{"gene":"TTR","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2012,"finding":"TTR forms two thyroxine (T4) binding sites at the center of the dimer-dimer interface and contains retinol-binding protein (holo-RBP) binding sites on both faces of the tetramer, as revealed by nearly 200 X-ray crystal structures of TTR and its complexes.","method":"X-ray crystallography (structural studies of TTR and complexes)","journal":"Current medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — based on nearly 200 independent X-ray crystal structures across multiple labs providing atomic-level structural validation of ligand binding sites","pmids":["22471981"],"is_preprint":false},{"year":2012,"finding":"TTR amyloid fibril formation proceeds via dissociation of the native tetramer into non-native monomers, which then associate into soluble oligomers and protofibrils that evolve into mature amyloid deposits; tetramer dissociation is the rate-limiting step.","method":"In vitro aggregation assays, structural studies, biophysical characterization","journal":"Current medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic model established by multiple independent structural and biochemical studies summarized across nearly 200 crystal structures and in vitro reconstitution experiments","pmids":["22471981","10940233"],"is_preprint":false},{"year":2000,"finding":"TTR T119M and R104H variants confer increased resistance to tetramer dissociation into monomers compared to wild-type TTR, as shown by stability assays; the His104 substitution increases tetramer stability in compound heterozygotes despite lower T4 binding affinity, indicating that tetramer stability and T4 binding affinity are not necessarily correlated.","method":"In vitro stability assays (resistance to dissociation), thyroxine binding studies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assays in a single lab with two orthogonal methods (stability and binding), but single study","pmids":["10772944"],"is_preprint":false},{"year":1993,"finding":"TTR Met119 variant increases T4 binding to TTR due to higher TTR protein concentration rather than an increased association constant; plasma retinol binding protein (RBP), which is almost entirely bound by TTR, is elevated in Met119 carriers, confirming TTR's role in RBP transport.","method":"Serum dialysis with stepwise saturation of iodothyronine binding sites, isoelectric focusing, cyanogen bromide peptide mapping, DNA restriction analysis","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (serum dialysis, protein analysis, DNA analysis) in a single study demonstrating mechanism of T4 and RBP binding","pmids":["8102146"],"is_preprint":false},{"year":1997,"finding":"TTR facilitates retinol uptake from the RBP-TTR complex into primary rat hepatocytes (both parenchymal and non-parenchymal cells); retinol uptake from the RBP-TTR complex was approximately twofold greater than from RBP alone, and excess free TTR inhibited this uptake, suggesting TTR acts as a positive regulator in RBP-bound retinol delivery, possibly via a membrane receptor.","method":"Primary rat hepatocyte cell culture with [3H]retinol-RBP and [3H]retinol-RBP-TTR complexes; HPLC analysis; competition/inhibition experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional cell uptake assay with multiple conditions and competition experiments, single lab","pmids":["9260907"],"is_preprint":false},{"year":2007,"finding":"TTR modulates Aβ deposition in vivo: APPswe/PS1deltaE9 transgenic mice hemizygous for TTR deletion (TTR+/-) showed significantly elevated detergent-soluble and formic acid-soluble Aβ levels and accelerated Aβ deposition in hippocampus and cortex compared to TTR+/+ controls, establishing that TTR plays a critical role in modulating Aβ deposition in vivo.","method":"Genetic ablation (TTR knockout crossed with AD model mice), biochemical Aβ quantification, histological assessment of amyloid deposition","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function (hemizygous KO) with defined quantitative phenotypic readouts (soluble/insoluble Aβ levels and deposition) using two orthogonal methods","pmids":["17596449"],"is_preprint":false},{"year":2014,"finding":"TTR expression in neurons (but not hepatocytes or cardiomyocytes) is regulated by heat shock factor 1 (HSF1): HSF1 occupies TTR promoter heat shock elements in APP23 mouse hippocampus, primary hippocampal neurons, and SH-SY5Y cells (demonstrated by ChIP), and HSF1 overexpression increases TTR transcription and protein