{"gene":"SNX14","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2015,"finding":"SNX14 localizes to lysosomes and associates with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Loss of SNX14 in patient-derived cells causes engorged lysosomes and slower autophagosome clearance upon starvation-induced autophagy.","method":"Cell fractionation/localization, phosphoinositide binding assay, autophagosome clearance assay in patient-derived cells, zebrafish morphant model","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, lipid binding, functional autophagy assay, in vivo morphant) replicated across 12 families","pmids":["25848753"],"is_preprint":false},{"year":2014,"finding":"SNX14 contains PX and RGS domains; loss-of-function mutations affecting the PX domain or reducing SNX14 levels cause increased cytoplasmic vacuolation in cultured fibroblasts, indicating a role in vesicle-mediated transport and cellular protein metabolism.","method":"Homozygosity mapping, whole-exome sequencing, Sanger sequencing, cellular vacuolation phenotype in patient fibroblasts","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain mapping and patient cell phenotype across three families, but mechanism is indirect (vacuolation readout only)","pmids":["25439728"],"is_preprint":false},{"year":2015,"finding":"SNX14 directly interacts with the 5-HT6 receptor (5-HT6R), promoting its internalization and lysosomal degradation. The RGS domain of SNX14 is non-functional as a GTPase activator for Gαs but specifically binds and sequesters Gαs to inhibit downstream cAMP production. PKA-mediated phosphorylation of SNX14 inhibits its binding to Gαs and redirects SNX14 to bind 5-HT6R, facilitating receptor endocytic degradation.","method":"Co-immunoprecipitation, receptor internalization/degradation assays, cAMP measurement, siRNA knockdown, PKA phosphorylation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional cAMP assay, and phosphorylation experiment in a single lab with multiple orthogonal methods","pmids":["25795301"],"is_preprint":false},{"year":2014,"finding":"SNX14 is a neuronally imprinted gene in mice; SNX14 protein levels increase during neuronal development. Knockdown of Snx14 reduces intrinsic neuronal excitability and severely impairs both excitatory and inhibitory synaptic transmission.","method":"Laser capture microdissection, allele-specific expression analysis, siRNA knockdown, electrophysiology (intrinsic excitability and synaptic transmission recording)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with defined electrophysiological phenotype, single lab","pmids":["24859318"],"is_preprint":false},{"year":2019,"finding":"SNX14 is an ER-resident protein that localizes to ER-lipid droplet (LD) contact sites following fatty acid (FA) treatment, where it promotes LD maturation and growth. SNX14 is ER-anchored and binds LDs in trans, independently of Seipin. SNX14 is recruited to ER microdomains containing the fatty acyl-CoA ligase ACSL3, where nascent LDs bud. SNX14 loss perturbs LD morphology, while overexpression promotes LD biogenesis and extends ER-LD contacts.","method":"Proximity-based APEX labeling, live-cell multi-time point imaging, topological dissection, overexpression/KO cell phenotyping, co-localization with ACSL3","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — APEX proximity labeling, topological dissection, live imaging, KO and overexpression with orthogonal readouts in single rigorous study","pmids":["30765438"],"is_preprint":false},{"year":2018,"finding":"SNX14 is an ER-associated protein requiring its N-terminal transmembrane helices for ER localization (PX domain dispensable for localization). SNX14 loss leads to cholesterol accumulation in LAMP1-positive lysosomal structures and decreased cholesterol ester levels. SNX14 associates with ER-derived lipid droplets following oleate treatment. ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating SNX14 is not required for ER-endolysosomal tethering.","method":"Domain deletion/mutation analysis, subcellular fractionation, filipin staining for cholesterol, cholesterol ester quantification, lipid droplet association assay in SNX14KO HEK293 cells and patient fibroblasts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping, KO cell lines, patient fibroblasts, multiple lipid assays, negative result for tethering function confirmed orthogonally","pmids":["29635513"],"is_preprint":false},{"year":2020,"finding":"Snx14 is required to maintain lipid saturation balance of cell membranes. Following saturated FA (SFA) treatment, SNX14KO cells show compromised ER integrity and are hypersensitive to SFA-mediated lipotoxic cell death. APEX2 proximity labeling identifies a functional interaction between Snx14 and the Δ-9 FA desaturase SCD1. Lipidomic profiling shows SNX14KO cells increase membrane lipid saturation after palmitate exposure, phenocopying SCD1-deficient cells. Lipotoxicity in SNX14KO cells can be rescued by SCD1 overexpression.","method":"APEX2-based proximity labeling, lipidomic profiling, SFA lipotoxicity assay, SCD1 overexpression rescue, ER integrity assay in SNX14KO cells and SCAR20 patient cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — APEX2 proximity labeling, lipidomics, KO + rescue with SCD1, patient-derived cells, multiple orthogonal methods","pmids":["33310904"],"is_preprint":false},{"year":2021,"finding":"SNX14 deficiency in mice destabilizes the microtubule-severing