668, PMID:25761634]. It spans the membrane via two transmembrane domains that orient both the N-terminal GTP-binding domain and C-terminal domain to the cytoplasm, and it self-associates into oligomers [PMID:14506257]. Membrane fusion proceeds through nucleotide-dependent dimerization: crystal structures of the G and middle domains captured two conformations sharing a common G-domain dimer, and dimer formation in solution requires GTP or transition-state analogs rather than GDP alone, driving an extended-to-crossover conformational change that draws apposed membranes together [PMID:21220294]. Purified ATL1 is sufficient to remodel liposomes into branched tubules and polygonal networks and to catalyze fusion in vitro, activities blocked by GDP and dynasore [PMID:19573020, PMID:25761634]. Beyond ER shaping, ATL1 cooperates with VCP and its cofactor p47 so that tubular ER morphology supports efficient protein synthesis and dendritic spine formation, and ER fusion activity sustains lipid (phosphatidylcholine and cholesterol) synthesis tied to the membrane reservoir [PMID:26984393, PMID:bio_10.1101_2025.04.12.648519]. In neurons ATL1 localizes to the cis-Golgi, axonal growth cones, varicosities and branch points, and is required for axon formation and elongation, binding the partners NIPA1 and p24/REEP1 in this context [PMID:14506257, PMID:16537571, PMID:20816793]. ATL1 mutations cause SPG3A hereditary spastic paraplegia: disease variants variously impair GTP hydrolysis, dimerization, membrane fusion, or protein stability, although at least one common variant retains full in vitro activity, indicating fusion deficit is a key but not obligatory contributor to disease [PMID:16537571, PMID:25761634, PMID:17427918]. Patient iPSC-derived cortical neurons show impaired axon growth, synaptic protein/calcium deficits and axonal degeneration that are rescued by microtubule-binding agents or by LXR-agonist restoration of lipid and synaptic programs [PMID:24908668, PMID:41250225].","teleology":[{"year":2003,"claim":"Establishing ATL1's membrane topology, oligomeric state, and subcellular location was the first step toward defining how it acts on membranes.","evidence":"Co-IP, yeast two-hybrid, gel-exclusion chromatography, cross-linking, protease protection and immunogold EM in cortical neurons","pmids":["14506257"],"confidence":"High","gaps":["The functional consequence of oligomerization was not yet defined","cis-Golgi localization did not yet connect to a fusion or ER-shaping role"]},{"year":2006,"claim":"Linking ATL1 to axon development and showing SPG3A mutations impair GTPase activity tied the gene to a neuronal phenotype and a candidate dominant-negative disease mechanism.","evidence":"shRNA knockdown, confocal and EM localization, GTPase assays, oligomerization analysis in cortical neurons","pmids":["16537571"],"confidence":"High","gaps":["Molecular substrate of the GTPase activity not yet identified","dominant-negative model inferred from mixed-oligomer formation, not directly demonstrated in vivo"]},{"year":2007,"claim":"Two studies tied ATL1 to the early secretory pathway and demonstrated a loss-of-function disease mechanism, distinguishing enzymatic from stability defects.","evidence":"Mutant expression with vesicle transport assays and p24 Co-IP; GTPase assay, spastin Co-IP and patient lymphoblast immunoblot for the del436N variant","pmids":["17321752","17427918"],"confidence":"Medium","gaps":["Direct role in vesicle budding vs ER tubule fusion not yet resolved","p24 interaction shown by Co-IP only","del436N destabilization mechanism not defined"]},{"year":2009,"claim":"Reconstitution with purified protein showed ATL1 intrinsically remodels membranes, moving the mechanism from cellular correlation to direct biochemistry.","evidence":"In vitro liposome tubulation with purified ATL1, GDP/dynasore inhibition, mutagenesis of GTPase-domain residues","pmids":["19573020"],"confidence":"Medium","gaps":["Tubulation assay did not directly demonstrate bilayer fusion","single lab, no structural model of the active conformation"]},{"year":2010,"claim":"Identification of NIPA1 as a direct, mutually-dependent partner placed ATL1 in a defined HSP protein complex with shared trafficking and neuronal sprouting functions.","evidence":"Reciprocal Co-IP, confocal co-localization, flow cytometry and loss-of-function in primary rat neurons","pmids":["20816793"],"confidence":"Medium","gaps":["Functional consequence of complex sequestration on ER fusion not measured","single lab Co-IP-based interaction"]},{"year":2011,"claim":"Crystal structures and solution scattering defined the nucleotide-dependent dimerization mechanism that powers fusion and showed how disease mutations disrupt it.","evidence":"X-ray crystallography of G/middle domains in two conformations, SAXS, GTP/GDP/transition-state dimerization assays","pmids":["21220294"],"confidence":"High","gaps":["Full-length transmembrane-anchored fusion intermediate not captured","membrane fusion not directly demonstrated in this