production in neurons, an effect blocked by shHSF1 antisense. This neuron-specific regulation is not observed in liver or cardiac cell lines.","method":"Chromatin immunoprecipitation (ChIP), HSF1 overexpression/knockdown (shRNA), heat shock and celastrol treatments, in vivo and in vitro experiments","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP assay directly demonstrating HSF1 occupancy of TTR promoter, combined with gain- and loss-of-function experiments, multiple cell types and in vivo model, single lab with multiple orthogonal methods","pmids":["24849358"],"is_preprint":false},{"year":2011,"finding":"The A25T-TTR mutant tetramer is 3 kcal/mol less thermodynamically stable than L55P-TTR as assessed by pressure-induced dissociation; A25T-TTR forms mature amyloid fibrils after 15 days at 37°C (pH 7.3). In cerebrospinal fluid, A25T-TTR rapidly co-aggregates with 19 partner proteins including clusterin, apolipoprotein E, complement proteins, and blood coagulation proteins.","method":"X-ray crystallography, pressure-induced dissociation (stability assay), in vitro fibrillation assay, proteomics/mass spectrometry of co-aggregated proteins","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — X-ray structure, thermodynamic stability assay, in vitro fibrillation, and proteomics in a single study with multiple orthogonal methods","pmids":["22091638"],"is_preprint":false},{"year":2012,"finding":"TTR has peptidase (proteolytic) activity: it cleaves FRET peptides at multiple sites without strict sequence specificity, is inhibited by metal chelators (ortho-phenanthroline, EDTA) but not classical protease inhibitors, and pH/temperature profiling with proton inventory suggests a carboxylate and an ammonium group (possibly from lysine) are involved in catalysis, supporting a metalloprotease mechanism.","method":"Fluorescence resonance energy transfer (FRET) peptide cleavage assay, inhibitor studies, pH-profile and proton inventory analysis","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with multiple substrates, inhibitor panel, and mechanistic pH/temperature profiling in a single study","pmids":["23000319"],"is_preprint":false},{"year":2013,"finding":"Serum amyloid P component (SAP) binds to early aggregates of amyloidogenic TTR mutants (not just mature fibrils) and prevents TTR aggregate-induced cell death in vitro. In a Drosophila model of TTR amyloidosis, SAP overexpression almost completely reduced TTR-induced abnormal wing posture and protected retinal structure, establishing SAP as a protective factor that attenuates TTR aggregate toxicity in vivo.","method":"In vitro binding assay, cell viability assay, Drosophila transgenic model with genetic cross, retinal histology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (in vitro binding, cell death assay, in vivo Drosophila genetic model, retinal analysis) in a single lab","pmids":["23390551"],"is_preprint":false},{"year":2016,"finding":"TTR V30M aggregates partially impair the autophagic machinery in cell culture (p62 accumulation without blocking early steps such as autophagosome formation or LC3 turnover); in TTR V30M transgenic mice, TUDCA and curcumin reverse p62 accumulation in the GI tract, demonstrating that autophagy impairment is a cellular consequence of TTR V30M aggregates that can be pharmacologically modulated.","method":"Cell culture with TTR V30M aggregates, p62 accumulation assay, LC3 turnover assay, autophagosome counting; in vivo transgenic mouse model with TUDCA/curcumin treatment","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo methods (cell culture, autophagy flux assays, transgenic mouse model) in a single lab","pmids":["27382986"],"is_preprint":false},{"year":1987,"finding":"The human TTR (prealbumin/PALB) gene was mapped to chromosome region 18q11.2-q12.1 using human genomic probes in somatic cell hybrids and in situ hybridization.","method":"Somatic cell hybrid analysis, in situ hybridization","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal methods (somatic cell hybrids and in situ hybridization) used to map the gene, foundational chromosomal localization","pmids":["3028932"],"is_preprint":false},{"year":2018,"finding":"TTR stabilizers (tafamidis, diflunisal) act at the dimer-dimer interface to prevent tetramer dissociation into monomers, which is the initiating step for amyloid fibril formation; treatment with stabilizers was associated with decreased death/orthotopic heart transplant in TTR cardiac amyloidosis patients.","method":"Mechanistic model