enzyme spastin, disrupting microtubule organization and axonal mitochondrial transport in Purkinje cells. This leads to compromised axonal integrity and mitochondrial dysfunction, causing degeneration of Purkinje cells and cerebellar ataxia. Valproate restores mitochondrial transport and function in SNX14-deficient Purkinje cells and ameliorates motor deficits.","method":"Snx14 knockout mouse model, motor behavior assays, immunofluorescence for spastin and microtubules, axonal transport live imaging, mitochondrial function assays, valproate treatment rescue","journal":"National science review","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined cellular phenotype, live axonal transport imaging, molecular pathway (spastin destabilization), drug rescue, multiple orthogonal readouts","pmids":["34691693"],"is_preprint":false},{"year":2021,"finding":"Yeast Mdm1 (ortholog of human SNX14) functions at the nucleus-vacuole junction (NVJ) to mediate TORC1 inactivation-induced nucleolar dynamics and is required for proper nucleophagic degradation of nucleolar proteins; Mdm1 is dispensable for the induction of nucleophagic flux itself.","method":"Yeast genetic analysis, fluorescence microscopy of nucleolar protein dynamics, nucleophagy flux assays in mdm1 mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in yeast ortholog with defined nucleolar phenotype, single lab","pmids":["33740659"],"is_preprint":false},{"year":2024,"finding":"SNX14-deficient mouse cerebella show widespread lipid storage and metabolism defects, with selective vulnerability of Purkinje cells. Pre-degenerating SNX14-deficient cerebella accumulate acylcarnitines and are depleted of triglycerides. Purkinje cells show defects in lipid droplet content and telolysosome enlargement prior to degeneration, suggesting lipotoxicity as a pathogenic mechanism.","method":"SNX14-deficient mouse model, ultrastructural analysis (electron microscopy), lipidomic profiling, immunofluorescence for lipid droplets and lysosomes","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with ultrastructure, lipidomics, and cell-type-specific phenotyping using multiple orthogonal methods","pmids":["38625743"],"is_preprint":false},{"year":2025,"finding":"SNX14 promotes GluA2 (AMPA receptor subunit) protein degradation via the lysosomal pathway, thereby modulating glutamatergic synaptic transmission. SNX14 downregulation in hippocampus decreases seizure susceptibility, while overexpression increases it.","method":"SNX14 knockdown/overexpression in mouse hippocampus, western blotting for GluA2, lysosomal inhibitor experiments, in vivo seizure susceptibility assay","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD/OE with defined pathway (lysosomal GluA2 degradation), single lab, mechanistic follow-up with inhibitor experiment","pmids":["40237949"],"is_preprint":false}],"current_model":"SNX14 is an ER-resident protein (anchored via N-terminal transmembrane helices) that localizes to ER–lipid droplet contact sites to promote lipid droplet growth and fatty acid desaturation (via functional interaction with SCD1), associates with phosphatidylinositol (3,5)-bisphosphate at late endosomes/lysosomes to support lysosome–autophagosome function, stabilizes the microtubule-severing enzyme spastin to maintain axonal mitochondrial transport in Purkinje cells, binds and sequesters Gαs through its RGS domain (inhibiting cAMP signaling), directly interacts with 5-HT6R to promote its lysosomal degradation in a PKA phosphorylation-dependent manner, and regulates GluA2 AMPA receptor subunit degradation via the lysosomal pathway—collectively establishing SNX14 as a multifunctional organelle-contact and lipid homeostasis protein whose loss causes Purkinje cell degeneration and cerebellar ataxia (SCAR20)."},"narrative":{"mechanistic_narrative":"SNX14 is an endoplasmic reticulum-resident protein that functions at organelle contact sites to govern cellular lipid homeostasis, with loss-of-function mutations causing autosomal recessive cerebellar ataxia (SCAR20) [PMID:25439728, PMID:29635513]. Anchored in the ER through its N-terminal transmembrane helices, SNX14 relocalizes to ER–lipid droplet contact sites upon fatty acid loading, where it is recruited to ACSL3-marked microdomains and promotes lipid droplet maturation and growth in a Seipin-independent manner [PMID:30765438, PMID:29635513]. It maintains membrane lipid saturation balance through a functional interaction with the Δ-9 desaturase SCD1, such that SNX14 loss raises membrane lipid saturation and sensitizes cells to saturated fatty acid lipotoxicity, a defect rescued by SCD1 overexpression [PMID:33310904]. SNX14 also associates with phosphatidylinositol (3,5)-bisphosphate at late endosomes/lysosomes and supports lysosome–autophagosome function, with its loss producing engorged lysosomes, cholesterol accumulation, and impaired autophagosome clearance [PMID:25848753, PMID:29635513]. In the nervous system these activities converge on Purkinje cell survival: SNX14-deficient cerebella accumulate acylcarnitines, deplete triglycerides, and exhibit lipid droplet and lysosomal defects preceding degeneration, while SNX14 also stabilizes the microtubule-severing enzyme spastin to maintain axonal mitochondrial transport [PMID:34691693, PMID:38625743]. Through its RGS domain SNX14 binds and sequesters Gαs to inhibit cAMP signaling and, in a PKA phosphorylation-dependent switch, promotes lysosomal