study"]},{"year":2014,"claim":"Demonstrating ATL1 mediates homotypic ER tubule fusion in human neurons and that axon defects are rescued by microtubule agents connected ER morphology to cytoskeletal dynamics in disease.","evidence":"SPG3A patient iPSC-derived neurons, axon growth and mitochondrial motility assays, microtubule-binding drug rescue","pmids":["24908668"],"confidence":"Medium","gaps":["Mechanism linking ER-microtubule interaction to axon growth not fully resolved","single lab"]},{"year":2015,"claim":"A variant panel established that ATL1 is sufficient for fusion but that fusion deficit, while a key contributor, is not obligatory for SPG3A, refining the disease model.","evidence":"Cell ER-network assays, in vitro GTP hydrolysis, dimerization and membrane fusion assays, REEP1 co-redistribution across disease variants","pmids":["25761634"],"confidence":"High","gaps":["Alternative pathogenic mechanism for fusion-competent variants unexplained","in vivo relevance of REEP1 co-redistribution not tested"]},{"year":2016,"claim":"Placing ATL1 upstream of VCP/p47, ER morphology and protein synthesis in dendritic spinogenesis extended its role beyond axons to synaptic structure, with a pharmacologic rescue.","evidence":"Knockdown, disease-mutation knockin mice, leucine supplementation rescue, dendritic spine and ER morphology quantification","pmids":["26984393"],"confidence":"High","gaps":["Molecular nature of the ATL1-VCP-p47 functional link not structurally defined","how ER morphology controls translation efficiency remains mechanistically open"]},{"year":2022,"claim":"A non-neuronal report linked ATL1 to mTOR-dependent control of trophoblast proliferation and invasion, raising a possible signaling role.","evidence":"siRNA knockdown/overexpression in HTR-8/SVneo cells, p-p70S6K/p-mTOR immunoblot, rapamycin rescue","pmids":["36193555"],"confidence":"Low","gaps":["Single cell line, single lab, no direct molecular link between ATL1 and mTOR pathway components","mechanism limited to pathway-marker correlation"]},{"year":2025,"claim":"Two studies connected ATL ER-fusion activity to lipid synthesis and synaptic vesicle/synaptic gene maintenance, and showed LXR-agonist rescue of patient neurons, framing lipid metabolism as a downstream disease axis.","evidence":"ATL2-KO mice with lipid measurements, synaptic vesicle EM and calyx electrophysiology (preprint); SPG3A patient iPSC cortical neurons with RNA-seq, calcium imaging and LXR623 rescue","pmids":["bio_10.1101_2025.04.12.648519","41250225"],"confidence":"Medium","gaps":["Direct biochemical coupling of ER membrane area to lipid synthesis rates not established","one study is a preprint and uses ATL2 knockout","whether lipid restoration corrects the primary fusion defect is untested"]},{"year":null,"claim":"How fusion-competent SPG3A variants cause length-dependent axonopathy, and the precise molecular coupling of ER tubule fusion to lipid synthesis, protein synthesis and synaptic maintenance, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism for fusion-independent pathogenicity","no structure of the full-length membrane-anchored fusion intermediate","in vivo causal chain from ER morphology to axon degeneration incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1,4,7,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,6]}],"complexes":[],"partners":["NIPA1","VCP","REEP1","TMED2","SPAST"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXF7","full_name":"Atlastin-1","aliases":["Brain-specific GTP-binding protein","GTP-binding protein 3","GBP-3","hGBP3","Guanine nucleotide-binding protein 3","Spastic paraplegia 3 protein A"],"length_aa":558,"mass_kda":63.5,"function":"Atlastin-1 (ATL1) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network. It facilitates the formation of three-way junctions where ER tubules intersect (PubMed:14506257, PubMed:18270207, PubMed:19665976, PubMed:27619977, PubMed:34817557, PubMed:38509071). Two atlastin-1 on neighboring ER tubules bind GTP and form loose homodimers through the GB1/RHD3-type G domains and 3HB regions. Upon GTP hydrolysis, the 3HB regions tighten, pulling the membranes together to drive their fusion. After fusion, the homodimer disassembles upon release of inorganic phosphate (Pi). Subsequently, GDP dissociates, resetting the monomers to a conformation ready for a new fusion cycle (PubMed:14506257, PubMed:21220294, PubMed:21368113, PubMed:23334294, PubMed:38509071). May also regulate more or less directly Golgi biogenesis (PubMed:17321752). Indirectly regulates axonal development (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q8WXF7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATL1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATL3","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"ESYT1","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATL1","total_profiled":1310},"omim":[{"mim_id":"614751","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 12; HMND12","url":"https://www.omim.org/entry/614751"},{"mim_id":"613708","title":"NEUROPATHY, HEREDITARY SENSORY, TYPE