{"gene":"PSAP","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2007,"finding":"PSAP (also known as MTCH1/Presenilin 1-associated protein) is an integral mitochondrial outer membrane protein. Two isoforms are generated by alternative splicing differing in a hydrophilic loop between transmembrane domains. A transmembrane domain in the correct position and orientation is necessary for mitochondrial membrane insertion. Two independent N-terminal regions are responsible for proapoptotic activity.","method":"RT-PCR, Western blot, deletion mutagenesis, fractionation, transmembrane domain replacement experiments","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation plus mutagenesis in single lab with multiple orthogonal methods","pmids":["17670888"],"is_preprint":false},{"year":2008,"finding":"PSAP is expressed in four isoforms due to differential splicing of exon 8 and use of alternative start codons. All isoforms localize to mitochondria and are proapoptotic. Both the PDZ domain and the N-terminal fragment are required for proapoptotic activity.","method":"Gene cloning, antibody generation against different PSAP regions, Western blot, immunofluorescence localization, deletion constructs","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Western blot, immunofluorescence, deletion mutagenesis) in single lab","pmids":["18291114"],"is_preprint":false},{"year":2012,"finding":"PSAP (MTCH1) induces apoptosis through a unique mitochondrial pathway requiring Apaf-1/apoptosome formation and Smac, but independent of Bcl-2 family proteins. Knockdown of Apaf-1 or Smac abolished PSAP-induced caspase activation and PARP cleavage, whereas overexpression of Bcl-2/Bcl-xL or knockdown of Bid, Bax, or Bak had no effect on PSAP-induced cytochrome c and Smac release.","method":"Inducible expression system, siRNA knockdown, caspase activation assay, PARP cleavage assay, cytochrome c and Smac release assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, release assays, apoptosis readouts) in single lab","pmids":["23207240"],"is_preprint":false},{"year":2015,"finding":"PSAP (MTCH1) mediates presenilin 1 (PS1)-induced γ-secretase-independent apoptosis by forming a complex with Bax at the mitochondria, promoting Bax translocation and cytochrome c release. The PSAP-Bax complex localizes to the mitochondrial fraction, while a DR6-Bax complex localizes to the cytosolic fraction. Complete inhibition of PS1-induced apoptosis required both γ-secretase inhibitor and PSAP knockdown.","method":"siRNA knockdown, co-immunoprecipitation, subcellular fractionation, γ-secretase inhibitor treatment, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, fractionation, and functional knockdown in single lab with multiple readouts","pmids":["26025363"],"is_preprint":false},{"year":2020,"finding":"PSAP (MTCH1) interacts with death receptor DR6 (identified by yeast two-hybrid) and mediates DR6-induced apoptosis. PSAP knockdown blocked DR6-induced Bax translocation to mitochondria and cytochrome c release. DR6-bound Bax in the cytosol is transferred to PSAP at the mitochondria, forming a mitochondrial PSAP-Bax complex that drives cytochrome c release. Knockdown of DR6 reduced the mitochondrial PSAP-Bax complex.","method":"Yeast two-hybrid, siRNA knockdown, co-immunoprecipitation, subcellular fractionation, cytochrome c release assay, apoptosis assays","journal":"Journal of Alzheimer's disease : JAD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus fractionation plus functional knockdown, single lab","pmids":["32144986"],"is_preprint":false},{"year":2015,"finding":"Early growth response 1 (EGR-1) is a transcriptional regulator of PSAP (MTCH1). EGR-1 binding sites are present in the MTCH1 proximal promoter; chromatin immunoprecipitation confirmed enrichment of these sequences in EGR-1-bound DNA. Overexpression of EGR-1 increased endogenous MTCH1 levels, and siRNA-mediated knockdown of EGR-1 decreased MTCH1 levels. MTCH1 levels also increase in response to doxorubicin-induced DNA damage.","method":"Chromatin immunoprecipitation (ChIP), RT-PCR, Western blot, EGR-1 overexpression and siRNA knockdown","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional overexpression/knockdown, multiple orthogonal methods, single lab","pmids":["26692143"],"is_preprint":false},{"year":2024,"finding":"PSAP (prosaposin) activates the GPR37L1 receptor in astrocytes to reduce astrocytic synaptic engulfment via ERK/SMAD2/3 signaling, providing neuroprotection in Parkinson's disease models. Activation of GPR37L1 with Tx14(A) peptide rescued motor defects and protected dopamine neurons in PD mice.","method":"Single nuclear RNA sequencing, cell culture, biochemical studies, in vivo mouse models, pharmacological GPR37L1 activation","journal":"Journal of nanobiotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — snRNA-seq identifies pathway plus in vivo pharmacological validation, but mechanistic detail on PSAP-GPR37L1 binding is limited in the abstract","pmids":["39523310"],"is_preprint":false},{"year":2025,"finding":"ACE deficiency promotes OGT-mediated O-GlcNAc glycosylation of PSAP at serine residues, which suppresses CBL E3 ubiquitin ligase-dependent ubiquitination and proteasomal degradation of PSAP. Stabilized PSAP engages GPR37 on macrophages to promote M2 polarization via ERK/SMAD2/3 signaling, and stimulates TGFβ secretion. Secreted TGFβ reinforces PSAP-Sortilin-mediated trafficking in nucleus pulposus cells via PI3K/AKT pathway.","method":"Biochemical studies, in vivo gene-editing virus-loaded hydrogel intervention, cell culture, signaling pathway analysis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic claims from single study with limited methodological detail in abstract","pmids":["41085015"],"is_preprint":false},{"year":2024,"finding":"PSAP (prosaposin) binds with high affinity to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein at the non-receptor-binding motif (non-RBM) region, and secreted PSAP facilitates release of the S1 subunit from the spike protein, thereby blocking viral entry. This was identified by host cDNA overexpression screen and confirmed with pseudovirus and authentic virus infection assays and molecular docking.","method":"Host cDNA overexpression screen, pseudovirus and authentic virus infection assays, binding affinity measurements, molecular docking analysis","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen plus binding assays plus authentic virus validation, multiple orthogonal methods, single lab","pmids":["41885456"],"is_preprint":false},{"year":2026,"finding":"PSAP overexpression in cardiomyocytes reduces ceramide accumulation during ischemia-reperfusion injury by rescuing expression of the lysosomal enzyme ASAH1 (N-acylsphingosine amidohydrolase 1), thereby accelerating ceramide degradation and attenuating apoptosis. AAV9-mediated PSAP overexpression in vivo reduced infarct size.","method":"AAV9-mediated overexpression in vivo, siRNA knockdown in OGD/R-treated primary cardiomyocytes, ceramide quantification, apoptosis assays, Western blot","journal":"Journal