from structural studies; retrospective clinical cohort study with Cox proportional hazards modeling","journal":"Circulation. Heart failure","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural mechanism well established; clinical evidence is retrospective single-center cohort, not an experimental mechanistic study per se","pmids":["29615436"],"is_preprint":false},{"year":2019,"finding":"Systemically administered TTR siRNA (NTLA-2001/inotersen) reduces blood TTR protein levels and promotes clearance of TTR non-fibrillar deposits in meninges and brain blood vessels in V30M TTR transgenic mice; however, despite striking blood TTR reduction, CSF TTR levels were unaffected, indicating that choroid plexus-derived CSF TTR is produced independently of hepatic plasma TTR.","method":"siRNA systemic administration in transgenic mice, immunohistochemistry of meningeal/vascular TTR deposits, measurement of blood and CSF TTR levels","journal":"Amyloid","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo gene silencing experiment with quantitative protein-level outcomes in multiple compartments, single lab","pmids":["27884058"],"is_preprint":false}],"current_model":"TTR is a homotetrameric plasma and CSF protein that transports thyroxine (T4) via two binding sites at the dimer-dimer interface and facilitates retinol delivery as a complex with retinol-binding protein (RBP); tetramer dissociation into non-native monomers is the rate-limiting step for amyloid fibril formation underlying TTR amyloidoses, and this process is inhibited by small-molecule kinetic stabilizers that bind at the T4 sites; TTR also possesses metallopeptidase activity and sequesters Aβ peptides in vivo, reducing Aβ deposition; in neurons (but not hepatocytes), TTR expression is upregulated by the stress-responsive transcription factor HSF1 via direct occupancy of TTR promoter heat shock elements."},"narrative":{"mechanistic_narrative":"TTR is a homotetrameric transport protein that carries thyroxine (T4) through two binding sites at the center of the dimer-dimer interface and binds retinol-binding protein (holo-RBP) on both faces of the tetramer [PMID:22471981], functioning as a positive regulator of RBP-bound retinol delivery into cells [PMID:8102146, PMID:9260907]. The same dimer-dimer interface that forms the T4 sites is the locus of TTR's pathological behavior: amyloid fibril formation proceeds through rate-limiting dissociation of the native tetramer into non-native monomers that assemble into oligomers, protofibrils, and mature deposits [PMID:22471981, PMID:10940233], and destabilizing mutations such as A25T accelerate this cascade in proportion to their loss of tetramer stability [PMID:22091638]. This mechanistic link is exploited therapeutically by small-molecule kinetic stabilizers (tafamidis, diflunisal) that occupy the T4 sites at the dimer-dimer interface to block dissociation [PMID:29615436], while stabilizing variants such as T119M and R104H confer intrinsic resistance to dissociation, showing tetramer stability is separable from T4 binding affinity [PMID:10772944]. Beyond transport, TTR possesses metal-dependent peptidase activity that cleaves peptides without strict sequence specificity through a metalloprotease mechanism [PMID:23000319], and it modulates amyloid-beta in vivo, with TTR haploinsufficiency accelerating Abeta deposition in an Alzheimer model [PMID:17596449]. TTR expression is compartment-specific: neuronal TTR is transcriptionally induced by the stress-responsive factor HSF1 acting directly at promoter heat shock elements, a regulation absent in hepatocytes and cardiomyocytes [PMID:24849358], and choroid plexus-derived CSF TTR is produced independently of hepatic plasma TTR [PMID:27884058].","teleology":[{"year":1987,"claim":"Establishing the chromosomal locus of human TTR provided the genetic foundation for linking the gene to inherited amyloid disease.","evidence":"somatic cell hybrid analysis and in situ hybridization mapping to 18q11.2-q12.1","pmids":["3028932"],"confidence":"High","gaps":["Localization alone established no protein function or disease mechanism"]},{"year":1993,"claim":"Resolving whether a TTR variant alters T4 handling distinguished concentration effects from intrinsic affinity changes and confirmed TTR's physiological role in RBP transport.","evidence":"serum dialysis, isoelectric focusing, peptide mapping and DNA analysis of Met119 carriers","pmids":["8102146"],"confidence":"Medium","gaps":["Did not resolve the structural basis of the binding