ID; HSN1D","url":"https://www.omim.org/entry/613708"},{"mim_id":"610243","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 27; ZFYVE27","url":"https://www.omim.org/entry/610243"},{"mim_id":"610236","title":"LUNAPARK; LNPK","url":"https://www.omim.org/entry/610236"},{"mim_id":"609369","title":"ATLASTIN GTPase 3; ATL3","url":"https://www.omim.org/entry/609369"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":56.1}],"url":"https://www.proteinatlas.org/search/ATL1"},"hgnc":{"alias_symbol":["FSP1","AD-FSP"],"prev_symbol":["SPG3","SPG3A"]},"alphafold":{"accession":"Q8WXF7","domains":[{"cath_id":"3.40.50.300","chopping":"33-344","consensus_level":"medium","plddt":94.8913,"start":33,"end":344},{"cath_id":"1.20.58.420","chopping":"345-532","consensus_level":"medium","plddt":85.7354,"start":345,"end":532}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXF7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXF7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXF7-F1-predicted_aligned_error_v6.png","plddt_mean":86.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATL1","jax_strain_url":"https://www.jax.org/strain/search?query=ATL1"},"sequence":{"accession":"Q8WXF7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXF7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXF7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXF7"}},"corpus_meta":[{"pmid":"21220294","id":"PMC_21220294","title":"Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21220294","citation_count":152,"is_preprint":false},{"pmid":"14506257","id":"PMC_14506257","title":"Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14506257","citation_count":125,"is_preprint":false},{"pmid":"16537571","id":"PMC_16537571","title":"SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16537571","citation_count":100,"is_preprint":false},{"pmid":"26984393","id":"PMC_26984393","title":"VCP and ATL1 regulate endoplasmic reticulum and protein synthesis for dendritic spine formation.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26984393","citation_count":66,"is_preprint":false},{"pmid":"17321752","id":"PMC_17321752","title":"Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis.","date":"2007","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/17321752","citation_count":56,"is_preprint":false},{"pmid":"24908668","id":"PMC_24908668","title":"Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24908668","citation_count":54,"is_preprint":false},{"pmid":"18193074","id":"PMC_18193074","title":"ATL-1, an analogue of aspirin-triggered lipoxin A4, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor.","date":"2008","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18193074","citation_count":53,"is_preprint":false},{"pmid":"20932283","id":"PMC_20932283","title":"Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.","date":"2010","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20932283","citation_count":51,"is_preprint":false},{"pmid":"16533974","id":"PMC_16533974","title":"De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy.","date":"2006","source":"Archives of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16533974","citation_count":50,"is_preprint":false},{"pmid":"14695538","id":"PMC_14695538","title":"Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus.","date":"2004","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/14695538","citation_count":50,"is_preprint":false},{"pmid":"24473461","id":"PMC_24473461","title":"Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24473461","citation_count":40,"is_preprint":false},{"pmid":"15517445","id":"PMC_15517445","title":"Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A.","date":"2004","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/15517445","citation_count":39,"is_preprint":false},{"pmid":"12499504","id":"PMC_12499504","title":"SPG3A: An additional family carrying a new atlastin 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chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17285536","citation_count":7,"is_preprint":false},{"pmid":"23059787","id":"PMC_23059787","title":"Synthesis of oligodeoxyribonucleotides containing a conformationally-locked anti analogue of O6-methyl-2'-deoxyguanosine and their recognition by MGMT and Atl1.","date":"2012","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23059787","citation_count":7,"is_preprint":false},{"pmid":"28736820","id":"PMC_28736820","title":"Disease-Causing Variants in the ATL1 Gene Are a Rare Cause of Hereditary Spastic Paraplegia among Czech Patients.","date":"2017","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28736820","citation_count":6,"is_preprint":false},{"pmid":"23434802","id":"PMC_23434802","title":"Caenorhabditis elegans ATR checkpoint kinase ATL-1 influences life span through mitochondrial 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It self-associates to form oligomers (likely tetramers) in vivo, as demonstrated by yeast two-hybrid, co-immunoprecipitation, gel-exclusion chromatography, and chemical cross-linking. It localizes predominantly to the cis-Golgi in cultured cortical neurons, as shown by co-localization with Golgi markers and immunogold electron microscopy.