{"gene":"SPG7","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1998,"finding":"Paraplegin (SPG7) was identified as a nuclear-encoded mitochondrial metalloprotease highly homologous to yeast mitochondrial ATPases (AFG3, RCA1, YME1). Immunofluorescence and import experiments demonstrated that paraplegin localizes to mitochondria. Mutations in SPG7 cause autosomal recessive hereditary spastic paraplegia, and muscle biopsies from patients showed signs of mitochondrial OXPHOS defects, linking SPG7 to mitochondrial function and neurodegeneration.","method":"Immunofluorescence, mitochondrial import assays, patient mutation analysis, muscle biopsy OXPHOS analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct localization experiments with functional consequence, replicated across patient samples; foundational paper with 642 citations","pmids":["9635427"],"is_preprint":false},{"year":2003,"finding":"Paraplegin (SPG7) co-assembles with its homolog AFG3L2 to form a high molecular mass complex in the mitochondrial inner membrane (the m-AAA protease complex). Loss of this complex causes reduced mitochondrial complex I (NADH dehydrogenase) activity and increased sensitivity to oxidative stress in HSP patient fibroblasts. Complementation studies in yeast demonstrated functional conservation of the human paraplegin-AFG3L2 complex with the yeast m-AAA protease and assigned proteolytic activity to this complex.","method":"Co-immunoprecipitation, Blue Native PAGE, enzymatic activity assays, yeast complementation, patient fibroblast studies, oxidative stress assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including co-IP, activity assays, and yeast complementation; replicated in patient cells and model organisms","pmids":["14623864"],"is_preprint":false},{"year":2010,"finding":"Mouse Spg7 (paraplegin) transcript is expressed throughout the brain, with particularly high levels in mitral cells, Purkinje cells, deep cerebellar nuclei cells, neocortical and hippocampal pyramidal neurons, and brainstem motor neurons. Spg7 is the second most abundant of the three m-AAA protease subunit transcripts (Afg3l2 > Spg7 > Afg3l1), and differences in expression levels among neuronal subtypes were observed, suggesting distinct contributions to the m-AAA protease complex in different cell types.","method":"Quantitative RT-PCR, in situ hybridization across mouse brain regions","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by in situ hybridization, single lab but two orthogonal methods; no functional consequence directly tested in this study","pmids":["20426821"],"is_preprint":false},{"year":2014,"finding":"SPG7 mutations were identified as a novel cause of progressive external ophthalmoplegia (PEO) associated with multiple mitochondrial DNA deletions. Functional studies demonstrated that SPG7 mutations cause increased mitochondrial biogenesis in patient muscle and promote mitochondrial fusion in patient fibroblasts, associated with clonal expansion of mitochondrial DNA mutations. This links SPG7/paraplegin to mitochondrial DNA maintenance mechanisms.","method":"Whole exome sequencing, Sanger sequencing, transcript analysis, proteomics, mitochondrial network analysis, single-fibre mtDNA analysis, deep mtDNA re-sequencing, patient fibroblast and muscle studies","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across patient tissues; strong mechanistic functional studies with defined cellular phenotypes","pmids":["24727571"],"is_preprint":false},{"year":2015,"finding":"SPG7 (paraplegin) was identified as an essential and conserved core component of the mitochondrial permeability transition pore (mPTP). RNAi-based screening showed that SPG7 loss results in higher mitochondrial Ca2+ retention capacity and sustained mitochondrial membrane potential (ΔΨm) during Ca2+ and ROS stress, similar to cyclophilin D (CypD/PPIF) knockdown. Biochemical analyses revealed that the mPTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced ΔΨm depolarization and cell death. SPG7 was identified as a ubiquitously expressed inner mitochondrial membrane (IMM) integral protein functioning at the OMM-IMM contact site.","method":"RNAi screen, Co-immunoprecipitation, mitochondrial membrane potential assays (ΔΨm), Ca2+ retention capacity assays, cell death assays, biochemical fractionation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — RNAi-based functional screen with multiple biochemical validations including Co-IP of the PTP complex, Ca2+ assays, and cell death readouts; 168 citations","pmids":["26387735"],"is_preprint":false},{"year":2016,"finding":"The m-AAA protease (which includes SPG7/paraplegin as a subunit) degrades non-assembled EMRE (a regulatory subunit of the mitochondrial calcium uniporter MCU) and ensures efficient assembly of gatekeeper subunits (MICU1/MICU2) with MCU. Loss of the m-AAA protease results in accumulation of constitutively active MCU-EMRE channels lacking gatekeeper subunits in neuronal mitochondria, facilitating mitochondrial Ca2+ overload, mPTP opening, and neuronal death. The m-AAA protease interactome was determined in mouse neurons, identifying a complex with MAIP1 (C2ORF47) that counteracts cell death by regulating MCU assembly.","method":"Neuronal interactome mapping by co-immunoprecipitation/mass spectrometry, EMRE turnover assays, MCU complex assembly analysis by BN-PAGE, mitochondrial Ca2+ uptake assays, neuronal death assays, genetic mouse models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including interactome mapping, complex assembly analysis, Ca2+ assays, and in vivo neuronal death; mechanistic pathway established with strong controls","pmids":["27642048"],"is_preprint":false},{"year":2016,"finding":"Mitochondrial protein interaction mapping using affinity enrichment mass spectrometry confirmed SPG7/paraplegin's interactions within the m-AAA protease complex and connected it to respiratory chain function. The study identified interactions linking the m-AAA complex to OXPHOS assembly and mitochondrial proteostasis networks.","method":"Affinity enrichment mass spectrometry (AE-MS) of 50 mitochondrial proteins under multiple conditions","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — systematic AP-MS with condition-specific interactions; SPG7 included but not the primary focus; single methodology","pmids":["27499296"],"is_preprint":false},{"year":2020,"finding":"Paraplegin (SPG7) is required for efficient transient (flickering) opening of the mPTP. SPG7-deficient patient fibroblasts and primary neurons from Spg7-/- mice show impaired mPTP flickering. Lack of paraplegin increases expression and activity of sirtuin 3 (SIRT3), which promotes deacetylation of cyclophilin D (CypD), thereby hampering mPTP opening. Dysregulation of mPTP flickering at the pre-synaptic terminal impairs neurotransmitter release and leads to ineffective synaptic transmission. Pharmacological treatment with the benzodiazepine Bz-423, which bypasses CypD activity, normalizes synaptic transmission and rescues motor impairment in the Spg7-/- mouse model.","method":"Fluorescence-based mPTP flickering assay in living cells, SIRT3 activity assays, CypD acetylation analysis, synaptic transmission electrophysiology, Bz-423 pharmacological rescue in Spg7-/- mice, behavioral motor testing","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including live-cell mPTP assays, biochemical pathway dissection (SIRT3-CypD axis), electrophysiology, and in vivo pharmacological rescue; mechanistic pathway fully defined","pmids":["33045469"],"is_preprint":false},{"year":2012,"finding":"SPG7 mutations were identified as the cause of autosomal recessive hereditary spastic paraplegia with optic neuropathy, and a novel heterozygous SPG7 missense mutation (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family. Optical coherence tomography (OCT) abnormalities were found in all SPG7-positive patients tested, indicating OCT as a potential clinical biomarker. The Ala510Val variant was confirmed as pathogenic by segregation analysis in a large autosomal recessive family.","method":"SPG31/SPG7 multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, optical coherence tomography, segregation analysis in large pedigrees","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 3 — genetic and clinical study with segregation analysis; establishes pathogenicity of specific variants but limited direct mechanistic biochemical data","pmids":["23065789"],"is_preprint":false}],"current_model":"SPG7 (paraplegin) is a subunit of the mitochondrial inner membrane m-AAA protease complex (co-assembled with AFG3L2), where it performs proteolytic and chaperone-like activities essential for mitochondrial proteostasis including degradation of non-assembled MCU regulatory subunit EMRE to ensure proper gating of the mitochondrial Ca2+ uniporter; loss of SPG7 causes impaired mPTP flickering via a SIRT3-mediated hyperdeacetylation of cyclophilin D, leading to mitochondrial Ca2+ overload, defective synaptic neurotransmitter release, complex I deficiency, mtDNA maintenance failure, and ultimately corticospinal neurodegeneration underlying hereditary spastic paraplegia type 7."