degradation of the 5-HT6 receptor; it likewise drives lysosomal degradation of the GluA2 AMPA receptor subunit to modulate glutamatergic transmission [PMID:25795301, PMID:40237949].","teleology":[{"year":2014,"claim":"Establishing SNX14 as a disease gene and defining its domain architecture answered whether SNX14 loss is causative for a neurological phenotype and pointed toward a vesicular/trafficking role.","evidence":"Homozygosity mapping and exome sequencing across families with cellular vacuolation phenotype in patient fibroblasts","pmids":["25439728"],"confidence":"Medium","gaps":["Vacuolation is an indirect readout with no defined molecular mechanism","PX and RGS domain functions not yet assigned","no link to specific lipid or trafficking pathway"]},{"year":2014,"claim":"Defining SNX14 expression and electrophysiological consequences of its loss addressed whether the protein has a neuronal-functional role beyond cell viability.","evidence":"Allele-specific expression analysis and siRNA knockdown with electrophysiological recording of excitability and synaptic transmission","pmids":["24859318"],"confidence":"Medium","gaps":["Molecular basis of altered excitability not identified","imprinting status in human not established","no connection to a defined signaling or trafficking pathway"]},{"year":2015,"claim":"Localizing SNX14 to lysosomes and linking it to PI(3,5)P2 and autophagy answered where SNX14 acts and connected its loss to defective lysosome–autophagosome function.","evidence":"Cell fractionation, phosphoinositide binding, autophagosome clearance assays in patient cells, and zebrafish morphant model across 12 families","pmids":["25848753"],"confidence":"High","gaps":["Mechanism by which PI(3,5)P2 binding supports autophagy not resolved","does not address ER residence","no substrate of degradation identified"]},{"year":2015,"claim":"Defining the RGS domain as a Gαs sequester and the PKA-dependent switch to 5-HT6R binding established a signaling and receptor-degradation function for SNX14.","evidence":"Reciprocal Co-IP, cAMP measurement, receptor internalization/degradation assays, and PKA phosphorylation experiments with siRNA knockdown","pmids":["25795301"],"confidence":"Medium","gaps":["Performed in a single lab without independent replication","physiological relevance in Purkinje cells not tested","relationship to lipid functions unclear"]},{"year":2018,"claim":"Mapping SNX14 to the ER via N-terminal transmembrane helices and linking its loss to lysosomal cholesterol accumulation reoriented SNX14 from a classic sorting nexin to an ER membrane protein, while excluding an ER–endolysosome tethering role.","evidence":"Domain deletion analysis, fractionation, filipin/cholesterol ester quantification, and lipid droplet association assays in SNX14KO cells and patient fibroblasts","pmids":["29635513"],"confidence":"High","gaps":["How ER-anchored SNX14 influences distal lysosomal cholesterol not mechanistically resolved","PX domain function despite being dispensable for localization unclear"]},{"year":2019,"claim":"Demonstrating recruitment to ER–lipid droplet contact sites and promotion of LD growth defined a direct organelle-contact function for SNX14 in lipid droplet biogenesis.","evidence":"APEX proximity labeling, live-cell imaging, topological dissection, and KO/overexpression phenotyping with ACSL3 co-localization","pmids":["30765438"],"confidence":"High","gaps":["Molecular determinants of trans-LD binding not fully defined","Seipin-independence mechanism not detailed","link to neuronal disease not established here"]},{"year":2020,"claim":"Identifying a functional SNX14–SCD1 interaction governing membrane lipid saturation answered how SNX14 loss causes lipotoxic vulnerability and provided a rescuable molecular axis.","evidence":"APEX2 proximity labeling, lipidomics, saturated-fatty-acid lipotoxicity assays, and SCD1 overexpression rescue in KO and SCAR20 patient cells","pmids":["33310904"],"confidence":"High","gaps":["Whether the SNX14–SCD1 interaction is direct/physical not resolved","in vivo relevance to Purkinje cell lipotoxicity not yet tested"]},{"year":2021,"claim":"Showing SNX14 stabilizes spastin to maintain axonal mitochondrial transport connected SNX14 loss to a cytoskeletal/mitochondrial mechanism of Purkinje cell degeneration and identified valproate as a rescue.","evidence":"Snx14 knockout mouse with motor assays, immunofluorescence for spastin/microtubules, live axonal transport imaging, and valproate rescue","pmids":["34691693"],"confidence":"High","gaps":["Mechanism by which SNX14 stabilizes spastin not defined","relationship between this pathway and SNX14 lipid functions unresolved"]},{"year":2021,"claim":"Characterizing the yeast ortholog Mdm1 at the nucleus-vacuole junction in nucleophagy extended the contact-site/autophagy role of the SNX14 family to nucleolar protein degradation.","evidence":"Yeast genetic loss-of-function with fluorescence microscopy of nucleolar dynamics and nucleophagy flux assays","pmids":["33740659"],"confidence":"Medium","gaps":["Conservation of NVJ/nucleophagy function in human SNX14 not demonstrated","single-lab yeast study","no link to lipid droplet function shown"]},{"year":2024,"claim":"Profiling SNX14-deficient cerebella established lipid storage/metabolism defects and lipotoxicity as an in vivo pathogenic mechanism with selective Purkinje cell vulnerability.","evidence":"SNX14-deficient mouse model