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, gel-exclusion chromatography, chemical cross-linking, membrane fractionation, protease protection assay, immunogold electron microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, yeast two-hybrid, chromatography, cross-linking, EM) in a single study with rigorous controls\",\n      \"pmids\": [\"14506257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ATL1 is highly enriched in vesicular structures within axonal growth cones, varicosities, and axonal branch points in cultured cortical neurons. Knockdown of ATL1 by shRNA reduces the number of neuronal processes and impairs axon formation and elongation during development. Several SPG3A missense mutations have impaired GTPase activity, and may act in a dominant-negative manner by forming mixed oligomers with wild-type atlastin-1.\",\n      \"method\": \"shRNA knockdown, confocal microscopy, electron microscopy, GTPase activity assay, dominant-negative oligomerization analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined cellular phenotype (axon elongation), localization by EM, enzymatic activity assay, multiple orthogonal methods\",\n      \"pmids\": [\"16537571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ATL1 mutations in the GTPase domain interfere with Golgi maturation by preventing ER-derived vesicle budding, while mutations in other regions disrupt fission of ER-derived vesicles or their migration to Golgi targets. ATL1 co-immunoprecipitates p24 (a member of the p24/emp/gp25L family that regulates vesicle budding), suggesting a functional relationship in the early secretory pathway.\",\n      \"method\": \"Cell culture expression of wild-type and mutant ATL1, co-immunoprecipitation, vesicle transport assays\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus cell-based vesicle trafficking assays, single lab, two methods\",\n      \"pmids\": [\"17321752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Purified ATL1 transforms phosphatidylserine liposomes into branched tubules and polygonal networks of tubules and vesicles in vitro, an activity inhibited by GDP and the dynamin inhibitor dynasore. GTPase domain mutations T162P and R217C decrease but do not completely prevent this membrane remodeling activity. ATL1 is incorporated into ER microsome-derived vesicles, implicating it in vesicle formation.\",\n      \"method\": \"In vitro liposome tubulation assay with purified ATL1, pharmacological inhibition (GDP, dynasore), microsome vesicle incorporation assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified protein and mutagenesis, single lab\",\n      \"pmids\": [\"19573020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structures of ATL1 comprising the G and middle domains were solved in two different conformations, both revealing dimeric assemblies with a common GDP-bound G domain dimer. Dimer formation in solution occurs only in the presence of GTP and transition state analogs (not GDP alone), consistent with nucleotide-dependent dimerization. Solution scattering data indicate the protein adopts an extended dimeric conformation upon nucleotide binding. Several HSP-associated mutations affect this nucleotide-dependent dimerization mechanism.\",\n      \"method\": \"X-ray crystallography, small-angle X-ray scattering (SAXS), solution dimerization assays with GTP/GDP/transition state analogs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures in two conformations plus SAXS solution analysis, multiple orthogonal structural and biochemical methods, rigorous controls\",\n      \"pmids\": [\"21220294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATL1 and NIPA1 are direct binding partners, demonstrated by co-immunoprecipitation and confocal co-localization. Their endogenous expression and trafficking are mutually dependent on coexpression. HSP-causing mutations in atlastin-1 (R239C, R495W) cause sequestration of atlastin-1:NIPA1 complexes in the Golgi complex, while NIPA1 mutations (T45R, G106R) cause sequestration in the ER. Both atlastin-1 and NIPA1 mutations reduce axonal and dendritic sprouting in cultured rat cortical neurons.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, flow cytometry, loss-of-function in primary neurons\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, confocal, neuronal phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"20816793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATL1 mediates homotypic fusion of ER tubules to form the polygonal ER network. A disease-associated mutation (P342S) in the hinge region between the GTPase and assembly domains impairs this function. SPG3A patient iPSC-derived neurons show impaired axon growth, and this defect can be rescued by microtubule-binding agents, establishing that tubular ER interactions with the microtubule cytoskeleton are important for axon growth in SPG3A.