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of SPG7 as a nuclear-encoded mitochondrial metalloprotease whose mutations cause hereditary spastic paraplegia established the first link between mitochondrial proteolysis and corticospinal neurodegeneration.","evidence":"Immunofluorescence, mitochondrial import assays, patient mutation analysis, and muscle biopsy OXPHOS studies in human cells and patient tissue","pmids":["9635427"],"confidence":"High","gaps":["Protease substrates unknown","Assembly state of paraplegin in the inner membrane not defined","Mechanism linking OXPHOS defect to selective neurodegeneration unresolved"]},{"year":2003,"claim":"Demonstration that paraplegin co-assembles with AFG3L2 into the m-AAA protease complex resolved the quaternary structure of the active enzyme and linked complex I deficiency and oxidative stress sensitivity to loss of this complex.","evidence":"Co-immunoprecipitation, Blue Native PAGE, enzymatic activity assays, yeast complementation, and patient fibroblast studies","pmids":["14623864"],"confidence":"High","gaps":["Direct substrates of the human m-AAA protease not yet identified","Relative contribution of homo- vs hetero-oligomeric complexes in different tissues unclear"]},{"year":2012,"claim":"Extension of the SPG7 disease spectrum to optic neuropathy — including a dominant missense variant — broadened understanding of paraplegin's role beyond spastic paraplegia to visual pathway neurodegeneration.","evidence":"MLPA, Sanger sequencing, OCT imaging, and segregation analysis in large pedigrees","pmids":["23065789"],"confidence":"Medium","gaps":["Biochemical consequence of the Asp411Ala variant not characterized","Mechanism of dominance not established","Limited to genetic and clinical evidence without reconstitution"]},{"year":2014,"claim":"Discovery that SPG7 mutations cause progressive external ophthalmoplegia with multiple mtDNA deletions revealed a direct role for the m-AAA protease in mitochondrial DNA maintenance.","evidence":"Whole exome sequencing, mitochondrial network analysis, single-fibre mtDNA deletion mapping, and deep mtDNA resequencing in patient muscle and fibroblasts","pmids":["24727571"],"confidence":"High","gaps":["Molecular mechanism by which paraplegin loss leads to mtDNA deletions undefined","Whether mtDNA instability is a primary or secondary consequence of proteostasis failure unclear"]},{"year":2015,"claim":"Identification of SPG7 as a core component of the mitochondrial permeability transition pore, interacting with VDAC and cyclophilin D, established an unexpected structural role beyond canonical proteolysis.","evidence":"RNAi screen, co-immunoprecipitation of the PTP complex, mitochondrial Ca²⁺ retention capacity assays, ΔΨm measurements, and cell death assays","pmids":["26387735"],"confidence":"High","gaps":["Whether the mPTP role is separable from the protease catalytic function not determined","Stoichiometry and architecture of the SPG7-VDAC-CypD complex unresolved"]},{"year":2016,"claim":"Identification of EMRE as a direct m-AAA protease substrate explained how paraplegin loss causes mitochondrial Ca²⁺ overload: unprocessed EMRE generates constitutively active MCU channels lacking MICU1/MICU2 gatekeeper subunits, linking protease activity to Ca²⁺ signaling and neuronal death.","evidence":"Neuronal interactome mapping by co-IP/mass spectrometry, EMRE turnover assays, BN-PAGE MCU complex analysis, mitochondrial Ca²⁺ uptake assays, and genetic mouse models","pmids":["27642048"],"confidence":"High","gaps":["Full substrate repertoire of the SPG7-containing m-AAA protease beyond EMRE remains unknown","Contribution of MAIP1 (C2ORF47) cofactor to substrate specificity not fully defined"]},{"year":2020,"claim":"Dissection of the SIRT3–cyclophilin D axis showed that paraplegin loss upregulates SIRT3, hyperdeacetylates CypD, and thereby impairs transient mPTP flickering — a mechanism directly responsible for defective presynaptic neurotransmitter release; pharmacological bypass with Bz-423 rescued motor deficits in vivo.","evidence":"Live-cell mPTP flickering assays, SIRT3 activity and CypD acetylation analysis, electrophysiology of synaptic transmission, and Bz-423 pharmacological rescue in Spg7⁻/⁻ mice","pmids":["33045469"],"confidence":"High","gaps":["How SPG7 loss leads to SIRT3 upregulation is mechanistically unclear","Whether mPTP flickering defect contributes to all SPG7-associated phenotypes (e.g., optic neuropathy, PEO) untested"]},{"year":null,"claim":"A unified structural model explaining how SPG7 participates simultaneously in m-AAA protease catalysis and mPTP regulation — and whether these are separable or interdependent functions — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the human SPG7-AFG3L2 m-AAA complex","Complete substrate catalog of the m-AAA protease not established","Mechanism linking paraplegin loss to mtDNA instability remains undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,4]}],"pathway":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,8]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,5]}],"complexes":["m-AAA protease (SPG7-AFG3L2)","mPTP (SPG7-VDAC-CypD)"],"partners":["AFG3L2","PPIF","VDAC1","EMRE","MAIP1","SIRT3"],"other_free_text":[]},"mechanistic_narrative":"SPG7 (paraplegin) is a subunit of the mitochondrial inner membrane m-AAA protease complex, where it co-assembles with AFG3L2 to perform ATP-dependent proteolysis essential for mitochondrial proteostasis, respiratory chain function, and mitochondrial DNA maintenance [PMID:14623864, PMID:24727571]. The m-AAA protease degrades non-assembled EMRE, thereby preventing constitutively active MCU channels from causing mitochondrial Ca²⁺ overload and neuronal death [PMID:27642048]. SPG7 is also required for transient mPTP flickering through a SIRT3–cyclophilin D acetylation axis; loss of SPG7 impairs mPTP opening, disrupts presynaptic neurotransmitter release, and causes corticospinal neurodegeneration underlying autosomal recessive hereditary spastic paraplegia type 7 and progressive external ophthalmoplegia with multiple mtDNA deletions [PMID:33045469, PMID:9635427, PMID:24727571]."},"prefetch_data":{"uniprot":{"accession":"Q9UQ90","full_name":"Mitochondrial inner membrane m-AAA protease component paraplegin","aliases":["Cell matrix adhesion regulator","Paraplegin","Spastic paraplegia 7 protein"],"length_aa":795,"mass_kda":88.2,"function":"Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development (PubMed:11549317, PubMed:28396416, PubMed:31097542, PubMed:9635427). SPG7 possesses both ATPase and protease activities: the ATPase activity is required to unfold substrates, threading them into the internal proteolytic cavity for hydrolysis into small peptide fragments (By similarity). The m-AAA protease exerts a dual role in the mitochondrial inner membrane: it mediates the processing of specific regulatory proteins and ensures protein quality control by degrading misfolded polypeptides (By similarity). Mediates protein maturation of the mitochondrial ribosomal subunit MRPL32/bL32m by catalyzing the cleavage of the presequence of MRPL32/bL32m prior to assembly into the mitochondrial ribosome (By similarity). Acts as a regulator of calcium in neurons by mediating degradation of SMDT1/EMRE before its assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU (PubMed:28396416, PubMed:31097542). Also regulates mitochondrial calcium by catalyzing degradation of MCU (PubMed:31097542). Plays a role in the formation and regulation of the mitochondrial permeability transition pore (mPTP) and its proteolytic activity is dispensable for this function (PubMed:26387735)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9UQ90/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPG7","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPG7","total_profiled":1310},"omim":[{"mim_id":"617267","title":"MATRIX AAA PEPTIDASE-INTERACTING PROTEIN 1; MAIP1","url":"https://www.omim.org/entry/617267"},{"mim_id":"616184","title":"CLUSTERED MITOCHONDRIA, D. DISCOIDEUM, HOMOLOG OF; CLUH","url":"https://www.omim.org/entry/616184"},{"mim_id":"615588","title":"SINGLE-PASS MEMBRANE PROTEIN WITH ASPARTATE-RICH TAIL 1; SMDT1","url":"https://www.omim.org/entry/615588"},{"mim_id":"615031","title":"NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IX, WITH DEVELOPMENTAL DELAY; HSAN9","url":"https://www.omim.org/entry/615031"},{"mim_id":"615000","title":"TECTONIN BETA-PROPELLER REPEAT-CONTAINING PROTEIN 2; TECPR2","url":"https://www.omim.org/entry/615000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPG7"},"hgnc":{"alias_symbol":["CAR","SPG5C"],"prev_symbol":["CMAR"]},"alphafold":{"accession":"Q9UQ90","domains":[{"cath_id":"3.40.1690.20","chopping":"164-252","consensus_level":"high","plddt":82.696,"start":164,"end":252},{"cath_id":"3.40.50.300","chopping":"292-417_427-477","consensus_level":"high","plddt":86.0155,"start":292,"end":477},{"cath_id":"1.10.8.60","chopping":"483-555","consensus_level":"high","plddt":90.2737,"start":483,"end":555},{"cath_id":"1.20.58.760","chopping":"566-676_693-748","consensus_level":"high","plddt":89.6433,"start":566,"end":748}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ90","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ90-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ90-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPG7","jax_strain_url":"https://www.jax.org/strain/search?query=SPG7"},"sequence":{"accession":"Q9UQ90","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQ90.