with electron microscopy, lipidomic profiling, and immunofluorescence for lipid droplets and lysosomes","pmids":["38625743"],"confidence":"High","gaps":["Causal chain from lipid imbalance to Purkinje death not fully resolved","why Purkinje cells are selectively vulnerable not explained"]},{"year":2025,"claim":"Demonstrating SNX14-driven lysosomal degradation of GluA2 and its effect on seizure susceptibility linked SNX14 to glutamatergic synaptic regulation in vivo.","evidence":"SNX14 knockdown/overexpression in mouse hippocampus with GluA2 western blots, lysosomal inhibitor experiments, and seizure susceptibility assays","pmids":["40237949"],"confidence":"Medium","gaps":["Whether SNX14 binds GluA2 directly not shown","single-lab study","relationship to cerebellar lipid phenotype unclear"]},{"year":null,"claim":"How SNX14's distinct activities—ER–LD contact lipid handling, lysosomal receptor degradation, RGS/Gαs signaling, and spastin stabilization—are mechanistically integrated within a single protein, and which is primary in SCAR20 pathogenesis, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical model linking lipid and signaling/degradation roles","structural basis of multidomain function undetermined","primary disease-driving pathway not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["SCD1","ACSL3","GNAS","HTR6","SPAST","GRIA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5W7","full_name":"Sorting nexin-14","aliases":[],"length_aa":946,"mass_kda":110.2,"function":"Plays a role in maintaining normal neuronal excitability and synaptic transmission. May be involved in several stages of intracellular trafficking (By similarity). Required for autophagosome clearance, possibly by mediating the fusion of lysosomes with autophagosomes (Probable). Binds phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), a key component of late endosomes/lysosomes (PubMed:25848753). Does not bind phosphatidylinositol 3-phosphate (PtdIns(3P)) (PubMed:25148684, PubMed:25848753)","subcellular_location":"Lysosome membrane; Late endosome membrane; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q9Y5W7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX14","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CYP51A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SNX14","total_profiled":1310},"omim":[{"mim_id":"620961","title":"SORTING NEXIN 25; SNX25","url":"https://www.omim.org/entry/620961"},{"mim_id":"616354","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 20; SCAR20","url":"https://www.omim.org/entry/616354"},{"mim_id":"616105","title":"SORTING NEXIN 14; SNX14","url":"https://www.omim.org/entry/616105"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX14"},"hgnc":{"alias_symbol":["RGS-PX2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5W7","domains":[{"cath_id":"-","chopping":"19-67","consensus_level":"high","plddt":75.4447,"start":19,"end":67},{"cath_id":"-","chopping":"119-302_313-321_787-939","consensus_level":"high","plddt":85.5337,"start":119,"end":939},{"cath_id":"1.10.167.10","chopping":"336-468","consensus_level":"high","plddt":84.4071,"start":336,"end":468},{"cath_id":"3.30.1520.10","chopping":"566-576_586-682","consensus_level":"high","plddt":86.9144,"start":566,"end":682}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5W7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5W7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5W7-F1-predicted_aligned_error_v6.png","plddt_mean":73.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX14","jax_strain_url":"https://www.jax.org/strain/search?query=SNX14"},"sequence":{"accession":"Q9Y5W7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5W7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5W7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5W7"}},"corpus_meta":[{"pmid":"25848753","id":"PMC_25848753","title":"Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25848753","citation_count":105,"is_preprint":false},{"pmid":"30765438","id":"PMC_30765438","title":"Cerebellar ataxia disease-associated Snx14 promotes lipid droplet growth at ER-droplet contacts.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30765438","citation_count":95,"is_preprint":false},{"pmid":"25439728","id":"PMC_25439728","title":"Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25439728","citation_count":86,"is_preprint":false},{"pmid":"29635513","id":"PMC_29635513","title":"SNX14 mutations affect endoplasmic reticulum-associated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29635513","citation_count":58,"is_preprint":false},{"pmid":"24859318","id":"PMC_24859318","title":"Snx14 regulates neuronal excitability, promotes synaptic transmission, and is imprinted in the brain of mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24859318","citation_count":33,"is_preprint":false},{"pmid":"25795301","id":"PMC_25795301","title":"SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25795301","citation_count":28,"is_preprint":false},{"pmid":"36670083","id":"PMC_36670083","title":"Apoptotic Vesicles Regulate Bone Metabolism via the miR1324/SNX14/SMAD1/5 Signaling Axis.","date":"2023","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36670083","citation_count":27,"is_preprint":false},{"pmid":"27566131","id":"PMC_27566131","title":"Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed.","date":"2016","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27566131","citation_count":21,"is_preprint":false},{"pmid":"34691693","id":"PMC_34691693","title":"SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate.","date":"2021","source":"National science review","url":"https://pubmed.ncbi.nlm.nih.gov/34691693","citation_count":21,"is_preprint":false},{"pmid":"33310904","id":"PMC_33310904","title":"Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33310904","citation_count":18,"is_preprint":false},{"pmid":"38625743","id":"PMC_38625743","title":"Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38625743","citation_count":8,"is_preprint":false},{"pmid":"33740659","id":"PMC_33740659","title":"Sorting nexin Mdm1/SNX14 regulates nucleolar dynamics at the NVJ after TORC1 inactivation.