\",\n      \"method\": \"iPSC-derived human neurons, axon growth assays, microtubule-binding drug rescue, mitochondrial motility assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC disease model with pharmacologic rescue, single lab, multiple readouts\",\n      \"pmids\": [\"24908668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATL1 is sufficient to catalyze membrane fusion and required for ER network formation. Biochemical analysis of SPG3A disease variants showed that some variants have clear deficits in GTP hydrolysis, dimer formation, and membrane fusion, but at least two disease variants (including the most frequently identified in SPG3A HSP patients) displayed wild-type levels of activity in all assays, including co-redistribution of ER-localized REEP1. This indicates that a deficit in membrane fusion activity of ATL1 is a key contributor but is not required for HSP causation.\",\n      \"method\": \"Cell-based ER network formation assays, in vitro GTP hydrolysis assay, biochemical dimer formation assay, in vitro membrane fusion assay, REEP1 co-redistribution assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro and cell-based functional assays across a panel of disease variants, rigorous controls\",\n      \"pmids\": [\"25761634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATL1 cooperates with VCP (valosin-containing protein) and its cofactor p47 to regulate tubular ER formation, which in turn influences the efficiency of protein synthesis and controls dendritic spine formation in neurons. Knockdown or disease-mutation knockin of ATL1 reduces dendritic spine density. Augmenting protein synthesis (via leucine supplementation) ameliorates dendritic spine defects caused by ATL1 deficiency, placing ATL1 upstream of ER morphology and protein synthesis in dendritic spinogenesis.\",\n      \"method\": \"Knockdown, disease mutation knockin mice, leucine supplementation rescue, dendritic spine density quantification, ER morphology analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockin mouse model plus knockdown plus pharmacologic rescue, multiple orthogonal methods, replication across conditions\",\n      \"pmids\": [\"26984393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"An in-frame deletion (p.del436N) in ATL1 does not affect GTPase activity or interactions between atlastin and spastin, but causes a significant reduction in ATL1 protein levels in patient lymphoblasts, supporting a loss-of-function mechanism for this HSP mutation.\",\n      \"method\": \"GTPase activity assay, co-immunoprecipitation (atlastin-spastin interaction), immunoblot of patient lymphoblasts\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic assay, Co-IP, and patient material immunoblot, single lab, multiple methods\",\n      \"pmids\": [\"17427918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATL-mediated ER fusion activity is essential for sustained lipid synthesis (phosphatidylcholine and cholesterol). In ATL-deleted mice, reduced ER membrane area correlates with decreased phosphatidylcholine and cholesterol synthesis. At calyx-type synapses in ATL-deleted mice, a reduced membrane reservoir (fewer presynaptic vesicles) leads to defective synaptic function and deafness, linking ATL1/ATL2 ER-shaping activity to synaptic vesicle pool maintenance.\",\n      \"method\": \"ATL2-knockout mice, lipid synthesis measurements, electron microscopy of synaptic vesicles, electrophysiology at calyx synapses\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with biochemical (lipid) and functional (electrophysiology, EM) readouts; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.04.12.648519\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATL1 inhibits proliferation, migration, and invasion of trophoblast (HTR-8/SVneo) cells through inhibition of the mTOR signaling pathway. Downregulation of ATL1 increased p-p70S6K and p-mTOR levels, while upregulation decreased them. Rapamycin (mTOR inhibitor) reversed the promotive effect of ATL1 knockdown on proliferation and invasion.\",\n      \"method\": \"siRNA knockdown, overexpression, cell viability/proliferation/migration/invasion assays, western blot for p-p70S6K and p-mTOR, pharmacologic rescue with rapamycin\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, mechanistic follow-up limited to pathway marker levels, no direct enzymatic or structural evidence\",\n      \"pmids\": [\"36193555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPG3A patient iPSC-derived cortical projection neurons show significant reductions in synaptic genes and proteins (compared to controls), reduced calcium activity, and axonal degeneration. Treatment with LXR623 (an LXR agonist) rescues synaptic protein levels, calcium activity, and axonal degeneration, and restores lipid and synaptic gene expression patterns, implicating lipid metabolism and synaptic dysfunction as downstream consequences of ATL1 loss.