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQ90/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ90"}},"corpus_meta":[{"pmid":"35361234","id":"PMC_35361234","title":"CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35361234","citation_count":520,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30680780","id":"PMC_30680780","title":"An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer.","date":"2019","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/30680780","citation_count":411,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30875739","id":"PMC_30875739","title":"Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30875739","citation_count":408,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28652918","id":"PMC_28652918","title":"Engineering CAR-T cells.","date":"2017","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/28652918","citation_count":408,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12120277","id":"PMC_12120277","title":"PXR, CAR and drug metabolism.","date":"2002","source":"Nature reviews. Drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/12120277","citation_count":400,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33098993","id":"PMC_33098993","title":"Side-effect management of chimeric antigen receptor (CAR) T-cell therapy.","date":"2020","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33098993","citation_count":385,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34861191","id":"PMC_34861191","title":"An NK-like CAR T cell transition in CAR T cell dysfunction.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/34861191","citation_count":314,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24329791","id":"PMC_24329791","title":"Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma.","date":"2014","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24329791","citation_count":295,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39134804","id":"PMC_39134804","title":"CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors.","date":"2024","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39134804","citation_count":229,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36097223","id":"PMC_36097223","title":"Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy.","date":"2022","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36097223","citation_count":204,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19595610","id":"PMC_19595610","title":"PXR and CAR in energy metabolism.","date":"2009","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/19595610","citation_count":199,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22554043","id":"PMC_22554043","title":"Role of CAR and PXR in xenobiotic sensing and metabolism.","date":"2012","source":"Expert opinion on drug metabolism & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/22554043","citation_count":190,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32714329","id":"PMC_32714329","title":"Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32714329","citation_count":187,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36765623","id":"PMC_36765623","title":"CAR-T: What Is Next?","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36765623","citation_count":173,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26387735","id":"PMC_26387735","title":"SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26387735","citation_count":168,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31221182","id":"PMC_31221182","title":"Target selection for CAR-T therapy.","date":"2019","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31221182","citation_count":157,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27231717","id":"PMC_27231717","title":"CAR models: next-generation CAR modifications for enhanced T-cell function.","date":"2016","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/27231717","citation_count":137,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24727571","id":"PMC_24727571","title":"Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24727571","citation_count":137,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38012406","id":"PMC_38012406","title":"Forks in the road for CAR T and CAR NK cell cancer therapies.","date":"2023","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38012406","citation_count":134,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33168929","id":"PMC_33168929","title":"Counteracting CAR T cell dysfunction.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33168929","citation_count":129,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34429382","id":"PMC_34429382","title":"Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/34429382","citation_count":125,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30369931","id":"PMC_30369931","title":"Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30369931","citation_count":123,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22889594","id":"PMC_22889594","title":"Targeting xenobiotic receptors PXR and CAR for metabolic diseases.","date":"2012","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22889594","citation_count":121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35278370","id":"PMC_35278370","title":"3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR T cells.","date":"2022","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/35278370","citation_count":116,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35203496","id":"PMC_35203496","title":"CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/35203496","citation_count":100,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12573482","id":"PMC_12573482","title":"Functional and structural comparison of PXR and CAR.","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12573482","citation_count":100,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28110394","id":"PMC_28110394","title":"Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies.","date":"2017","source":"Drugs","url":"https://pubmed.ncbi.nlm.nih.gov/28110394","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34422667","id":"PMC_34422667","title":"From CAR-T Cells to CAR-NK Cells: A Developing Immunotherapy Method for Hematological Malignancies.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34422667","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24667955","id":"PMC_24667955","title":"CD19-CAR trials.","date":"2014","source":"Cancer journal (Sudbury, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/24667955","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16534102","id":"PMC_16534102","title":"Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.","date":"2006","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16534102","citation_count":90,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24474196","id":"PMC_24474196","title":"Signaling control of the constitutive androstane receptor (CAR).","date":"2014","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/24474196","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36429120","id":"PMC_36429120","title":"CAR-Macrophages and CAR-T Cells Synergistically Kill Tumor Cells In Vitro.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36429120","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29370379","id":"PMC_29370379","title":"Glycan-directed CAR-T cells.","date":"2018","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29370379","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28718815","id":"PMC_28718815","title":"Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy.","date":"2017","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/28718815","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36179026","id":"PMC_36179026","title":"CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36179026","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33670139","id":"PMC_33670139","title":"Adoptive Immunotherapy beyond CAR T-Cells.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33670139","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38865661","id":"PMC_38865661","title":"Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy.","date":"2024","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38865661","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33463538","id":"PMC_33463538","title":"Insight into next-generation CAR therapeutics: designing CAR T cells to improve clinical outcomes.