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33740659","citation_count":7,"is_preprint":false},{"pmid":"33193593","id":"PMC_33193593","title":"Two Compound Heterozygous Variants in SNX14 Cause Stereotypies and Dystonia in Autosomal Recessive Spinocerebellar Ataxia 20.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33193593","citation_count":6,"is_preprint":false},{"pmid":"37485342","id":"PMC_37485342","title":"Homozygous deep intronic variant in SNX14 cause autosomal recessive Spinocerebellar ataxia 20: a case report.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37485342","citation_count":5,"is_preprint":false},{"pmid":"38869753","id":"PMC_38869753","title":"SNX14 inhibits autophagy via the PI3K/AKT/mTOR signaling cascade in breast cancer cells.","date":"2024","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/38869753","citation_count":4,"is_preprint":false},{"pmid":"35195341","id":"PMC_35195341","title":"Autosomal recessive spinocerebellar ataxia-20 due to a novel SNX14 variant in an Indian girl.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/35195341","citation_count":4,"is_preprint":false},{"pmid":"38655056","id":"PMC_38655056","title":"Compound heterozygous mutation of the SNX14 gene causes autosomal recessive spinocerebellar ataxia 20.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38655056","citation_count":2,"is_preprint":false},{"pmid":"40237949","id":"PMC_40237949","title":"Inhibiting SNX14 Alleviates Epileptic Seizures by Regulating GluA2 Degradation via the Lysosomal Pathway.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40237949","citation_count":1,"is_preprint":false},{"pmid":"41294032","id":"PMC_41294032","title":"Exploring the Genetic Variations Underlying SNX14-Linked Autosomal Recessive Spinocerebellar Ataxia Type 20: A Case Series of 17 Patients From a Single Center in the Omani Population and Review of Literature.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41294032","citation_count":1,"is_preprint":false},{"pmid":"42074495","id":"PMC_42074495","title":"A Homozygous Deep Intronic SNX14 Variant Activates Pseudo-Exon Inclusion in a Patient with SCAR20.","date":"2026","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/42074495","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11625,"output_tokens":3129,"usd":0.040905,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10583,"output_tokens":4046,"usd":0.077033,"stage2_stop_reason":"end_turn"},"total_usd":0.117938,"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\": 2015,\n      \"finding\": \"SNX14 localizes to lysosomes and associates with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Loss of SNX14 in patient-derived cells causes engorged lysosomes and slower autophagosome clearance upon starvation-induced autophagy.\",\n      \"method\": \"Cell fractionation/localization, phosphoinositide binding assay, autophagosome clearance assay in patient-derived cells, zebrafish morphant model\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, lipid binding, functional autophagy assay, in vivo morphant) replicated across 12 families\",\n      \"pmids\": [\"25848753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNX14 contains PX and RGS domains; loss-of-function mutations affecting the PX domain or reducing SNX14 levels cause increased cytoplasmic vacuolation in cultured fibroblasts, indicating a role in vesicle-mediated transport and cellular protein metabolism.\",\n      \"method\": \"Homozygosity mapping, whole-exome sequencing, Sanger sequencing, cellular vacuolation phenotype in patient fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain mapping and patient cell phenotype across three families, but mechanism is indirect (vacuolation readout only)\",\n      \"pmids\": [\"25439728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SNX14 directly interacts with the 5-HT6 receptor (5-HT6R), promoting its internalization and lysosomal degradation. The RGS domain of SNX14 is non-functional as a GTPase activator for Gαs but specifically binds and sequesters Gαs to inhibit downstream cAMP production. PKA-mediated phosphorylation of SNX14 inhibits its binding to Gαs and redirects SNX14 to bind 5-HT6R, facilitating receptor endocytic degradation.\",\n      \"method\": \"Co-immunoprecipitation, receptor internalization/degradation assays, cAMP measurement, siRNA knockdown, PKA phosphorylation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional cAMP assay, and phosphorylation experiment in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25795301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNX14 is a neuronally imprinted gene in mice; SNX14 protein levels increase during neuronal development. Knockdown of Snx14 reduces intrinsic neuronal excitability and severely impairs both excitatory and inhibitory synaptic transmission.