\",\n      \"method\": \"Patient iPSC-derived cortical neurons, RNA-sequencing, calcium imaging, western blot for synaptic proteins, LXR623 pharmacologic rescue\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient iPSC model with RNA-seq, functional calcium imaging, and pharmacologic rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41250225\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATL1 (atlastin-1) is an oligomeric, integral membrane GTPase that undergoes nucleotide-dependent dimerization to mediate homotypic fusion of ER tubules, forming the polygonal ER network; it localizes to the cis-Golgi and axonal growth cones in neurons, where it promotes axon elongation, and together with VCP regulates tubular ER morphology to support efficient protein synthesis and dendritic spine formation, with disease-causing mutations impairing GTPase activity, ER network formation, membrane fusion, or protein stability to cause the length-dependent axonopathy of SPG3A hereditary spastic paraplegia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATL1 (atlastin-1) is an oligomeric integral-membrane GTPase that catalyzes homotypic fusion of endoplasmic reticulum tubules to build and maintain the polygonal ER network, with a dedicated role in neuronal process formation [#0, #6, #7]. It spans the membrane via two transmembrane domains that orient both the N-terminal GTP-binding domain and C-terminal domain to the cytoplasm, and it self-associates into oligomers [#0]. Membrane fusion proceeds through nucleotide-dependent dimerization: crystal structures of the G and middle domains captured two conformations sharing a common G-domain dimer, and dimer formation in solution requires GTP or transition-state analogs rather than GDP alone, driving an extended-to-crossover conformational change that draws apposed membranes together [#4]. Purified ATL1 is sufficient to remodel liposomes into branched tubules and polygonal networks and to catalyze fusion in vitro, activities blocked by GDP and dynasore [#3, #7]. Beyond ER shaping, ATL1 cooperates with VCP and its cofactor p47 so that tubular ER morphology supports efficient protein synthesis and dendritic spine formation, and ER fusion activity sustains lipid (phosphatidylcholine and cholesterol) synthesis tied to the membrane reservoir [#8, #10]. In neurons ATL1 localizes to the cis-Golgi, axonal growth cones, varicosities and branch points, and is required for axon formation and elongation, binding the partners NIPA1 and p24/REEP1 in this context [#0, #1, #5]. ATL1 mutations cause SPG3A hereditary spastic paraplegia: disease variants variously impair GTP hydrolysis, dimerization, membrane fusion, or protein stability, although at least one common variant retains full in vitro activity, indicating fusion deficit is a key but not obligatory contributor to disease [#1, #7, #9]. Patient iPSC-derived cortical neurons show impaired axon growth, synaptic protein/calcium deficits and axonal degeneration that are rescued by microtubule-binding agents or by LXR-agonist restoration of lipid and synaptic programs [#6, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing ATL1's membrane topology, oligomeric state, and subcellular location was the first step toward defining how it acts on membranes.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, gel-exclusion chromatography, cross-linking, protease protection and immunogold EM in cortical neurons\",\n      \"pmids\": [\"14506257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The functional consequence of oligomerization was not yet defined\", \"cis-Golgi localization did not yet connect to a fusion or ER-shaping role\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking ATL1 to axon development and showing SPG3A mutations impair GTPase activity tied the gene to a neuronal phenotype and a candidate dominant-negative disease mechanism.\",\n      \"evidence\": \"shRNA knockdown, confocal and EM localization, GTPase assays, oligomerization analysis in cortical neurons\",\n      \"pmids\": [\"16537571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate of the GTPase activity not yet identified\", \"dominant-negative model inferred from mixed-oligomer formation, not directly demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two studies tied ATL1 to the early secretory pathway and demonstrated a loss-of-function disease mechanism, distinguishing enzymatic from stability defects.\",\n      \"evidence\": \"Mutant expression with vesicle transport assays and p24 Co-IP; GTPase assay, spastin Co-IP and patient lymphoblast immunoblot for the del436N variant\",\n      \"pmids\": [\"17321752\", \"17427918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role in vesicle budding vs ER tubule fusion not yet resolved\", \"p24 interaction shown by Co-IP only\", \"del436N destabilization mechanism not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reconstitution with purified protein showed ATL1 intrinsically remodels membranes, moving the mechanism from cellular correlation to direct biochemistry.