of cardiovascular translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, limited methodological detail in abstract, no reconstitution or direct binding assay shown","pmids":["42234286"],"is_preprint":false},{"year":2024,"finding":"The PSAP complex (comprising Pinin/PNN, RNPS1, and SAP18) controls periodic pre-mRNA splicing across the cell cycle, distinct from the ASAP complex (Acinus, RNPS1, SAP18). RNPS1 protein levels oscillate in a cell cycle-dependent manner via the ubiquitin-proteasome pathway, and RNPS1 and PNN are both required for precise splicing of AURKB intron 5. Whole-transcriptome sequencing of RNPS1- and PNN-deficient cells confirmed RNPS1/PSAP complex as essential for a subset of introns.","method":"siRNA-mediated knockdown of RNPS1 and PNN, whole-transcriptome sequencing, proteasome inhibitor experiments, cell cycle analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with transcriptome-wide readout and pharmacological validation, single lab, multiple orthogonal methods","pmids":["39687031"],"is_preprint":false},{"year":2024,"finding":"A missense mutation in PSAP (c.643A>G, p.N215D) does not affect PSAP protein lysosomal localization but is associated with decreased lysosomal pH and reduced cathepsin D activity, as well as abnormal lysosome morphology and protein aggregation.","method":"Immunofluorescence assay of cultured cells, lysosomal pH measurement, cathepsin D activity assay, transmission electron microscopy","journal":"The Journal of international medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case report, single lab, limited controls","pmids":["39612318"],"is_preprint":false},{"year":2009,"finding":"Prosaposin (PSAP gene product) is the precursor for four sphingolipid activator proteins (saposins A-D). PSAP null mutations cause accumulation of multiple sphingolipids (most prominently globotriaosylceramide), whereas mutations affecting only the saposin B domain cause sulfatide accumulation resembling metachromatic leukodystrophy. This establishes the role of specific saposin domains in activating distinct lysosomal hydrolases.","method":"Urinary sphingolipid analysis by electrospray ionization tandem mass spectrometry, RT-PCR for splice mutation characterization, PSAP gene mutation analysis","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical substrate accumulation analysis combined with molecular characterization of splice mutations, replicated across multiple patients in literature","pmids":["19267410"],"is_preprint":false},{"year":2024,"finding":"In PSAP-deficient fibroblasts (lacking all four saposins), GCase undergoes lysosomal degradation (in contrast to LIMP-2-deficient fibroblasts where GCase undergoes proteasomal degradation). PSAP-mutant fibroblasts showed reduced GCase activity, and glucosylsphingosine was elevated in plasma of PSAP-mutant patients.","method":"Fibroblast cell culture, GCase activity assays, proteasome/lysosome inhibitor experiments, plasma biomarker measurements (glucosylsphingosine, chitotriosidase)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of degradation pathway in patient-derived cells with multiple biochemical readouts","pmids":["38928321"],"is_preprint":false}],"current_model":"PSAP encodes prosaposin, a precursor protein cleaved into four saposin activators (A–D) that facilitate lysosomal sphingolipid degradation; as MTCH1, it is also an integral mitochondrial outer membrane protein that promotes apoptosis by forming complexes with Bax, driving cytochrome c and Smac release through an Apaf-1/apoptosome-dependent but Bcl-2-family-independent pathway; additionally, secreted prosaposin acts as a ligand for GPR37/GPR37L1 receptors in glia and binds the SARS-CoV-2 spike RBD to inhibit viral entry, while in the nucleus PSAP complex (Pinin–RNPS1–SAP18) controls cell-cycle-periodic pre-mRNA splicing."},"narrative":{"mechanistic_narrative":"PSAP encodes prosaposin, the lysosomal precursor of four saposin activator proteins (A–D) that activate distinct lysosomal hydrolases for sphingolipid degradation; null mutations cause broad sphingolipid accumulation while domain-specific mutations cause selective accumulation, establishing each saposin's role in activating a particular hydrolase [PMID:19267410]. In the lysosome, prosaposin (via its saposins) supports glucocerebrosidase (GCase): loss of all four saposins routes GCase to lysosomal degradation and reduces its activity, with elevated glucosylsphingosine in patient plasma [PMID:38928321], and prosaposin can restrain ceramide accumulation by rescuing expression of the ceramidase ASAH1 [PMID:42234286]. Secreted prosaposin also acts in cell signaling as a ligand for GPR37/GPR37L1 receptors, activating ERK/SMAD2/3 signaling to modulate astrocytic synaptic engulfment and macrophage M2 polarization [PMID:39523310, PMID:41085015], and binds the SARS-CoV-2 spike receptor-binding domain to promote S1 shedding and block viral entry [PMID:41885456]. Independently, the literature describes PSAP/MTCH1 as an integral mitochondrial outer-membrane protein that promotes apoptosis: it forms a mitochondrial complex with Bax, drives Bax-dependent cytochrome c and Smac release, and triggers caspase activation through an Apaf-1/apoptosome- and Smac-dependent but Bcl-2-family-independent pathway [PMID:23207240, PMID:26025363], acting downstream of presenilin 1 and the death receptor DR6 [PMID:26025363, PMID:32144986]. A distinct nuclear PSAP complex composed of Pinin/PNN, RNPS1, and SAP18 controls cell-cycle-periodic pre-mRNA splicing of a subset of introns [PMID:39687031].","teleology":[{"year":2007,"claim":"Established that the MTCH1/PSAP gene product is an integral mitochondrial outer-membrane protein whose insertion and proapoptotic activity depend on defined structural elements, framing it as a membrane-anchored apoptotic effector.","evidence":"RT-PCR, fractionation, deletion mutagenesis and transmembrane-domain replacement in cultured cells","pmids":["17670888"],"confidence":"Medium","gaps":["No partner protein identified at this stage","Mechanism linking N-terminal regions to apoptosis unresolved"]},{"year":2008,"claim":"Showed all four splice isoforms localize to mitochondria and are proapoptotic, requiring both PDZ domain and N-terminal fragment, refining the structure–function map.","evidence":"Gene cloning, region-specific antibodies, immunofluorescence and deletion constructs","pmids":["18291114"],"confidence":"Medium","gaps":["Molecular target of the PDZ domain not defined","No downstream effector identified"]},{"year":2009,"claim":"Defined prosaposin as the precursor of four saposins and linked specific saposin domains to activation of distinct lysosomal hydrolases, explaining genotype-specific sphingolipid accumulation.","evidence":"Urinary sphingolipid mass spectrometry and PSAP mutation analysis across patients","pmids":["19267410"],"confidence":"Medium","gaps":["Direct enzymatic activation mechanism for each saposin not reconstituted","No structural basis for hydrolase selectivity"]},{"year":2012,"claim":"Resolved the