\",\n      \"method\": \"Laser capture microdissection, allele-specific expression analysis, siRNA knockdown, electrophysiology (intrinsic excitability and synaptic transmission recording)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with defined electrophysiological phenotype, single lab\",\n      \"pmids\": [\"24859318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX14 is an ER-resident protein that localizes to ER-lipid droplet (LD) contact sites following fatty acid (FA) treatment, where it promotes LD maturation and growth. SNX14 is ER-anchored and binds LDs in trans, independently of Seipin. SNX14 is recruited to ER microdomains containing the fatty acyl-CoA ligase ACSL3, where nascent LDs bud. SNX14 loss perturbs LD morphology, while overexpression promotes LD biogenesis and extends ER-LD contacts.\",\n      \"method\": \"Proximity-based APEX labeling, live-cell multi-time point imaging, topological dissection, overexpression/KO cell phenotyping, co-localization with ACSL3\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — APEX proximity labeling, topological dissection, live imaging, KO and overexpression with orthogonal readouts in single rigorous study\",\n      \"pmids\": [\"30765438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX14 is an ER-associated protein requiring its N-terminal transmembrane helices for ER localization (PX domain dispensable for localization). SNX14 loss leads to cholesterol accumulation in LAMP1-positive lysosomal structures and decreased cholesterol ester levels. SNX14 associates with ER-derived lipid droplets following oleate treatment. ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating SNX14 is not required for ER-endolysosomal tethering.\",\n      \"method\": \"Domain deletion/mutation analysis, subcellular fractionation, filipin staining for cholesterol, cholesterol ester quantification, lipid droplet association assay in SNX14KO HEK293 cells and patient fibroblasts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping, KO cell lines, patient fibroblasts, multiple lipid assays, negative result for tethering function confirmed orthogonally\",\n      \"pmids\": [\"29635513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Snx14 is required to maintain lipid saturation balance of cell membranes. Following saturated FA (SFA) treatment, SNX14KO cells show compromised ER integrity and are hypersensitive to SFA-mediated lipotoxic cell death. APEX2 proximity labeling identifies a functional interaction between Snx14 and the Δ-9 FA desaturase SCD1. Lipidomic profiling shows SNX14KO cells increase membrane lipid saturation after palmitate exposure, phenocopying SCD1-deficient cells. Lipotoxicity in SNX14KO cells can be rescued by SCD1 overexpression.\",\n      \"method\": \"APEX2-based proximity labeling, lipidomic profiling, SFA lipotoxicity assay, SCD1 overexpression rescue, ER integrity assay in SNX14KO cells and SCAR20 patient cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — APEX2 proximity labeling, lipidomics, KO + rescue with SCD1, patient-derived cells, multiple orthogonal methods\",\n      \"pmids\": [\"33310904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX14 deficiency in mice destabilizes the microtubule-severing enzyme spastin, disrupting microtubule organization and axonal mitochondrial transport in Purkinje cells. This leads to compromised axonal integrity and mitochondrial dysfunction, causing degeneration of Purkinje cells and cerebellar ataxia. Valproate restores mitochondrial transport and function in SNX14-deficient Purkinje cells and ameliorates motor deficits.\",\n      \"method\": \"Snx14 knockout mouse model, motor behavior assays, immunofluorescence for spastin and microtubules, axonal transport live imaging, mitochondrial function assays, valproate treatment rescue\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined cellular phenotype, live axonal transport imaging, molecular pathway (spastin destabilization), drug rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"34691693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Mdm1 (ortholog of human SNX14) functions at the nucleus-vacuole junction (NVJ) to mediate TORC1 inactivation-induced nucleolar dynamics and is required for proper nucleophagic degradation of nucleolar proteins; Mdm1 is dispensable for the induction of nucleophagic flux itself.\",\n      \"method\": \"Yeast genetic analysis, fluorescence microscopy of nucleolar protein dynamics, nucleophagy flux assays in mdm1 mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in yeast ortholog with defined nucleolar phenotype, single lab\",\n      \"pmids\": [\"33740659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX14-deficient mouse cerebella show widespread lipid storage and metabolism defects, with selective vulnerability of Purkinje cells. Pre-degenerating SNX14-deficient cerebella accumulate acylcarnitines and are depleted of triglycerides. Purkinje cells show defects in lipid droplet content and telolysosome enlargement prior to degeneration, suggesting lipotoxicity as a pathogenic mechanism.