\",\n      \"evidence\": \"In vitro liposome tubulation with purified ATL1, GDP/dynasore inhibition, mutagenesis of GTPase-domain residues\",\n      \"pmids\": [\"19573020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tubulation assay did not directly demonstrate bilayer fusion\", \"single lab, no structural model of the active conformation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of NIPA1 as a direct, mutually-dependent partner placed ATL1 in a defined HSP protein complex with shared trafficking and neuronal sprouting functions.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal co-localization, flow cytometry and loss-of-function in primary rat neurons\",\n      \"pmids\": [\"20816793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of complex sequestration on ER fusion not measured\", \"single lab Co-IP-based interaction\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystal structures and solution scattering defined the nucleotide-dependent dimerization mechanism that powers fusion and showed how disease mutations disrupt it.\",\n      \"evidence\": \"X-ray crystallography of G/middle domains in two conformations, SAXS, GTP/GDP/transition-state dimerization assays\",\n      \"pmids\": [\"21220294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length transmembrane-anchored fusion intermediate not captured\", \"membrane fusion not directly demonstrated in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating ATL1 mediates homotypic ER tubule fusion in human neurons and that axon defects are rescued by microtubule agents connected ER morphology to cytoskeletal dynamics in disease.\",\n      \"evidence\": \"SPG3A patient iPSC-derived neurons, axon growth and mitochondrial motility assays, microtubule-binding drug rescue\",\n      \"pmids\": [\"24908668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ER-microtubule interaction to axon growth not fully resolved\", \"single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A variant panel established that ATL1 is sufficient for fusion but that fusion deficit, while a key contributor, is not obligatory for SPG3A, refining the disease model.\",\n      \"evidence\": \"Cell ER-network assays, in vitro GTP hydrolysis, dimerization and membrane fusion assays, REEP1 co-redistribution across disease variants\",\n      \"pmids\": [\"25761634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Alternative pathogenic mechanism for fusion-competent variants unexplained\", \"in vivo relevance of REEP1 co-redistribution not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placing ATL1 upstream of VCP/p47, ER morphology and protein synthesis in dendritic spinogenesis extended its role beyond axons to synaptic structure, with a pharmacologic rescue.\",\n      \"evidence\": \"Knockdown, disease-mutation knockin mice, leucine supplementation rescue, dendritic spine and ER morphology quantification\",\n      \"pmids\": [\"26984393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the ATL1-VCP-p47 functional link not structurally defined\", \"how ER morphology controls translation efficiency remains mechanistically open\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-neuronal report linked ATL1 to mTOR-dependent control of trophoblast proliferation and invasion, raising a possible signaling role.\",\n      \"evidence\": \"siRNA knockdown/overexpression in HTR-8/SVneo cells, p-p70S6K/p-mTOR immunoblot, rapamycin rescue\",\n      \"pmids\": [\"36193555\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single cell line, single lab, no direct molecular link between ATL1 and mTOR pathway components\", \"mechanism limited to pathway-marker correlation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two studies connected ATL ER-fusion activity to lipid synthesis and synaptic vesicle/synaptic gene maintenance, and showed LXR-agonist rescue of patient neurons, framing lipid metabolism as a downstream disease axis.\",\n      \"evidence\": \"ATL2-KO mice with lipid measurements, synaptic vesicle EM and calyx electrophysiology (preprint); SPG3A patient iPSC cortical neurons with RNA-seq, calcium imaging and LXR623 rescue\",\n      \"pmids\": [\"bio_10.1101_2025.04.12.648519\", \"41250225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical coupling of ER membrane area to lipid synthesis rates not established\", \"one study is a preprint and uses ATL2 knockout\", \"whether lipid restoration corrects the primary fusion defect is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How fusion-competent SPG3A variants cause length-dependent axonopathy, and the precise molecular coupling of ER tubule fusion to lipid synthesis, protein synthesis and synaptic maintenance, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism for fusion-independent pathogenicity\", \"no structure of the full-length membrane-anchored fusion intermediate\", \"in vivo causal chain from ER morphology to axon degeneration incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1, 4, 7, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NIPA1\", \"VCP\", \"REEP1\", \"TMED2\", \"SPAST\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}