apoptotic pathway downstream of PSAP/MTCH1 as Apaf-1/apoptosome- and Smac-dependent yet Bcl-2-family-independent, distinguishing it from canonical intrinsic apoptosis.","evidence":"Inducible expression, siRNA knockdown, caspase/PARP and cytochrome c/Smac release assays","pmids":["23207240"],"confidence":"Medium","gaps":["How PSAP triggers release without Bax/Bak requirement unexplained at this stage","No reconstitution of the release event"]},{"year":2015,"claim":"Identified PSAP/MTCH1 as the mitochondrial effector of presenilin 1-induced, γ-secretase-independent apoptosis through formation of a mitochondrial PSAP-Bax complex.","evidence":"Co-IP, fractionation, γ-secretase inhibitor treatment and knockdown apoptosis assays","pmids":["26025363"],"confidence":"Medium","gaps":["Direct PSAP-Bax binding interface not mapped","Reconciliation with earlier Bax-independent release claim unresolved"]},{"year":2015,"claim":"Placed MTCH1 under transcriptional control of EGR-1 and linked its induction to DNA damage, connecting apoptotic effector levels to stress signaling.","evidence":"ChIP, EGR-1 overexpression/knockdown and doxorubicin treatment with Western blot","pmids":["26692143"],"confidence":"Medium","gaps":["Other transcriptional inputs not surveyed","Causal link from DNA damage to apoptosis via MTCH1 not demonstrated end-to-end"]},{"year":2020,"claim":"Connected death receptor DR6 to mitochondrial apoptosis through PSAP, showing cytosolic DR6-bound Bax is handed off to mitochondrial PSAP to drive cytochrome c release.","evidence":"Yeast two-hybrid, Co-IP, fractionation and knockdown cytochrome c release assays","pmids":["32144986"],"confidence":"Medium","gaps":["Biophysical detail of Bax transfer not resolved","Single-lab interaction without reciprocal independent validation"]},{"year":2024,"claim":"Defined a nuclear PSAP complex (PNN-RNPS1-SAP18) controlling cell-cycle-periodic pre-mRNA splicing, distinct from the ASAP complex.","evidence":"siRNA knockdown of RNPS1/PNN, whole-transcriptome sequencing, proteasome inhibition and cell-cycle analysis","pmids":["39687031"],"confidence":"Medium","gaps":["Relationship of this nuclear complex to prosaposin polypeptide unclear in corpus","Full set of regulated introns not delineated"]},{"year":2024,"claim":"Identified secreted prosaposin as a GPR37L1 ligand that limits astrocytic synaptic engulfment via ERK/SMAD2/3, implicating PSAP in neuroprotection.","evidence":"snRNA-seq, cell culture and in vivo PD mouse models with pharmacological GPR37L1 activation","pmids":["39523310"],"confidence":"Low","gaps":["Direct PSAP-GPR37L1 binding mechanism limited in available detail","Endogenous ligand contribution versus peptide agonist not separated"]},{"year":2024,"claim":"Showed prosaposin binds the SARS-CoV-2 spike RBD at a non-RBM region and promotes S1 shedding to block entry, revealing an antiviral role for secreted PSAP.","evidence":"Host cDNA overexpression screen, pseudovirus and authentic virus assays, binding affinity and docking","pmids":["41885456"],"confidence":"Medium","gaps":["Structural basis of S1 release not determined","In vivo relevance not established"]},{"year":2024,"claim":"Demonstrated that lysosomal GCase fate depends on saposins: in PSAP-deficient cells GCase undergoes lysosomal degradation with reduced activity, distinguishing the role of prosaposin from LIMP-2.","evidence":"Patient-derived fibroblasts, GCase activity assays, degradation-pathway inhibitors and plasma biomarkers","pmids":["38928321"],"confidence":"Medium","gaps":["Which saposin stabilizes GCase not pinpointed","Mechanism of lysosomal routing not detailed"]},{"year":2024,"claim":"Characterized a PSAP missense variant (p.N215D) that preserves lysosomal localization but disrupts lysosomal pH and cathepsin D activity, linking PSAP to lysosomal homeostasis.","evidence":"Immunofluorescence, lysosomal pH and cathepsin D assays, electron microscopy in a single case","pmids":["39612318"],"confidence":"Low","gaps":["Single case report with limited controls","Causal mechanism linking variant to pH defect unresolved"]},{"year":2025,"claim":"Linked PSAP protein stability to post-translational control, with OGT-mediated O-GlcNAcylation blocking CBL-dependent ubiquitination, and engaged GPR37 on macrophages to drive M2 polarization and TGFβ secretion.","evidence":"Biochemical studies, in vivo gene-editing hydrogel and signaling pathway analysis","pmids":["41085015"],"confidence":"Low","gaps":["Mechanistic detail limited in available account","Direct CBL-PSAP and OGT-PSAP interactions not independently validated"]},{"year":2026,"claim":"Showed prosaposin overexpression rescues ASAH1 expression to reduce ceramide and apoptosis in cardiac ischemia-reperfusion, extending its sphingolipid role to cardioprotection.","evidence":"AAV9 overexpression in vivo, siRNA in OGD/R cardiomyocytes, ceramide quantification and apoptosis assays","pmids":["42234286"],"confidence":"Low","gaps":["No direct binding or reconstitution shown","Mechanism by which PSAP regulates ASAH1 expression unknown"]},{"year":null,"claim":"How a single gene product reconciles its mitochondrial proapoptotic activity, lysosomal saposin function, secreted receptor-ligand signaling, and nuclear splicing roles into one coherent biology remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or trafficking model across compartments","Isoform-specific contributions to each role not delineated","Relationship between MTCH1 mitochondrial activity and prosaposin lysosomal function unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,13]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[11,12,13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[6,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,13,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7]}],"complexes":["PSAP complex (PNN-RNPS1-SAP18)","mitochondrial PSAP-Bax complex"],"partners":["BAX","DR6","PSEN1","GPR37L1","GPR37","PNN","RNPS1","SAP18"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZJ7","full_name":"Mitochondrial carrier homolog 1","aliases":["Presenilin-associated protein"],"length_aa":389,"mass_kda":41.5,"function":"Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane (PubMed:36264797). Catalyzes insertion of proteins with alpha-helical transmembrane regions, such as signal-anchored, tail-anchored and multi-pass membrane proteins (By similarity). Does not mediate insertion of beta-barrel transmembrane proteins (By similarity). May play a role in apoptosis (PubMed:12377771)","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZJ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSAP","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PSAP","total_profiled":1310},"omim":[{"mim_id":"619788","title":"ARRESTIN DOMAIN-CONTAINING PROTEIN 4; ARRDC4","url":"https://www.omim.org/entry/619788"},{"mim_id":"619768","title":"ARRESTIN DOMAIN-CONTAINING PROTEIN 1; ARRDC1","url":"https://www.omim.org/entry/619768"},{"mim_id":"619491","title":"PARKINSON DISEASE 24, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO; PARK24","url":"https://www.omim.org/entry/619491"},{"mim_id":"619029","title":"KERATINOCYTE-ASSOCIATED PROTEIN 2; KRTCAP2","url":"https://www.omim.org/entry/619029"},{"mim_id":"618932","title":"OLIGOSACCHARYLTRANSFERASE COMPLEX, SUBUNIT 4, NONCATALYTIC; OST4","url":"https://www.omim.org/entry/618932"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSAP"},"hgnc":{"alias_symbol":[],"prev_symbol":["SAP1","GLBA","SAP2"]},"alphafold":{"accession":"Q9NZJ7","domains":[{"cath_id":"1.50.40.10","chopping":"79-282_302-378","consensus_level":"high","plddt":88.1931,"start":79,"end":378}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZJ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZJ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZJ7-F1-predicted_aligned_error_v6.png","plddt_mean":74.