\",\n      \"method\": \"SNX14-deficient mouse model, ultrastructural analysis (electron microscopy), lipidomic profiling, immunofluorescence for lipid droplets and lysosomes\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with ultrastructure, lipidomics, and cell-type-specific phenotyping using multiple orthogonal methods\",\n      \"pmids\": [\"38625743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX14 promotes GluA2 (AMPA receptor subunit) protein degradation via the lysosomal pathway, thereby modulating glutamatergic synaptic transmission. SNX14 downregulation in hippocampus decreases seizure susceptibility, while overexpression increases it.\",\n      \"method\": \"SNX14 knockdown/overexpression in mouse hippocampus, western blotting for GluA2, lysosomal inhibitor experiments, in vivo seizure susceptibility assay\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD/OE with defined pathway (lysosomal GluA2 degradation), single lab, mechanistic follow-up with inhibitor experiment\",\n      \"pmids\": [\"40237949\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX14 is an ER-resident protein (anchored via N-terminal transmembrane helices) that localizes to ER–lipid droplet contact sites to promote lipid droplet growth and fatty acid desaturation (via functional interaction with SCD1), associates with phosphatidylinositol (3,5)-bisphosphate at late endosomes/lysosomes to support lysosome–autophagosome function, stabilizes the microtubule-severing enzyme spastin to maintain axonal mitochondrial transport in Purkinje cells, binds and sequesters Gαs through its RGS domain (inhibiting cAMP signaling), directly interacts with 5-HT6R to promote its lysosomal degradation in a PKA phosphorylation-dependent manner, and regulates GluA2 AMPA receptor subunit degradation via the lysosomal pathway—collectively establishing SNX14 as a multifunctional organelle-contact and lipid homeostasis protein whose loss causes Purkinje cell degeneration and cerebellar ataxia (SCAR20).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX14 is an endoplasmic reticulum-resident protein that functions at organelle contact sites to govern cellular lipid homeostasis, with loss-of-function mutations causing autosomal recessive cerebellar ataxia (SCAR20) [#1, #5]. Anchored in the ER through its N-terminal transmembrane helices, SNX14 relocalizes to ER\\u2013lipid droplet contact sites upon fatty acid loading, where it is recruited to ACSL3-marked microdomains and promotes lipid droplet maturation and growth in a Seipin-independent manner [#4, #5]. It maintains membrane lipid saturation balance through a functional interaction with the \\u0394-9 desaturase SCD1, such that SNX14 loss raises membrane lipid saturation and sensitizes cells to saturated fatty acid lipotoxicity, a defect rescued by SCD1 overexpression [#6]. SNX14 also associates with phosphatidylinositol (3,5)-bisphosphate at late endosomes/lysosomes and supports lysosome\\u2013autophagosome function, with its loss producing engorged lysosomes, cholesterol accumulation, and impaired autophagosome clearance [#0, #5]. In the nervous system these activities converge on Purkinje cell survival: SNX14-deficient cerebella accumulate acylcarnitines, deplete triglycerides, and exhibit lipid droplet and lysosomal defects preceding degeneration, while SNX14 also stabilizes the microtubule-severing enzyme spastin to maintain axonal mitochondrial transport [#7, #9]. Through its RGS domain SNX14 binds and sequesters G\\u03b1s to inhibit cAMP signaling and, in a PKA phosphorylation-dependent switch, promotes lysosomal degradation of the 5-HT6 receptor; it likewise drives lysosomal degradation of the GluA2 AMPA receptor subunit to modulate glutamatergic transmission [#2, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing SNX14 as a disease gene and defining its domain architecture answered whether SNX14 loss is causative for a neurological phenotype and pointed toward a vesicular/trafficking role.\",\n      \"evidence\": \"Homozygosity mapping and exome sequencing across families with cellular vacuolation phenotype in patient fibroblasts\",\n      \"pmids\": [\"25439728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Vacuolation is an indirect readout with no defined molecular mechanism\", \"PX and RGS domain functions not yet assigned\", \"no link to specific lipid or trafficking pathway\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining SNX14 expression and electrophysiological consequences of its loss addressed whether the protein has a neuronal-functional role beyond cell viability.\",\n      \"evidence\": \"Allele-specific expression analysis and siRNA knockdown with electrophysiological recording of excitability and synaptic transmission\",\n      \"pmids\": [\"24859318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of altered excitability not identified\", \"imprinting status in human not established\", \"no connection to a defined signaling or trafficking pathway\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Localizing SNX14 to lysosomes and linking it to PI(3,5)P2 and autophagy answered where SNX14 acts and connected its loss to defective lysosome\\u2013autophagosome function.\",\n      \"evidence\": \"Cell fractionation, phosphoinositide binding, autophagosome clearance assays in patient cells, and zebrafish morphant model across 12 families\",\n      \"pmids\": [\"25848753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PI(3,5)P2 binding supports autophagy not resolved\", \"does not address ER residence\", \"no substrate of degradation identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the RGS domain as a G\\u03b1s sequester and the PKA-dependent switch to 5-HT6R binding established a signaling and receptor-degradation function for SNX14.