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/33463538","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29107016","id":"PMC_29107016","title":"Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies.","date":"2017","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29107016","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32634192","id":"PMC_32634192","title":"Approval of First CAR-Ts: Have we Solved all Hurdles for ATMPs?","date":"2019","source":"Cell medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32634192","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26921498","id":"PMC_26921498","title":"Small-molecule modulators of PXR and CAR.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26921498","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11479928","id":"PMC_11479928","title":"Receptor for the group B coxsackieviruses and adenoviruses: CAR.","date":"2001","source":"Reviews in medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/11479928","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31114756","id":"PMC_31114756","title":"A Metabolism Toolbox for CAR T Therapy.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31114756","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30814337","id":"PMC_30814337","title":"Driving CAR T cell translation forward.","date":"2019","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30814337","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38143263","id":"PMC_38143263","title":"Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape.","date":"2023","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38143263","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37932456","id":"PMC_37932456","title":"Harnessing CD3 diversity to optimize CAR T cells.","date":"2023","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37932456","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31707680","id":"PMC_31707680","title":"Analysis of CAR-Mediated Tonic Signaling.","date":"2020","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/31707680","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37124148","id":"PMC_37124148","title":"Non-viral chimeric antigen receptor (CAR) T cells going viral.","date":"2023","source":"Immuno-oncology technology","url":"https://pubmed.ncbi.nlm.nih.gov/37124148","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35149294","id":"PMC_35149294","title":"Novel insights in CAR-NK cells beyond CAR-T cell technology; promising advantages.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35149294","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26791002","id":"PMC_26791002","title":"Chimeric Antigen Receptor (CAR) therapy for multiple myeloma.","date":"2016","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/26791002","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37205115","id":"PMC_37205115","title":"Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37205115","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38670972","id":"PMC_38670972","title":"CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38670972","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40379910","id":"PMC_40379910","title":"In vivo CAR engineering for immunotherapy.","date":"2025","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40379910","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30549299","id":"PMC_30549299","title":"Treating osteosarcoma with CAR T cells.","date":"2019","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30549299","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38039964","id":"PMC_38039964","title":"ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells.","date":"2023","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/38039964","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38067179","id":"PMC_38067179","title":"AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38067179","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32139020","id":"PMC_32139020","title":"CAR T and CAR NK cells in multiple myeloma: Expanding the targets.","date":"2020","source":"Best practice & research. Clinical haematology","url":"https://pubmed.ncbi.nlm.nih.gov/32139020","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12747555","id":"PMC_12747555","title":"Adenovirus interaction with its cellular receptor CAR.","date":"2003","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12747555","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19686701","id":"PMC_19686701","title":"Retinoids activate RXR/CAR-mediated pathway and induce CYP3A.","date":"2009","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19686701","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28545889","id":"PMC_28545889","title":"CAR: A key regulator of adhesion and inflammation.","date":"2017","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28545889","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35392217","id":"PMC_35392217","title":"Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35392217","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34943898","id":"PMC_34943898","title":"NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34943898","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36831396","id":"PMC_36831396","title":"CAR-T-Derived Extracellular Vesicles: A Promising Development of CAR-T Anti-Tumor Therapy.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36831396","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33045469","id":"PMC_33045469","title":"Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia.","date":"2020","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/33045469","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32163104","id":"PMC_32163104","title":"Challenges of CAR- and TCR-T cell-based therapy for chronic infections.","date":"2020","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32163104","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23729557","id":"PMC_23729557","title":"An update on the constitutive androstane receptor (CAR).","date":"2013","source":"Drug metabolism and drug interactions","url":"https://pubmed.ncbi.nlm.nih.gov/23729557","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37403182","id":"PMC_37403182","title":"Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies.","date":"2023","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/37403182","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29568411","id":"PMC_29568411","title":"The development of CAR design for tumor CAR-T cell therapy.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29568411","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22098234","id":"PMC_22098234","title":"Constitutive androstane receptor (CAR) is a xenosensor and target for therapy.","date":"2011","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/22098234","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40179881","id":"PMC_40179881","title":"Engineering sonogenetic EchoBack-CAR T cells.","date":"2025","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/40179881","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32402724","id":"PMC_32402724","title":"Revving the CAR - Combination strategies to enhance CAR T cell effectiveness.","date":"2020","source":"Blood reviews","url":"https://pubmed.ncbi.nlm.nih.gov/32402724","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39079964","id":"PMC_39079964","title":"A CAR enhancer increases the activity and persistence of CAR T cells.","date":"2024","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39079964","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32301017","id":"PMC_32301017","title":"CAR T-Cells.","date":"2020","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/32301017","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31916100","id":"PMC_31916100","title":"Potential of Glioblastoma-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy.","date":"2020","source":"CNS drugs","url":"https://pubmed.ncbi.nlm.nih.gov/31916100","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37877819","id":"PMC_37877819","title":"CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar.","date":"2024","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/37877819","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39889712","id":"PMC_39889712","title":"CAR T cells, CAR NK cells, and CAR macrophages exhibit distinct traits in glioma models but are similarly enhanced when combined with cytokines.","date":"2025","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39889712","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39101835","id":"PMC_39101835","title":"Redirecting B7-H3.CAR T Cells to Chemokines Expressed in Osteosarcoma Enhances Homing and Antitumor Activity in Preclinical Models.","date":"2024","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/39101835","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31181279","id":"PMC_31181279","title":"The making and function of CAR cells.","date":"2019","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31181279","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33249047","id":"PMC_33249047","title":"CAR T-cells profiling in carcinogenesis and tumorigenesis: An overview of CAR T-cells cancer therapy.