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSAP","jax_strain_url":"https://www.jax.org/strain/search?query=PSAP"},"sequence":{"accession":"Q9NZJ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZJ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZJ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZJ7"}},"corpus_meta":[{"pmid":"21068219","id":"PMC_21068219","title":"A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells.","date":"2010","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/21068219","citation_count":139,"is_preprint":false},{"pmid":"12915562","id":"PMC_12915562","title":"The Mason-Pfizer monkey virus PPPY and PSAP motifs both contribute to virus release.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12915562","citation_count":106,"is_preprint":false},{"pmid":"26462614","id":"PMC_26462614","title":"Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.","date":"2015","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/26462614","citation_count":93,"is_preprint":false},{"pmid":"22388736","id":"PMC_22388736","title":"The structure of the ASAP core complex reveals the existence of a Pinin-containing PSAP complex.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22388736","citation_count":80,"is_preprint":false},{"pmid":"19267410","id":"PMC_19267410","title":"Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations.","date":"2009","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/19267410","citation_count":64,"is_preprint":false},{"pmid":"22438540","id":"PMC_22438540","title":"The PSAP motif within the ORF3 protein of an avian strain of the hepatitis E virus is not critical for viral infectivity in vivo but plays a role in virus release.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22438540","citation_count":46,"is_preprint":false},{"pmid":"15220457","id":"PMC_15220457","title":"Functional analysis of late-budding domain activity associated with the PSAP motif within the vesicular stomatitis virus M protein.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15220457","citation_count":37,"is_preprint":false},{"pmid":"28555048","id":"PMC_28555048","title":"Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28555048","citation_count":35,"is_preprint":false},{"pmid":"17670888","id":"PMC_17670888","title":"Two isoforms of PSAP/MTCH1 share two proapoptotic domains and multiple internal signals for import into the mitochondrial outer membrane.","date":"2007","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17670888","citation_count":29,"is_preprint":false},{"pmid":"9225972","id":"PMC_9225972","title":"Genetic fine localization of the beta-glucocerebrosidase (GBA) and prosaposin (PSAP) genes: implications for Gaucher disease.","date":"1997","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9225972","citation_count":29,"is_preprint":false},{"pmid":"18299979","id":"PMC_18299979","title":"TSC22D1 and PSAP predict clinical outcome of tamoxifen treatment in patients with recurrent breast cancer.","date":"2008","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/18299979","citation_count":25,"is_preprint":false},{"pmid":"19301031","id":"PMC_19301031","title":"Expression of prostatic acid phosphatase (PSAP) in transurethral resection specimens of the prostate is predictive of histopathologic tumor stage in subsequent radical prostatectomies.","date":"2009","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19301031","citation_count":21,"is_preprint":false},{"pmid":"17698667","id":"PMC_17698667","title":"Modifications of the PSAP region of the matrix protein lead to attenuation of vesicular stomatitis virus in vitro and in vivo.","date":"2007","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/17698667","citation_count":19,"is_preprint":false},{"pmid":"15220358","id":"PMC_15220358","title":"Technical variations in prostatic immunohistochemistry: need for standardisation and stringent quality assurance in PSA and PSAP immunostaining.","date":"2004","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15220358","citation_count":19,"is_preprint":false},{"pmid":"22190013","id":"PMC_22190013","title":"Phenotypes of vesicular stomatitis virus mutants with mutations in the PSAP motif of the matrix protein.","date":"2011","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/22190013","citation_count":19,"is_preprint":false},{"pmid":"23207240","id":"PMC_23207240","title":"PSAP induces a unique Apaf-1 and Smac-dependent mitochondrial apoptotic pathway independent of Bcl-2 family proteins.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23207240","citation_count":17,"is_preprint":false},{"pmid":"26025363","id":"PMC_26025363","title":"Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26025363","citation_count":17,"is_preprint":false},{"pmid":"30632081","id":"PMC_30632081","title":"Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene.","date":"2019","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/30632081","citation_count":15,"is_preprint":false},{"pmid":"24478108","id":"PMC_24478108","title":"A novel homozygous splicing mutation in PSAP gene causes metachromatic leukodystrophy in two Moroccan brothers.","date":"2014","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24478108","citation_count":12,"is_preprint":false},{"pmid":"39523310","id":"PMC_39523310","title":"Genetically modified E. Coli secreting melanin (E.melanin) activates the astrocytic PSAP-GPR37L1 pathway and mitigates the pathogenesis of Parkinson's disease.","date":"2024","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39523310","citation_count":9,"is_preprint":false},{"pmid":"26692143","id":"PMC_26692143","title":"Early growth response 1 (EGR-1) is a transcriptional regulator of mitochondrial carrier homolog 1 (MTCH 1)/presenilin 1-associated protein (PSAP).","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26692143","citation_count":9,"is_preprint":false},{"pmid":"32144986","id":"PMC_32144986","title":"Proapoptotic Mitochondrial Carrier Homolog Protein PSAP Mediates Death Receptor 6 Induced Apoptosis.","date":"2020","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/32144986","citation_count":8,"is_preprint":false},{"pmid":"35456468","id":"PMC_35456468","title":"Phenotype Expansion for Atypical Gaucher Disease Due to Homozygous Missense PSAP Variant in a Large Consanguineous Pakistani Family.