sites","Single variant in human carriers"]},{"year":1997,"claim":"Showing TTR enhances cellular retinol uptake from the RBP-TTR complex established TTR as an active facilitator rather than a passive carrier in retinol delivery.","evidence":"primary rat hepatocyte uptake assays with labeled retinol complexes and competition experiments","pmids":["9260907"],"confidence":"Medium","gaps":["The putative membrane receptor mediating uptake was not identified","Demonstrated in rat hepatocytes only"]},{"year":2000,"claim":"Demonstrating that stabilizing variants resist dissociation while differing in T4 affinity showed tetramer stability and ligand binding are mechanistically separable, a key principle for stabilizer design.","evidence":"in vitro dissociation-resistance stability assays and T4 binding studies of T119M and R104H","pmids":["10772944"],"confidence":"Medium","gaps":["Single-lab in vitro study","Did not establish in vivo protection from amyloidosis"]},{"year":2011,"claim":"Linking the thermodynamic instability of A25T-TTR to fibril formation and CSF co-aggregation defined how destabilizing mutations drive the amyloid cascade and engage partner proteins.","evidence":"X-ray crystallography, pressure-induced dissociation, in vitro fibrillation, and proteomics of co-aggregates","pmids":["22091638"],"confidence":"High","gaps":["Functional consequence of co-aggregation with the 19 partner proteins not established","Relevance of CSF co-aggregation to in vivo disease unresolved"]},{"year":2012,"claim":"Crystallographic resolution of the T4 and holo-RBP binding sites and consolidation of the dissociation-driven amyloid model unified TTR's transport and pathological mechanisms onto the dimer-dimer interface.","evidence":"synthesis of nearly 200 X-ray crystal structures of TTR and complexes, plus in vitro aggregation and biophysical characterization","pmids":["22471981","10940233"],"confidence":"High","gaps":["Structures do not capture transient oligomeric/protofibril intermediates","Did not address tissue-specific regulation"]},{"year":2012,"claim":"Identifying intrinsic metal-dependent peptidase activity revealed a catalytic function for TTR beyond ligand transport.","evidence":"FRET peptide cleavage assays, metal chelator inhibition, and pH/proton-inventory mechanistic profiling","pmids":["23000319"],"confidence":"Medium","gaps":["Physiological substrates not identified","Catalytic metal and active-site residues not definitively assigned"]},{"year":2007,"claim":"Genetic ablation experiments established that TTR modulates Abeta deposition in vivo, extending its role to Alzheimer-relevant proteostasis.","evidence":"TTR hemizygous knockout crossed with APPswe/PS1deltaE9 mice, biochemical Abeta quantification and histology","pmids":["17596449"],"confidence":"High","gaps":["Molecular mechanism by which TTR limits Abeta deposition not resolved","Relationship to TTR's own aggregation propensity unclear"]},{"year":2013,"claim":"Demonstrating that SAP binds early TTR aggregates and rescues toxicity in vitro and in flies identified a protective modifier of TTR aggregate toxicity.","evidence":"in vitro binding and cell viability assays plus a Drosophila TTR amyloidosis model with retinal histology","pmids":["23390551"],"confidence":"Medium","gaps":["Mechanism of SAP-mediated protection not defined","Human relevance of the fly model phenotype not established"]},{"year":2014,"claim":"Identifying HSF1 as a direct, neuron-specific transcriptional activator of TTR explained compartment-restricted TTR induction under stress.","evidence":"ChIP for HSF1 occupancy of TTR promoter heat shock elements with HSF1 gain/loss-of-function across neuronal cells and APP23 mice","pmids":["24849358"],"confidence":"High","gaps":["Upstream signals activating HSF1 at the TTR promoter not defined","Functional outcome of elevated neuronal TTR not quantified"]},{"year":2016,"claim":"Linking TTR V30M aggregates to selective autophagy impairment defined a cellular pathology that is pharmacologically reversible.","evidence":"p62 accumulation and LC3 turnover assays in cells plus TUDCA/curcumin treatment in V30M transgenic mice","pmids":["27382986"],"confidence":"Medium","gaps":["Molecular step in autophagy targeted by aggregates not pinpointed","Single-lab study"]},{"year":2018,"claim":"Connecting interface-binding kinetic stabilizers to improved clinical outcomes validated the dissociation model as a therapeutic target in cardiac amyloidosis.","evidence":"structural mechanism of tafamidis/diflunisal