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33249047","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20426821","id":"PMC_20426821","title":"Mouse brain expression patterns of Spg7, Afg3l1, and Afg3l2 transcripts, encoding for the mitochondrial m-AAA protease.","date":"2010","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20426821","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16101576","id":"PMC_16101576","title":"Beyond CAR and PXR.","date":"2005","source":"Current drug metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/16101576","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38090576","id":"PMC_38090576","title":"Advancing CAR-based immunotherapies in solid tumors: CAR- macrophages and neutrophils.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38090576","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31611880","id":"PMC_31611880","title":"CAR Talk: How Cancer-Specific CAR T Cells Can Instruct How to Build CAR T Cells to Cure HIV.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31611880","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36700225","id":"PMC_36700225","title":"CAR T cell therapy becomes CHIC: \"cytokine help intensified CAR\" T cells.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36700225","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35259043","id":"PMC_35259043","title":"Lenalidomide enhances CD23.CAR T cell therapy in chronic lymphocytic leukemia.","date":"2022","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/35259043","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38745250","id":"PMC_38745250","title":"CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison.","date":"2024","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38745250","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35005887","id":"PMC_35005887","title":"Synthetic Biology in Chimeric Antigen Receptor T (CAR T) Cell Engineering.","date":"2022","source":"ACS synthetic biology","url":"https://pubmed.ncbi.nlm.nih.gov/35005887","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33529650","id":"PMC_33529650","title":"Role of the constitutive androstane receptor (CAR) in human liver cancer.","date":"2021","source":"Biochimica et biophysica acta. Reviews on cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33529650","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37715447","id":"PMC_37715447","title":"The physical landscape of CAR-T synapse.","date":"2023","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/37715447","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34582835","id":"PMC_34582835","title":"Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma.","date":"2021","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34582835","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37080711","id":"PMC_37080711","title":"Infectious complications of chimeric antigen receptor (CAR) T-cell therapies.","date":"2023","source":"Seminars in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/37080711","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28101686","id":"PMC_28101686","title":"Minicircle-Based Engineering of Chimeric Antigen Receptor (CAR) T Cells.","date":"2016","source":"Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28101686","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33575314","id":"PMC_33575314","title":"Novel progresses of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma.","date":"2021","source":"Stem cell investigation","url":"https://pubmed.ncbi.nlm.nih.gov/33575314","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33807867","id":"PMC_33807867","title":"Engineering Metabolism of Chimeric Antigen Receptor (CAR) Cells for Developing Efficient Immunotherapies.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33807867","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36409926","id":"PMC_36409926","title":"Rational Protein Design Yields a CD20 CAR with Superior Antitumor Efficacy Compared with CD19 CAR.","date":"2023","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/36409926","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31492448","id":"PMC_31492448","title":"The promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma.","date":"2019","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31492448","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34771581","id":"PMC_34771581","title":"The Race of CAR Therapies: CAR-NK Cells for Fighting B-Cell Hematological Cancers.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34771581","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38766710","id":"PMC_38766710","title":"Beyond CAR T cells: exploring alternative cell sources for CAR-like cellular therapies.","date":"2024","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38766710","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39411714","id":"PMC_39411714","title":"CAR immunotherapy in autoimmune diseases: promises and challenges.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39411714","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36498890","id":"PMC_36498890","title":"Joining Forces for Cancer Treatment: From \"TCR versus CAR\" to \"TCR and CAR\".","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36498890","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16189514","id":"PMC_16189514","title":"Towards a proteome-scale map of the human protein-protein interaction network.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16189514","citation_count":2090,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18854154","id":"PMC_18854154","title":"Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18854154","citation_count":787,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9635427","id":"PMC_9635427","title":"Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9635427","citation_count":642,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21900206","id":"PMC_21900206","title":"A directed protein interaction network for investigating intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32494073","id":"PMC_32494073","title":"Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32494073","citation_count":246,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34800366","id":"PMC_34800366","title":"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34800366","citation_count":239,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22554690","id":"PMC_22554690","title":"Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance.","date":"2012","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22554690","citation_count":228,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14623864","id":"PMC_14623864","title":"Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14623864","citation_count":227,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27499296","id":"PMC_27499296","title":"Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27499296","citation_count":220,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20579626","id":"PMC_20579626","title":"Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20579626","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21516116","id":"PMC_21516116","title":"Next-generation sequencing to generate interactome datasets.","date":"2011","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/21516116","citation_count":200,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27642048","id":"PMC_27642048","title":"The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27642048","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23755363","id":"PMC_23755363","title":"MCU encodes the pore conducting mitochondrial calcium currents.","date":"2013","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/23755363","citation_count":157,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27099988","id":"PMC_27099988","title":"Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27099988","citation_count":139,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23065789","id":"PMC_23065789","title":"Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy.","date":"2012","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23065789","citation_count":133,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38349,"output_tokens":1307,"usd":0.067326},"stage2":{"model":"claude-opus-4-6","input_tokens":4505,"output_tokens":1658,"usd":0.095963},"total_usd":0.398732,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":50692,"output_tokens":3764,"usd":0.104268},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6435,"output_tokens":2211,"usd":0.131175}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"SPG7 (paraplegin) is an essential core component of the mitochondrial permeability transition pore (PTP). RNAi-based screening identified SPG7 as required for Ca2+- and ROS-induced PTP opening. Biochemical analyses revealed the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced mitochondrial membrane potential depolarization and cell death. SPG7 localizes to the inner mitochondrial membrane (IMM) and functions at the OMM-IMM contact site.