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35456468","citation_count":8,"is_preprint":false},{"pmid":"6195266","id":"PMC_6195266","title":"Fate and mechanism of clearance of PSAP, a schistosome antigen, in schistosomiasis.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6195266","citation_count":8,"is_preprint":false},{"pmid":"36084426","id":"PMC_36084426","title":"Pan-cancer analysis of PSAP identifies its expression and clinical relevance in gastric cancer.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/36084426","citation_count":7,"is_preprint":false},{"pmid":"18291114","id":"PMC_18291114","title":"Both the N-terminal fragment and the protein-protein interaction domain (PDZ domain) are required for the pro-apoptotic activity of presenilin-associated protein PSAP.","date":"2008","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/18291114","citation_count":7,"is_preprint":false},{"pmid":"7526771","id":"PMC_7526771","title":"Correlation between immunohistochemical patterns and serum levels of PSA and PSAP in prostatic pathology: evaluation of 198 prostatic fine needle biopsies.","date":"1994","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7526771","citation_count":6,"is_preprint":false},{"pmid":"23170175","id":"PMC_23170175","title":"Cytopathogenesis of vesicular stomatitis virus is regulated by the PSAP motif of M protein in a species-dependent manner.","date":"2012","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/23170175","citation_count":6,"is_preprint":false},{"pmid":"35316504","id":"PMC_35316504","title":"A Type 3 Gaucher-Like Disease Due To Saposin C Deficiency in Two Emirati Families Caused by a Novel Splice Site Variant in the PSAP Gene.","date":"2022","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/35316504","citation_count":6,"is_preprint":false},{"pmid":"32367774","id":"PMC_32367774","title":"Exploring of InDel in bovine PSAP gene and their association with growth traits in different development stages.","date":"2020","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32367774","citation_count":5,"is_preprint":false},{"pmid":"38928321","id":"PMC_38928321","title":"Deficiency of Glucocerebrosidase Activity beyond Gaucher Disease: PSAP and LIMP-2 Dysfunctions.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38928321","citation_count":5,"is_preprint":false},{"pmid":"37404680","id":"PMC_37404680","title":"Late infantile and adult-onset metachromatic leukodystrophy due to novel missense variants in the PSAP gene: Case report from India.","date":"2023","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/37404680","citation_count":4,"is_preprint":false},{"pmid":"33383762","id":"PMC_33383762","title":"Functional Analysis of Haplotypes in Bovine PSAP Gene and Their Relationship with Beef Cattle Production Traits.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/33383762","citation_count":4,"is_preprint":false},{"pmid":"24043213","id":"PMC_24043213","title":"[PSAP expression in a primary presacral neuroendocrine tumor. Potential for confusion with prostate cancer].","date":"2014","source":"Der Pathologe","url":"https://pubmed.ncbi.nlm.nih.gov/24043213","citation_count":4,"is_preprint":false},{"pmid":"39687031","id":"PMC_39687031","title":"RNPS1 in PSAP complex controls periodic pre-mRNA splicing over the cell cycle.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39687031","citation_count":3,"is_preprint":false},{"pmid":"41085015","id":"PMC_41085015","title":"ACE-mediated Glycosylation Stabilizes PSAP To Promote GPR37-dependent Macrophage-Nucleus Pulposus Cells Crosstalk and TGFβ Signaling in Alleviating Intervertebral Disc Degeneration.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41085015","citation_count":3,"is_preprint":false},{"pmid":"39612318","id":"PMC_39612318","title":"A novel homozygous PSAP mutation identified by whole exome sequencing in a consanguineous family with metachromatic leukodystrophy: a case report.","date":"2024","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/39612318","citation_count":3,"is_preprint":false},{"pmid":"8641138","id":"PMC_8641138","title":"Assignment of the human prosaposin gene (PSAP) to 10q22.1 by fluorescence in situ hybridization. Giraffidae, okapi (Okapiajohnstoni), and giraffe (Giraffa camelopardalis): evidence for ancestral telomeres at the okapi polymorphic rob (4;26) fusion site.","date":"1996","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8641138","citation_count":3,"is_preprint":false},{"pmid":"38788933","id":"PMC_38788933","title":"Cold-chain free nucleic acid preservation using porous super-absorbent polymer (PSAP) beads to facilitate wastewater surveillance.","date":"2024","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/38788933","citation_count":2,"is_preprint":false},{"pmid":"41579784","id":"PMC_41579784","title":"Lysosomal trafficking markers covering PSAP, PGRN, SORT1 and LRP1 in body liquids and cerebral tissue as auxiliary indicative tool of traumatic brain injury.","date":"2026","source":"Forensic science international","url":"https://pubmed.ncbi.nlm.nih.gov/41579784","citation_count":0,"is_preprint":false},{"pmid":"40494321","id":"PMC_40494321","title":"Easy-PSAP: An Integrated Workflow to Prioritize Pathogenic Variants in Sequence Data from a Single Individual.","date":"2025","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/40494321","citation_count":0,"is_preprint":false},{"pmid":"42221844","id":"PMC_42221844","title":"Integrated Transcriptomics and Experimental Validation Reveal Müller Cell-Driven PANoptosis in Diabetic Retinopathy via PSAP-GPR37 Signaling.","date":"2026","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42221844","citation_count":0,"is_preprint":false},{"pmid":"42234286","id":"PMC_42234286","title":"PSAP Protects Against Acute Myocardial Ischemia-Reperfusion Injury by Promoting ASAH1-Mediated Ceramide Metabolism.","date":"2026","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/42234286","citation_count":0,"is_preprint":false},{"pmid":"41885456","id":"PMC_41885456","title":"Secretory full-length human prosaposin (PSAP) inhibits SARS-CoV-2 infection through facilitating the release of S1 subunit of spike protein.","date":"2026","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/41885456","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.16.608309","title":"Direction and modality of transcription changes caused by TAD boundary disruption in  <i>Slc29a3/Unc5b</i>  locus depends on tissue-specific epigenetic context","date":"2024-08-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.16.608309","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.01.601392","title":"Single-cell transcriptomic changes in oligodendroglial lineage cells derived from Parkinson’s disease patient-iPSCs with LRRK2-G2019S mutation","date":"2024-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.01.601392","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23847,"output_tokens":3814,"usd":0.064376,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11566,"output_tokens":4497,"usd":0.085127,"stage2_stop_reason":"end_turn"},"total_usd":0.149503,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"PSAP (also known as MTCH1/Presenilin 1-associated protein) is an integral mitochondrial outer membrane protein. Two isoforms are generated by alternative splicing differing in a hydrophilic loop between transmembrane domains. A transmembrane domain in the correct position and orientation is necessary for mitochondrial membrane insertion. Two independent N-terminal regions are responsible for proapoptotic activity.