at the dimer-dimer interface combined with a retrospective clinical cohort","pmids":["29615436"],"confidence":"Medium","gaps":["Clinical evidence is retrospective single-center","Not a prospective mechanistic intervention study"]},{"year":2019,"claim":"Systemic TTR knockdown that cleared peripheral deposits but left CSF TTR unchanged established that choroid plexus CSF TTR is produced independently of hepatic plasma TTR.","evidence":"systemic TTR siRNA in V30M transgenic mice with immunohistochemistry and blood/CSF TTR measurement","pmids":["27884058"],"confidence":"Medium","gaps":["Did not establish whether CSF TTR contributes to or protects against CNS amyloid","Single transgenic model"]},{"year":null,"claim":"The physiological substrates of TTR's metalloprotease activity and the molecular mechanism by which TTR limits Abeta and engages aggregate-modifying partners remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No endogenous peptidase substrate identified","Mechanism of TTR-Abeta interaction in vivo not defined","Receptor mediating RBP-TTR retinol uptake unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[8]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,13]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,7,12]}],"complexes":["TTR homotetramer","RBP-TTR complex"],"partners":["RBP4","APP","APCS","HSF1","CLU","APOE"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02766","full_name":"Transthyretin","aliases":["ATTR","Prealbumin","TBPA"],"length_aa":147,"mass_kda":15.9,"function":"Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain","subcellular_location":"Secreted; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P02766/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TTR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TTR","total_profiled":1310},"omim":[{"mim_id":"611294","title":"ONE CUT HOMEOBOX 3; ONECUT3","url":"https://www.omim.org/entry/611294"},{"mim_id":"610619","title":"COAGULATION FACTOR XII; F12","url":"https://www.omim.org/entry/610619"},{"mim_id":"606464","title":"HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP","url":"https://www.omim.org/entry/606464"},{"mim_id":"604164","title":"ONE CUT HOMEOBOX 1; ONECUT1","url":"https://www.omim.org/entry/604164"},{"mim_id":"600388","title":"MEPRIN, ALPHA SUBUNIT; MEP1A","url":"https://www.omim.org/entry/600388"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":672504.5}],"url":"https://www.proteinatlas.org/search/TTR"},"hgnc":{"alias_symbol":["HsT2651","CTS"],"prev_symbol":["PALB","CTS1"]},"alphafold":{"accession":"P02766","domains":[{"cath_id":"2.60.40.180","chopping":"31-141","consensus_level":"high","plddt":97.838,"start":31,"end":141}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02766","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02766-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02766-F1-predicted_aligned_error_v6.png","plddt_mean":88.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TTR","jax_strain_url":"https://www.jax.org/strain/search?query=TTR"},"sequence":{"accession":"P02766","fasta_url":"https://rest.uniprot.org/uniprotkb/P02766.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02766/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02766"}},"corpus_meta":[{"pmid":"15249622","id":"PMC_15249622","title":"Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy.","date":"2004","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15249622","citation_count":191,"is_preprint":false},{"pmid":"17698792","id":"PMC_17698792","title":"Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP).","date":"2007","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17698792","citation_count":181,"is_preprint":false},{"pmid":"26734951","id":"PMC_26734951","title":"Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP.","date":"2016","source":"Current opinion in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26734951","citation_count":174,"is_preprint":false},{"pmid":"30793974","id":"PMC_30793974","title":"Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations.","date":"2019","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/30793974","citation_count":154,"is_preprint":false},{"pmid":"26123279","id":"PMC_26123279","title":"Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans.","date":"2015","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/26123279","citation_count":144,"is_preprint":false},{"pmid":"17596449","id":"PMC_17596449","title":"Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin).","date":"2007","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17596449","citation_count":115,"is_preprint":false},{"pmid":"20526330","id":"PMC_20526330","title":"Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor.","date":"2010","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20526330","citation_count":101,"is_preprint":false},{"pmid":"8960746","id":"PMC_8960746","title":"Familial