\",\n      \"method\": \"RNAi screening, RNAi knockdown, Co-immunoprecipitation, biochemical fractionation, mitochondrial membrane potential assays, Ca2+ retention capacity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNAi screen, biochemical pulldown, functional assays) in a single rigorous study\",\n      \"pmids\": [\"26387735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Paraplegin (SPG7) is required for efficient transient (flickering) opening of the mitochondrial permeability transition pore (mPTP). Loss of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3 (SIRT3), which promotes deacetylation of cyclophilin D (CypD), thereby hampering mPTP opening. Dysregulation of mPTP flickering at the pre-synaptic terminal impairs neurotransmitter release and synaptic transmission. Pharmacological rescue with Bz-423 (which bypasses CypD activity) normalized synaptic transmission and rescued motor impairment in Spg7-/- mice.\",\n      \"method\": \"Fluorescence-based mPTP flickering assay in living cells, SPG7 patient-derived fibroblasts, primary neurons from Spg7-/- mice, biochemical assays for SIRT3 activity and CypD acetylation, electrophysiology, pharmacological rescue in animal model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including live-cell functional assays, biochemical pathway dissection, and in vivo rescue with defined molecular mechanism\",\n      \"pmids\": [\"33045469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SPG7 mutations cause progressive external ophthalmoplegia (PEO) associated with multiple mitochondrial DNA deletions. Functional studies demonstrated SPG7 mutations caused increased mitochondrial biogenesis in patient muscle and mitochondrial fusion in patient fibroblasts, associated with clonal expansion of mitochondrial DNA mutations. This places SPG7 in the pathway of mitochondrial DNA maintenance.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, transcript analysis, proteomics, mitochondrial network analysis, single-fibre mtDNA analysis, deep re-sequencing of mtDNA\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in patient tissue establishing pathway role, single study\",\n      \"pmids\": [\"24727571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Spg7 encodes a subunit of the mitochondrial m-AAA protease complex (an ATPase Associated with various cellular Activities metalloprotease located in the inner mitochondrial membrane), which in mouse forms a hetero-oligomer with Afg3l1 and Afg3l2. Brain expression analysis showed Spg7 is highly expressed in neurons involved in hereditary spastic paraplegia (Purkinje cells, pyramidal neurons, brainstem motor neurons), consistent with its role in neuronal maintenance.\",\n      \"method\": \"Quantitative RT-PCR, in situ hybridization of mouse brain regions\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — expression localization consistent with ortholog function, but no direct functional manipulation\",\n      \"pmids\": [\"20426821\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPG7 (paraplegin) is an inner mitochondrial membrane metalloprotease (m-AAA complex subunit) that forms a core heterooligomeric component of the mitochondrial permeability transition pore (mPTP) together with VDAC and cyclophilin D (CypD); it is required for transient mPTP flickering, a process regulated via SIRT3-mediated deacetylation of CypD, and loss of SPG7 impairs pre-synaptic Ca2+ homeostasis, neurotransmitter release, and mitochondrial DNA maintenance, collectively causing hereditary spastic paraplegia type 7.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n- Papers [1]-[13], [16]-[29] from the main corpus (100 papers) about CAR T cells, CAR NK cells, CAR macrophages, PXR/CAR nuclear receptors, coxsackievirus/adenovirus receptor CAR = EXCLUDE (alias collisions)\n- Paper [15] PMID:26387735 \"SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore\" = KEEP\n- Paper [18] PMID:24727571 \"Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance\" = KEEP\n- Paper [30] PMID:16534102 \"Mutation analysis of the paraplegin gene (SPG7)\" = KEEP\n- Paper [64] PMID:33045469 \"Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia\" = KEEP\n- Paper [80] PMID:20426821 \"Mouse brain expression patterns of Spg7, Afg3l1, and Afg3l2\" = KEEP\n\n**Additional curated papers:**\n- PMID:16189514, 16169070, 12477932, 26186194, 28514442, 26496610, 25416956, 32296183, 18854154, 14702039, 33961781, 22939629, 21873635 = EXCLUDE (interactome/cDNA databases, not SPG7-specific)\n- PMID:9635427 \"Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin\" = KEEP\n- PMID:14623864 \"Loss of m-AAA protease in mitochondria causes complex I deficiency\" = KEEP\n- PMID:27499296 \"Mitochondrial Protein Interaction Mapping\" = KEEP (contains SPG7/m-AAA relevant data)\n- PMID:32494073 \"Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex\" = KEEP (relevant to SPG7 pathway)\n- PMID:34800366 \"Quantitative high-confidence human mitochondrial proteome\" = EXCLUDE (proteome database)\n- PMID:22554690 \"Hereditary spastic paraplegias\" = EXCLUDE (clinical review, no mechanism)\n- PMID:27642048 \"The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity\" = KEEP\n- PMID:23755363 \"MCU encodes the pore conducting mitochondrial calcium currents\" = KEEP (directly relevant to SPG7 pathway)\n- PMID:27099988 \"Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex\" = KEEP\n- PMID:20579626 \"Identification of a frameshift mutation in Osterix\" = EXCLUDE (SP7/OSX, alias collision)\n- PMID:21516116, 21900206, 21988832, 31871319 = EXCLUDE (interactome/signaling network databases)\n- PMID:23065789 \"Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy\" = KEEP\n- PMID:16344560 = EXCLUDE (promoter study, not SPG7-specific)\n- PMID:15489334 = EXCLUDE (MGC database)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Paraplegin (SPG7) was identified as a nuclear-encoded mitochondrial metalloprotease highly homologous to yeast mitochondrial ATPases (AFG3, RCA1, YME1). Immunofluorescence and import experiments demonstrated that paraplegin localizes to mitochondria. Mutations in SPG7 cause autosomal recessive hereditary spastic paraplegia, and muscle biopsies from patients showed signs of mitochondrial OXPHOS defects, linking SPG7 to mitochondrial function and neurodegeneration.\",\n      \"method\": \"Immunofluorescence, mitochondrial import assays, patient mutation analysis, muscle biopsy OXPHOS analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct localization experiments with functional consequence, replicated across patient samples; foundational paper with 642 citations\",\n      \"pmids\": [\"9635427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Paraplegin (SPG7) co-assembles with its homolog AFG3L2 to form a high molecular mass complex in the mitochondrial inner membrane (the m-AAA protease complex). Loss of this complex causes reduced mitochondrial complex I (NADH dehydrogenase) activity and increased sensitivity to oxidative stress in HSP patient fibroblasts. Complementation studies in yeast demonstrated functional conservation of the human paraplegin-AFG3L2 complex with the yeast m-AAA protease and assigned proteolytic activity to this complex.\",\n      \"method\": \"Co-immunoprecipitation, Blue Native PAGE, enzymatic activity assays, yeast complementation, patient fibroblast studies, oxidative stress assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including co-IP, activity assays, and yeast complementation; replicated in patient cells and model organisms\",\n      \"pmids\": [\"14623864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mouse Spg7 (paraplegin) transcript is expressed throughout the brain, with particularly high levels in mitral cells, Purkinje cells, deep cerebellar nuclei cells, neocortical and hippocampal pyramidal neurons, and brainstem motor neurons. Spg7 is the second most abundant of the three m-AAA protease subunit transcripts (Afg3l2 > Spg7 > Afg3l1), and differences in expression levels among neuronal subtypes were observed, suggesting distinct contributions to the m-AAA protease complex in different cell types.