\",\n      \"method\": \"RT-PCR, Western blot, deletion mutagenesis, fractionation, transmembrane domain replacement experiments\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation plus mutagenesis in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17670888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PSAP is expressed in four isoforms due to differential splicing of exon 8 and use of alternative start codons. All isoforms localize to mitochondria and are proapoptotic. Both the PDZ domain and the N-terminal fragment are required for proapoptotic activity.\",\n      \"method\": \"Gene cloning, antibody generation against different PSAP regions, Western blot, immunofluorescence localization, deletion constructs\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Western blot, immunofluorescence, deletion mutagenesis) in single lab\",\n      \"pmids\": [\"18291114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PSAP (MTCH1) induces apoptosis through a unique mitochondrial pathway requiring Apaf-1/apoptosome formation and Smac, but independent of Bcl-2 family proteins. Knockdown of Apaf-1 or Smac abolished PSAP-induced caspase activation and PARP cleavage, whereas overexpression of Bcl-2/Bcl-xL or knockdown of Bid, Bax, or Bak had no effect on PSAP-induced cytochrome c and Smac release.\",\n      \"method\": \"Inducible expression system, siRNA knockdown, caspase activation assay, PARP cleavage assay, cytochrome c and Smac release assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, release assays, apoptosis readouts) in single lab\",\n      \"pmids\": [\"23207240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSAP (MTCH1) mediates presenilin 1 (PS1)-induced γ-secretase-independent apoptosis by forming a complex with Bax at the mitochondria, promoting Bax translocation and cytochrome c release. The PSAP-Bax complex localizes to the mitochondrial fraction, while a DR6-Bax complex localizes to the cytosolic fraction. Complete inhibition of PS1-induced apoptosis required both γ-secretase inhibitor and PSAP knockdown.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, subcellular fractionation, γ-secretase inhibitor treatment, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, fractionation, and functional knockdown in single lab with multiple readouts\",\n      \"pmids\": [\"26025363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSAP (MTCH1) interacts with death receptor DR6 (identified by yeast two-hybrid) and mediates DR6-induced apoptosis. PSAP knockdown blocked DR6-induced Bax translocation to mitochondria and cytochrome c release. DR6-bound Bax in the cytosol is transferred to PSAP at the mitochondria, forming a mitochondrial PSAP-Bax complex that drives cytochrome c release. Knockdown of DR6 reduced the mitochondrial PSAP-Bax complex.\",\n      \"method\": \"Yeast two-hybrid, siRNA knockdown, co-immunoprecipitation, subcellular fractionation, cytochrome c release assay, apoptosis assays\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus fractionation plus functional knockdown, single lab\",\n      \"pmids\": [\"32144986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Early growth response 1 (EGR-1) is a transcriptional regulator of PSAP (MTCH1). EGR-1 binding sites are present in the MTCH1 proximal promoter; chromatin immunoprecipitation confirmed enrichment of these sequences in EGR-1-bound DNA. Overexpression of EGR-1 increased endogenous MTCH1 levels, and siRNA-mediated knockdown of EGR-1 decreased MTCH1 levels. MTCH1 levels also increase in response to doxorubicin-induced DNA damage.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), RT-PCR, Western blot, EGR-1 overexpression and siRNA knockdown\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional overexpression/knockdown, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26692143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSAP (prosaposin) activates the GPR37L1 receptor in astrocytes to reduce astrocytic synaptic engulfment via ERK/SMAD2/3 signaling, providing neuroprotection in Parkinson's disease models. Activation of GPR37L1 with Tx14(A) peptide rescued motor defects and protected dopamine neurons in PD mice.\",\n      \"method\": \"Single nuclear RNA sequencing, cell culture, biochemical studies, in vivo mouse models, pharmacological GPR37L1 activation\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — snRNA-seq identifies pathway plus in vivo pharmacological validation, but mechanistic detail on PSAP-GPR37L1 binding is limited in the abstract\",\n      \"pmids\": [\"39523310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACE deficiency promotes OGT-mediated O-GlcNAc glycosylation of PSAP at serine residues, which suppresses CBL E3 ubiquitin ligase-dependent ubiquitination and proteasomal degradation of PSAP. Stabilized PSAP engages GPR37 on macrophages to promote M2 polarization via ERK/SMAD2/3 signaling, and stimulates TGFβ secretion. Secreted TGFβ reinforces PSAP-Sortilin-mediated trafficking in nucleus pulposus cells via PI3K/AKT pathway.\",\n      \"method\": \"Biochemical studies, in vivo gene-editing virus-loaded hydrogel intervention, cell culture, signaling pathway analysis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic claims from single study with limited methodological detail in abstract\",\n      \"pmids\": [\"41085015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSAP (prosaposin) binds with high affinity to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein at the non-receptor-binding motif (non-RBM) region, and secreted PSAP facilitates release of the S1 subunit from the spike protein, thereby blocking viral entry. This was identified by host cDNA overexpression screen and confirmed with pseudovirus and authentic virus infection assays and molecular docking.\",\n      \"method\": \"Host cDNA overexpression screen, pseudovirus and authentic virus infection assays, binding affinity measurements, molecular docking analysis\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen plus binding assays plus authentic virus validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41885456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PSAP overexpression in cardiomyocytes reduces ceramide accumulation during ischemia-reperfusion injury by rescuing expression of the lysosomal enzyme ASAH1 (N-acylsphingosine amidohydrolase 1), thereby accelerating ceramide degradation and attenuating apoptosis. AAV9-mediated PSAP overexpression in vivo reduced infarct size.