meningocerebrovascular amyloidosis, Hungarian type, with mutant transthyretin (TTR Asp18Gly).","date":"1996","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/8960746","citation_count":83,"is_preprint":false},{"pmid":"29615436","id":"PMC_29615436","title":"TTR (Transthyretin) Stabilizers Are Associated With Improved Survival in Patients With TTR Cardiac Amyloidosis.","date":"2018","source":"Circulation. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/29615436","citation_count":81,"is_preprint":false},{"pmid":"10517323","id":"PMC_10517323","title":"Regulated nuclear localisation of the yeast transcription factor Ace2p controls expression of chitinase (CTS1) in Saccharomyces cerevisiae.","date":"1999","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/10517323","citation_count":79,"is_preprint":false},{"pmid":"16214381","id":"PMC_16214381","title":"Candida albicans CHT3 encodes the functional homolog of the Cts1 chitinase of Saccharomyces cerevisiae.","date":"2005","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/16214381","citation_count":76,"is_preprint":false},{"pmid":"22727702","id":"PMC_22727702","title":"CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine expression on apoptotic and phagocytic cells.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22727702","citation_count":74,"is_preprint":false},{"pmid":"31499118","id":"PMC_31499118","title":"LncRNA-CTS promotes metastasis and epithelial-to-mesenchymal transition through regulating miR-505/ZEB2 axis in cervical cancer.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/31499118","citation_count":73,"is_preprint":false},{"pmid":"27858761","id":"PMC_27858761","title":"Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP): A Single-Center Experience in Sicily, an Italian Endemic Area.","date":"2015","source":"Journal of neuromuscular diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27858761","citation_count":73,"is_preprint":false},{"pmid":"28906150","id":"PMC_28906150","title":"Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy.","date":"2017","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/28906150","citation_count":70,"is_preprint":false},{"pmid":"34461737","id":"PMC_34461737","title":"Prevalence and Outcomes of p.Val142Ile TTR Amyloidosis Cardiomyopathy: A Systematic Review.","date":"2021","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34461737","citation_count":69,"is_preprint":false},{"pmid":"26870387","id":"PMC_26870387","title":"Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy.","date":"2016","source":"Open heart","url":"https://pubmed.ncbi.nlm.nih.gov/26870387","citation_count":66,"is_preprint":false},{"pmid":"22471981","id":"PMC_22471981","title":"Nearly 200 X-ray crystal structures of transthyretin: what do they tell us about this protein and the design of drugs for TTR amyloidoses?","date":"2012","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22471981","citation_count":65,"is_preprint":false},{"pmid":"10940233","id":"PMC_10940233","title":"Review: TTR amyloidosis-structural features leading to protein aggregation and their implications on therapeutic strategies.","date":"2000","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/10940233","citation_count":64,"is_preprint":false},{"pmid":"9745020","id":"PMC_9745020","title":"Ace2p, a regulator of CTS1 (chitinase) expression, affects pseudohyphal production in Saccharomyces cerevisiae.","date":"1998","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9745020","citation_count":61,"is_preprint":false},{"pmid":"25012480","id":"PMC_25012480","title":"Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials.","date":"2014","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25012480","citation_count":60,"is_preprint":false},{"pmid":"22446315","id":"PMC_22446315","title":"Applying unconventional secretion of the endochitinase Cts1 to export heterologous proteins in Ustilago maydis.","date":"2012","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22446315","citation_count":58,"is_preprint":false},{"pmid":"10772944","id":"PMC_10772944","title":"Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119M.