\",\n      \"method\": \"Quantitative RT-PCR, in situ hybridization across mouse brain regions\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by in situ hybridization, single lab but two orthogonal methods; no functional consequence directly tested in this study\",\n      \"pmids\": [\"20426821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SPG7 mutations were identified as a novel cause of progressive external ophthalmoplegia (PEO) associated with multiple mitochondrial DNA deletions. Functional studies demonstrated that SPG7 mutations cause increased mitochondrial biogenesis in patient muscle and promote mitochondrial fusion in patient fibroblasts, associated with clonal expansion of mitochondrial DNA mutations. This links SPG7/paraplegin to mitochondrial DNA maintenance mechanisms.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, transcript analysis, proteomics, mitochondrial network analysis, single-fibre mtDNA analysis, deep mtDNA re-sequencing, patient fibroblast and muscle studies\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across patient tissues; strong mechanistic functional studies with defined cellular phenotypes\",\n      \"pmids\": [\"24727571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPG7 (paraplegin) was identified as an essential and conserved core component of the mitochondrial permeability transition pore (mPTP). RNAi-based screening showed that SPG7 loss results in higher mitochondrial Ca2+ retention capacity and sustained mitochondrial membrane potential (ΔΨm) during Ca2+ and ROS stress, similar to cyclophilin D (CypD/PPIF) knockdown. Biochemical analyses revealed that the mPTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced ΔΨm depolarization and cell death. SPG7 was identified as a ubiquitously expressed inner mitochondrial membrane (IMM) integral protein functioning at the OMM-IMM contact site.\",\n      \"method\": \"RNAi screen, Co-immunoprecipitation, mitochondrial membrane potential assays (ΔΨm), Ca2+ retention capacity assays, cell death assays, biochemical fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — RNAi-based functional screen with multiple biochemical validations including Co-IP of the PTP complex, Ca2+ assays, and cell death readouts; 168 citations\",\n      \"pmids\": [\"26387735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The m-AAA protease (which includes SPG7/paraplegin as a subunit) degrades non-assembled EMRE (a regulatory subunit of the mitochondrial calcium uniporter MCU) and ensures efficient assembly of gatekeeper subunits (MICU1/MICU2) with MCU. Loss of the m-AAA protease results in accumulation of constitutively active MCU-EMRE channels lacking gatekeeper subunits in neuronal mitochondria, facilitating mitochondrial Ca2+ overload, mPTP opening, and neuronal death. The m-AAA protease interactome was determined in mouse neurons, identifying a complex with MAIP1 (C2ORF47) that counteracts cell death by regulating MCU assembly.\",\n      \"method\": \"Neuronal interactome mapping by co-immunoprecipitation/mass spectrometry, EMRE turnover assays, MCU complex assembly analysis by BN-PAGE, mitochondrial Ca2+ uptake assays, neuronal death assays, genetic mouse models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including interactome mapping, complex assembly analysis, Ca2+ assays, and in vivo neuronal death; mechanistic pathway established with strong controls\",\n      \"pmids\": [\"27642048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mitochondrial protein interaction mapping using affinity enrichment mass spectrometry confirmed SPG7/paraplegin's interactions within the m-AAA protease complex and connected it to respiratory chain function. The study identified interactions linking the m-AAA complex to OXPHOS assembly and mitochondrial proteostasis networks.\",\n      \"method\": \"Affinity enrichment mass spectrometry (AE-MS) of 50 mitochondrial proteins under multiple conditions\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic AP-MS with condition-specific interactions; SPG7 included but not the primary focus; single methodology\",\n      \"pmids\": [\"27499296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Paraplegin (SPG7) is required for efficient transient (flickering) opening of the mPTP. SPG7-deficient patient fibroblasts and primary neurons from Spg7-/- mice show impaired mPTP flickering. Lack of paraplegin increases expression and activity of sirtuin 3 (SIRT3), which promotes deacetylation of cyclophilin D (CypD), thereby hampering mPTP opening. Dysregulation of mPTP flickering at the pre-synaptic terminal impairs neurotransmitter release and leads to ineffective synaptic transmission. Pharmacological treatment with the benzodiazepine Bz-423, which bypasses CypD activity, normalizes synaptic transmission and rescues motor impairment in the Spg7-/- mouse model.\",\n      \"method\": \"Fluorescence-based mPTP flickering assay in living cells, SIRT3 activity assays, CypD acetylation analysis, synaptic transmission electrophysiology, Bz-423 pharmacological rescue in Spg7-/- mice, behavioral motor testing\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including live-cell mPTP assays, biochemical pathway dissection (SIRT3-CypD axis), electrophysiology, and in vivo pharmacological rescue; mechanistic pathway fully defined\",\n      \"pmids\": [\"33045469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SPG7 mutations were identified as the cause of autosomal recessive hereditary spastic paraplegia with optic neuropathy, and a novel heterozygous SPG7 missense mutation (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family. Optical coherence tomography (OCT) abnormalities were found in all SPG7-positive patients tested, indicating OCT as a potential clinical biomarker. The Ala510Val variant was confirmed as pathogenic by segregation analysis in a large autosomal recessive family.\",\n      \"method\": \"SPG31/SPG7 multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, optical coherence tomography, segregation analysis in large pedigrees\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic and clinical study with segregation analysis; establishes pathogenicity of specific variants but limited direct mechanistic biochemical data\",\n      \"pmids\": [\"23065789\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPG7 (paraplegin) is a subunit of the mitochondrial inner membrane m-AAA protease complex (co-assembled with AFG3L2), where it performs proteolytic and chaperone-like activities essential for mitochondrial proteostasis including degradation of non-assembled MCU regulatory subunit EMRE to ensure proper gating of the mitochondrial Ca2+ uniporter; loss of SPG7 causes impaired mPTP flickering via a SIRT3-mediated hyperdeacetylation of cyclophilin D, leading to mitochondrial Ca2+ overload, defective synaptic neurotransmitter release, complex I deficiency, mtDNA maintenance failure, and ultimately corticospinal neurodegeneration underlying hereditary spastic paraplegia type 7.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SPG7 (paraplegin) is a subunit of the mitochondrial m-AAA protease complex located in the inner mitochondrial membrane, where it also serves as an essential core component of the mitochondrial permeability transition pore (mPTP) in a heterooligomeric complex with VDAC and cyclophilin D (CypD) [PMID:26387735]. SPG7 is required for Ca²⁺- and ROS-induced mPTP opening and for transient mPTP flickering at presynaptic terminals; loss of SPG7 increases SIRT3 expression and CypD deacetylation, thereby impairing mPTP flickering, neurotransmitter release, and synaptic transmission [PMID:33045469]. SPG7 also participates in mitochondrial DNA maintenance, and its mutations cause hereditary spastic paraplegia type 7 as well as progressive external ophthalmoplegia with multiple mitochondrial DNA deletions [PMID:24727571].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that SPG7 encodes a subunit of the inner mitochondrial membrane m-AAA protease complex and is enriched in neurons vulnerable to spastic paraplegia provided an anatomical and molecular framework for understanding its neuronal maintenance role.\",\n      \"evidence\": \"Quantitative RT-PCR and in situ hybridization in mouse brain\",\n      \"pmids\": [\"20426821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct functional manipulation of SPG7 performed in this study\",\n        \"Protease substrates relevant to neurodegeneration not identified\",\n        \"Relationship between m-AAA protease activity and disease mechanism not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that SPG7 mutations cause progressive external ophthalmoplegia with multiple mtDNA deletions placed SPG7 in the mitochondrial DNA maintenance pathway, expanding its known disease spectrum beyond spastic paraplegia.\",\n      \"evidence\": \"Whole exome sequencing, single-fibre mtDNA analysis, and mitochondrial network analysis in patient muscle and fibroblasts\",\n      \"pmids\": [\"24727571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which SPG7 loss leads to mtDNA deletion accumulation is unknown\",\n        \"Causal link between mitochondrial fusion phenotype and mtDNA instability not demonstrated\",\n        \"No rescue experiment performed\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An unbiased RNAi screen identified SPG7 as an essential structural component of the mPTP, revealing it forms a heterooligomeric complex with VDAC and CypD at OMM-IMM contact sites — fundamentally redefining the molecular identity of the pore.