\",\n      \"method\": \"AAV9-mediated overexpression in vivo, siRNA knockdown in OGD/R-treated primary cardiomyocytes, ceramide quantification, apoptosis assays, Western blot\",\n      \"journal\": \"Journal of cardiovascular translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, limited methodological detail in abstract, no reconstitution or direct binding assay shown\",\n      \"pmids\": [\"42234286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The PSAP complex (comprising Pinin/PNN, RNPS1, and SAP18) controls periodic pre-mRNA splicing across the cell cycle, distinct from the ASAP complex (Acinus, RNPS1, SAP18). RNPS1 protein levels oscillate in a cell cycle-dependent manner via the ubiquitin-proteasome pathway, and RNPS1 and PNN are both required for precise splicing of AURKB intron 5. Whole-transcriptome sequencing of RNPS1- and PNN-deficient cells confirmed RNPS1/PSAP complex as essential for a subset of introns.\",\n      \"method\": \"siRNA-mediated knockdown of RNPS1 and PNN, whole-transcriptome sequencing, proteasome inhibitor experiments, cell cycle analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with transcriptome-wide readout and pharmacological validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39687031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A missense mutation in PSAP (c.643A>G, p.N215D) does not affect PSAP protein lysosomal localization but is associated with decreased lysosomal pH and reduced cathepsin D activity, as well as abnormal lysosome morphology and protein aggregation.\",\n      \"method\": \"Immunofluorescence assay of cultured cells, lysosomal pH measurement, cathepsin D activity assay, transmission electron microscopy\",\n      \"journal\": \"The Journal of international medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case report, single lab, limited controls\",\n      \"pmids\": [\"39612318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Prosaposin (PSAP gene product) is the precursor for four sphingolipid activator proteins (saposins A-D). PSAP null mutations cause accumulation of multiple sphingolipids (most prominently globotriaosylceramide), whereas mutations affecting only the saposin B domain cause sulfatide accumulation resembling metachromatic leukodystrophy. This establishes the role of specific saposin domains in activating distinct lysosomal hydrolases.\",\n      \"method\": \"Urinary sphingolipid analysis by electrospray ionization tandem mass spectrometry, RT-PCR for splice mutation characterization, PSAP gene mutation analysis\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical substrate accumulation analysis combined with molecular characterization of splice mutations, replicated across multiple patients in literature\",\n      \"pmids\": [\"19267410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In PSAP-deficient fibroblasts (lacking all four saposins), GCase undergoes lysosomal degradation (in contrast to LIMP-2-deficient fibroblasts where GCase undergoes proteasomal degradation). PSAP-mutant fibroblasts showed reduced GCase activity, and glucosylsphingosine was elevated in plasma of PSAP-mutant patients.\",\n      \"method\": \"Fibroblast cell culture, GCase activity assays, proteasome/lysosome inhibitor experiments, plasma biomarker measurements (glucosylsphingosine, chitotriosidase)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of degradation pathway in patient-derived cells with multiple biochemical readouts\",\n      \"pmids\": [\"38928321\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSAP encodes prosaposin, a precursor protein cleaved into four saposin activators (A–D) that facilitate lysosomal sphingolipid degradation; as MTCH1, it is also an integral mitochondrial outer membrane protein that promotes apoptosis by forming complexes with Bax, driving cytochrome c and Smac release through an Apaf-1/apoptosome-dependent but Bcl-2-family-independent pathway; additionally, secreted prosaposin acts as a ligand for GPR37/GPR37L1 receptors in glia and binds the SARS-CoV-2 spike RBD to inhibit viral entry, while in the nucleus PSAP complex (Pinin–RNPS1–SAP18) controls cell-cycle-periodic pre-mRNA splicing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSAP encodes prosaposin, the lysosomal precursor of four saposin activator proteins (A–D) that activate distinct lysosomal hydrolases for sphingolipid degradation; null mutations cause broad sphingolipid accumulation while domain-specific mutations cause selective accumulation, establishing each saposin's role in activating a particular hydrolase [#12]. In the lysosome, prosaposin (via its saposins) supports glucocerebrosidase (GCase): loss of all four saposins routes GCase to lysosomal degradation and reduces its activity, with elevated glucosylsphingosine in patient plasma [#13], and prosaposin can restrain ceramide accumulation by rescuing expression of the ceramidase ASAH1 [#9]. Secreted prosaposin also acts in cell signaling as a ligand for GPR37/GPR37L1 receptors, activating ERK/SMAD2/3 signaling to modulate astrocytic synaptic engulfment and macrophage M2 polarization [#6, #7], and binds the SARS-CoV-2 spike receptor-binding domain to promote S1 shedding and block viral entry [#8]. Independently, the literature describes PSAP/MTCH1 as an integral mitochondrial outer-membrane protein that promotes apoptosis: it forms a mitochondrial complex with Bax, drives Bax-dependent cytochrome c and Smac release, and triggers caspase activation through an Apaf-1/apoptosome- and Smac-dependent but Bcl-2-family-independent pathway [#2, #3], acting downstream of presenilin 1 and the death receptor DR6 [#3, #4]. A distinct nuclear PSAP complex composed of Pinin/PNN, RNPS1, and SAP18 controls cell-cycle-periodic pre-mRNA splicing of a subset of introns [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that the MTCH1/PSAP gene product is an integral mitochondrial outer-membrane protein whose insertion and proapoptotic activity depend on defined structural elements, framing it as a membrane-anchored apoptotic effector.\",\n      \"evidence\": \"RT-PCR, fractionation, deletion mutagenesis and transmembrane-domain replacement in cultured cells\",\n      \"pmids\": [\"17670888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No partner protein identified at this stage\", \"Mechanism linking N-terminal regions to apoptosis unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed all four splice isoforms localize to mitochondria and are proapoptotic, requiring both PDZ domain and N-terminal fragment, refining the structure–function map.\",\n      \"evidence\": \"Gene cloning, region-specific antibodies, immunofluorescence and deletion constructs\",\n      \"pmids\": [\"18291114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of the PDZ domain not defined\", \"No downstream effector identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined prosaposin as the precursor of four saposins and linked specific saposin domains to activation of distinct lysosomal hydrolases, explaining genotype-specific sphingolipid accumulation.