\",\n      \"evidence\": \"Reciprocal Co-IP, cAMP measurement, receptor internalization/degradation assays, and PKA phosphorylation experiments with siRNA knockdown\",\n      \"pmids\": [\"25795301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in a single lab without independent replication\", \"physiological relevance in Purkinje cells not tested\", \"relationship to lipid functions unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapping SNX14 to the ER via N-terminal transmembrane helices and linking its loss to lysosomal cholesterol accumulation reoriented SNX14 from a classic sorting nexin to an ER membrane protein, while excluding an ER\\u2013endolysosome tethering role.\",\n      \"evidence\": \"Domain deletion analysis, fractionation, filipin/cholesterol ester quantification, and lipid droplet association assays in SNX14KO cells and patient fibroblasts\",\n      \"pmids\": [\"29635513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ER-anchored SNX14 influences distal lysosomal cholesterol not mechanistically resolved\", \"PX domain function despite being dispensable for localization unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating recruitment to ER\\u2013lipid droplet contact sites and promotion of LD growth defined a direct organelle-contact function for SNX14 in lipid droplet biogenesis.\",\n      \"evidence\": \"APEX proximity labeling, live-cell imaging, topological dissection, and KO/overexpression phenotyping with ACSL3 co-localization\",\n      \"pmids\": [\"30765438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of trans-LD binding not fully defined\", \"Seipin-independence mechanism not detailed\", \"link to neuronal disease not established here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying a functional SNX14\\u2013SCD1 interaction governing membrane lipid saturation answered how SNX14 loss causes lipotoxic vulnerability and provided a rescuable molecular axis.\",\n      \"evidence\": \"APEX2 proximity labeling, lipidomics, saturated-fatty-acid lipotoxicity assays, and SCD1 overexpression rescue in KO and SCAR20 patient cells\",\n      \"pmids\": [\"33310904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the SNX14\\u2013SCD1 interaction is direct/physical not resolved\", \"in vivo relevance to Purkinje cell lipotoxicity not yet tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing SNX14 stabilizes spastin to maintain axonal mitochondrial transport connected SNX14 loss to a cytoskeletal/mitochondrial mechanism of Purkinje cell degeneration and identified valproate as a rescue.\",\n      \"evidence\": \"Snx14 knockout mouse with motor assays, immunofluorescence for spastin/microtubules, live axonal transport imaging, and valproate rescue\",\n      \"pmids\": [\"34691693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SNX14 stabilizes spastin not defined\", \"relationship between this pathway and SNX14 lipid functions unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Characterizing the yeast ortholog Mdm1 at the nucleus-vacuole junction in nucleophagy extended the contact-site/autophagy role of the SNX14 family to nucleolar protein degradation.\",\n      \"evidence\": \"Yeast genetic loss-of-function with fluorescence microscopy of nucleolar dynamics and nucleophagy flux assays\",\n      \"pmids\": [\"33740659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of NVJ/nucleophagy function in human SNX14 not demonstrated\", \"single-lab yeast study\", \"no link to lipid droplet function shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Profiling SNX14-deficient cerebella established lipid storage/metabolism defects and lipotoxicity as an in vivo pathogenic mechanism with selective Purkinje cell vulnerability.\",\n      \"evidence\": \"SNX14-deficient mouse model with electron microscopy, lipidomic profiling, and immunofluorescence for lipid droplets and lysosomes\",\n      \"pmids\": [\"38625743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from lipid imbalance to Purkinje death not fully resolved\", \"why Purkinje cells are selectively vulnerable not explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating SNX14-driven lysosomal degradation of GluA2 and its effect on seizure susceptibility linked SNX14 to glutamatergic synaptic regulation in vivo.\",\n      \"evidence\": \"SNX14 knockdown/overexpression in mouse hippocampus with GluA2 western blots, lysosomal inhibitor experiments, and seizure susceptibility assays\",\n      \"pmids\": [\"40237949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNX14 binds GluA2 directly not shown\", \"single-lab study\", \"relationship to cerebellar lipid phenotype unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX14's distinct activities\\u2014ER\\u2013LD contact lipid handling, lysosomal receptor degradation, RGS/G\\u03b1s signaling, and spastin stabilization\\u2014are mechanistically integrated within a single protein, and which is primary in SCAR20 pathogenesis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical model linking lipid and signaling/degradation roles\", \"structural basis of multidomain function undetermined\", \"primary disease-driving pathway not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SCD1\", \"ACSL3\", \"GNAS\", \"HTR6\", \"SPAST\", \"GRIA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}