\",\n      \"evidence\": \"RNAi screening, co-immunoprecipitation, biochemical fractionation, Ca²⁺ retention capacity and membrane potential assays in mammalian cells\",\n      \"pmids\": [\"26387735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular stoichiometry and structural architecture of the SPG7-VDAC-CypD complex remain undefined\",\n        \"Whether SPG7 protease activity is required for pore function versus a structural role was not distinguished\",\n        \"Independent replication of SPG7 as the mPTP pore-forming subunit by other groups not yet reported in this timeline\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mechanistic dissection showed SPG7 loss impairs transient mPTP flickering via a SIRT3-CypD deacetylation axis, directly linking mPTP dysfunction to presynaptic Ca²⁺ dysregulation, impaired neurotransmitter release, and motor deficits — and demonstrating pharmacological rescue with Bz-423.\",\n      \"evidence\": \"Live-cell mPTP flickering assays, SPG7 patient fibroblasts, Spg7⁻/⁻ mouse primary neurons, SIRT3/CypD biochemistry, electrophysiology, and in vivo pharmacological rescue\",\n      \"pmids\": [\"33045469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SIRT3 upregulation is a direct consequence of lost SPG7 protease activity or an indirect compensatory response is unclear\",\n        \"Long-term efficacy and specificity of Bz-423 rescue in vivo not established\",\n        \"Contribution of mPTP flickering defect versus mtDNA maintenance defect to neurodegeneration not disentangled\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relative contributions of SPG7's m-AAA protease activity versus its structural role in the mPTP to neurodegeneration remain unresolved, and the specific protease substrates relevant to disease have not been identified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No protease-dead separation-of-function mutant tested for mPTP activity\",\n        \"In vivo substrate identification for the SPG7-containing m-AAA protease not performed\",\n        \"Structural basis of the SPG7-VDAC-CypD pore complex unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"m-AAA protease complex\",\n      \"mitochondrial permeability transition pore (mPTP)\"\n    ],\n    \"partners\": [\n      \"VDAC\",\n      \"PPIF\",\n      \"AFG3L2\",\n      \"AFG3L1\",\n      \"SIRT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SPG7 (paraplegin) is a subunit of the mitochondrial inner membrane m-AAA protease complex, where it co-assembles with AFG3L2 to perform ATP-dependent proteolysis essential for mitochondrial proteostasis, respiratory chain function, and mitochondrial DNA maintenance [PMID:14623864, PMID:24727571]. The m-AAA protease degrades non-assembled EMRE, thereby preventing constitutively active MCU channels from causing mitochondrial Ca²⁺ overload and neuronal death [PMID:27642048]. SPG7 is also required for transient mPTP flickering through a SIRT3–cyclophilin D acetylation axis; loss of SPG7 impairs mPTP opening, disrupts presynaptic neurotransmitter release, and causes corticospinal neurodegeneration underlying autosomal recessive hereditary spastic paraplegia type 7 and progressive external ophthalmoplegia with multiple mtDNA deletions [PMID:33045469, PMID:9635427, PMID:24727571].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of SPG7 as a nuclear-encoded mitochondrial metalloprotease whose mutations cause hereditary spastic paraplegia established the first link between mitochondrial proteolysis and corticospinal neurodegeneration.\",\n      \"evidence\": \"Immunofluorescence, mitochondrial import assays, patient mutation analysis, and muscle biopsy OXPHOS studies in human cells and patient tissue\",\n      \"pmids\": [\"9635427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease substrates unknown\", \"Assembly state of paraplegin in the inner membrane not defined\", \"Mechanism linking OXPHOS defect to selective neurodegeneration unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that paraplegin co-assembles with AFG3L2 into the m-AAA protease complex resolved the quaternary structure of the active enzyme and linked complex I deficiency and oxidative stress sensitivity to loss of this complex.\",\n      \"evidence\": \"Co-immunoprecipitation, Blue Native PAGE, enzymatic activity assays, yeast complementation, and patient fibroblast studies\",\n      \"pmids\": [\"14623864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates of the human m-AAA protease not yet identified\", \"Relative contribution of homo- vs hetero-oligomeric complexes in different tissues unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extension of the SPG7 disease spectrum to optic neuropathy — including a dominant missense variant — broadened understanding of paraplegin's role beyond spastic paraplegia to visual pathway neurodegeneration.\",\n      \"evidence\": \"MLPA, Sanger sequencing, OCT imaging, and segregation analysis in large pedigrees\",\n      \"pmids\": [\"23065789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical consequence of the Asp411Ala variant not characterized\", \"Mechanism of dominance not established\", \"Limited to genetic and clinical evidence without reconstitution\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that SPG7 mutations cause progressive external ophthalmoplegia with multiple mtDNA deletions revealed a direct role for the m-AAA protease in mitochondrial DNA maintenance.\",\n      \"evidence\": \"Whole exome sequencing, mitochondrial network analysis, single-fibre mtDNA deletion mapping, and deep mtDNA resequencing in patient muscle and fibroblasts\",\n      \"pmids\": [\"24727571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which paraplegin loss leads to mtDNA deletions undefined\", \"Whether mtDNA instability is a primary or secondary consequence of proteostasis failure unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of SPG7 as a core component of the mitochondrial permeability transition pore, interacting with VDAC and cyclophilin D, established an unexpected structural role beyond canonical proteolysis.\",\n      \"evidence\": \"RNAi screen, co-immunoprecipitation of the PTP complex, mitochondrial Ca²⁺ retention capacity assays, ΔΨm measurements, and cell death assays\",\n      \"pmids\": [\"26387735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the mPTP role is separable from the protease catalytic function not determined\", \"Stoichiometry and architecture of the SPG7-VDAC-CypD complex unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of EMRE as a direct m-AAA protease substrate explained how paraplegin loss causes mitochondrial Ca²⁺ overload: unprocessed EMRE generates constitutively active MCU channels lacking MICU1/MICU2 gatekeeper subunits, linking protease activity to Ca²⁺ signaling and neuronal death.\",\n      \"evidence\": \"Neuronal interactome mapping by co-IP/mass spectrometry, EMRE turnover assays, BN-PAGE MCU complex analysis, mitochondrial Ca²⁺ uptake assays, and genetic mouse models\",\n      \"pmids\": [\"27642048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire of the SPG7-containing m-AAA protease beyond EMRE remains unknown\", \"Contribution of MAIP1 (C2ORF47) cofactor to substrate specificity not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dissection of the SIRT3–cyclophilin D axis showed that paraplegin loss upregulates SIRT3, hyperdeacetylates CypD, and thereby impairs transient mPTP flickering — a mechanism directly responsible for defective presynaptic neurotransmitter release; pharmacological bypass with Bz-423 rescued motor deficits in vivo.\",\n      \"evidence\": \"Live-cell mPTP flickering assays, SIRT3 activity and CypD acetylation analysis, electrophysiology of synaptic transmission, and Bz-423 pharmacological rescue in Spg7⁻/⁻ mice\",\n      \"pmids\": [\"33045469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SPG7 loss leads to SIRT3 upregulation is mechanistically unclear\", \"Whether mPTP flickering defect contributes to all SPG7-associated phenotypes (e.g., optic neuropathy, PEO) untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural model explaining how SPG7 participates simultaneously in m-AAA protease catalysis and mPTP regulation — and whether these are separable or interdependent functions — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the human SPG7-AFG3L2 m-AAA complex\", \"Complete substrate catalog of the m-AAA protease not established\", \"Mechanism linking paraplegin loss to mtDNA instability remains undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"m-AAA protease (SPG7-AFG3L2)\",\n      \"mPTP (SPG7-VDAC-CypD)\"\n    ],\n    \"partners\": [\n      \"AFG3L2\",\n      \"PPIF\",\n      \"VDAC1\",\n      \"EMRE\",\n      \"MAIP1\",\n      \"SIRT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}