\",\n      \"evidence\": \"Urinary sphingolipid mass spectrometry and PSAP mutation analysis across patients\",\n      \"pmids\": [\"19267410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic activation mechanism for each saposin not reconstituted\", \"No structural basis for hydrolase selectivity\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the apoptotic pathway downstream of PSAP/MTCH1 as Apaf-1/apoptosome- and Smac-dependent yet Bcl-2-family-independent, distinguishing it from canonical intrinsic apoptosis.\",\n      \"evidence\": \"Inducible expression, siRNA knockdown, caspase/PARP and cytochrome c/Smac release assays\",\n      \"pmids\": [\"23207240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PSAP triggers release without Bax/Bak requirement unexplained at this stage\", \"No reconstitution of the release event\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PSAP/MTCH1 as the mitochondrial effector of presenilin 1-induced, γ-secretase-independent apoptosis through formation of a mitochondrial PSAP-Bax complex.\",\n      \"evidence\": \"Co-IP, fractionation, γ-secretase inhibitor treatment and knockdown apoptosis assays\",\n      \"pmids\": [\"26025363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PSAP-Bax binding interface not mapped\", \"Reconciliation with earlier Bax-independent release claim unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed MTCH1 under transcriptional control of EGR-1 and linked its induction to DNA damage, connecting apoptotic effector levels to stress signaling.\",\n      \"evidence\": \"ChIP, EGR-1 overexpression/knockdown and doxorubicin treatment with Western blot\",\n      \"pmids\": [\"26692143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other transcriptional inputs not surveyed\", \"Causal link from DNA damage to apoptosis via MTCH1 not demonstrated end-to-end\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected death receptor DR6 to mitochondrial apoptosis through PSAP, showing cytosolic DR6-bound Bax is handed off to mitochondrial PSAP to drive cytochrome c release.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, fractionation and knockdown cytochrome c release assays\",\n      \"pmids\": [\"32144986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biophysical detail of Bax transfer not resolved\", \"Single-lab interaction without reciprocal independent validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a nuclear PSAP complex (PNN-RNPS1-SAP18) controlling cell-cycle-periodic pre-mRNA splicing, distinct from the ASAP complex.\",\n      \"evidence\": \"siRNA knockdown of RNPS1/PNN, whole-transcriptome sequencing, proteasome inhibition and cell-cycle analysis\",\n      \"pmids\": [\"39687031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship of this nuclear complex to prosaposin polypeptide unclear in corpus\", \"Full set of regulated introns not delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified secreted prosaposin as a GPR37L1 ligand that limits astrocytic synaptic engulfment via ERK/SMAD2/3, implicating PSAP in neuroprotection.\",\n      \"evidence\": \"snRNA-seq, cell culture and in vivo PD mouse models with pharmacological GPR37L1 activation\",\n      \"pmids\": [\"39523310\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct PSAP-GPR37L1 binding mechanism limited in available detail\", \"Endogenous ligand contribution versus peptide agonist not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed prosaposin binds the SARS-CoV-2 spike RBD at a non-RBM region and promotes S1 shedding to block entry, revealing an antiviral role for secreted PSAP.\",\n      \"evidence\": \"Host cDNA overexpression screen, pseudovirus and authentic virus assays, binding affinity and docking\",\n      \"pmids\": [\"41885456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of S1 release not determined\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that lysosomal GCase fate depends on saposins: in PSAP-deficient cells GCase undergoes lysosomal degradation with reduced activity, distinguishing the role of prosaposin from LIMP-2.\",\n      \"evidence\": \"Patient-derived fibroblasts, GCase activity assays, degradation-pathway inhibitors and plasma biomarkers\",\n      \"pmids\": [\"38928321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which saposin stabilizes GCase not pinpointed\", \"Mechanism of lysosomal routing not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Characterized a PSAP missense variant (p.N215D) that preserves lysosomal localization but disrupts lysosomal pH and cathepsin D activity, linking PSAP to lysosomal homeostasis.\",\n      \"evidence\": \"Immunofluorescence, lysosomal pH and cathepsin D assays, electron microscopy in a single case\",\n      \"pmids\": [\"39612318\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single case report with limited controls\", \"Causal mechanism linking variant to pH defect unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked PSAP protein stability to post-translational control, with OGT-mediated O-GlcNAcylation blocking CBL-dependent ubiquitination, and engaged GPR37 on macrophages to drive M2 polarization and TGFβ secretion.\",\n      \"evidence\": \"Biochemical studies, in vivo gene-editing hydrogel and signaling pathway analysis\",\n      \"pmids\": [\"41085015\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic detail limited in available account\", \"Direct CBL-PSAP and OGT-PSAP interactions not independently validated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed prosaposin overexpression rescues ASAH1 expression to reduce ceramide and apoptosis in cardiac ischemia-reperfusion, extending its sphingolipid role to cardioprotection.\",\n      \"evidence\": \"AAV9 overexpression in vivo, siRNA in OGD/R cardiomyocytes, ceramide quantification and apoptosis assays\",\n      \"pmids\": [\"42234286\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding or reconstitution shown\", \"Mechanism by which PSAP regulates ASAH1 expression unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single gene product reconciles its mitochondrial proapoptotic activity, lysosomal saposin function, secreted receptor-ligand signaling, and nuclear splicing roles into one coherent biology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or trafficking model across compartments\", \"Isoform-specific contributions to each role not delineated\", \"Relationship between MTCH1 mitochondrial activity and prosaposin lysosomal function unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [11, 12, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 13, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\n      \"PSAP complex (PNN-RNPS1-SAP18)\",\n      \"mitochondrial PSAP-Bax complex\"\n    ],\n    \"partners\": [\n      \"BAX\",\n      \"DR6\",\n      \"PSEN1\",\n      \"GPR37L1\",\n      \"GPR37\",\n      \"PNN\",\n      \"RNPS1\",\n      \"SAP18\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}