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10772944","citation_count":53,"is_preprint":false},{"pmid":"30829617","id":"PMC_30829617","title":"Clinical Presentation, Diagnosis and Treatment of TTR Amyloidosis.","date":"2019","source":"Journal of neuromuscular diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30829617","citation_count":51,"is_preprint":false},{"pmid":"19056728","id":"PMC_19056728","title":"Physiological involvement in pH signaling of Vps24-mediated recruitment of Aspergillus PalB cysteine protease to ESCRT-III.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19056728","citation_count":50,"is_preprint":false},{"pmid":"32456156","id":"PMC_32456156","title":"The Positive Side of the Alzheimer's Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1.","date":"2020","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32456156","citation_count":49,"is_preprint":false},{"pmid":"21808052","id":"PMC_21808052","title":"The RNA-binding protein Rrm4 is essential for efficient secretion of endochitinase Cts1.","date":"2011","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/21808052","citation_count":48,"is_preprint":false},{"pmid":"23064344","id":"PMC_23064344","title":"Promoter swapping unveils the role of the Citrobacter rodentium CTS1 type VI secretion system in interbacterial competition.","date":"2012","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23064344","citation_count":48,"is_preprint":false},{"pmid":"26800456","id":"PMC_26800456","title":"TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies.","date":"2016","source":"Expert opinion on pharmacotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/26800456","citation_count":46,"is_preprint":false},{"pmid":"3028932","id":"PMC_3028932","title":"Assignment of the prealbumin (PALB) gene (familial amyloidotic polyneuropathy) to human chromosome region 18q11.2-q12.1.","date":"1987","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3028932","citation_count":45,"is_preprint":false},{"pmid":"24849358","id":"PMC_24849358","title":"The systemic amyloid precursor transthyretin (TTR) behaves as a neuronal stress protein regulated by HSF1 in SH-SY5Y human neuroblastoma cells and APP23 Alzheimer's disease model mice.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24849358","citation_count":45,"is_preprint":false},{"pmid":"22592564","id":"PMC_22592564","title":"TTR-related amyloid neuropathy: clinical, electrophysiological and pathological findings in 15 unrelated patients.","date":"2012","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/22592564","citation_count":45,"is_preprint":false},{"pmid":"8566773","id":"PMC_8566773","title":"Isolation and characterization of two chitinase-encoding genes (cts1, cts2) from the fungus Coccidioides immitis.","date":"1995","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8566773","citation_count":42,"is_preprint":false},{"pmid":"14555485","id":"PMC_14555485","title":"Phospholipid-binding protein Cts1 controls septation and functions coordinately with calcineurin in Cryptococcus neoformans.","date":"2003","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/14555485","citation_count":39,"is_preprint":false},{"pmid":"30328212","id":"PMC_30328212","title":"Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30328212","citation_count":38,"is_preprint":false},{"pmid":"27652282","id":"PMC_27652282","title":"The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa.","date":"2016","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27652282","citation_count":38,"is_preprint":false},{"pmid":"1301926","id":"PMC_1301926","title":"Two transthyretin variants (TTR Ala-49 and TTR Gln-89) in two Sicilian kindreds with hereditary amyloidosis.","date":"1992","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/1301926","citation_count":35,"is_preprint":false},{"pmid":"8102146","id":"PMC_8102146","title":"Thyroxine binding in a TTR Met 119 kindred.","date":"1993","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/8102146","citation_count":34,"is_preprint":false},{"pmid":"33555371","id":"PMC_33555371","title":"In vitro human cell-based TTR-TRβ CALUX assay indicates thyroid hormone transport disruption of short-chain, medium-chain, and long-chain chlorinated paraffins.","date":"2021","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33555371","citation_count":34,"is_preprint":false},{"pmid":"36566436","id":"PMC_36566436","title":"In silico analysis decodes transthyretin (TTR) binding and thyroid disrupting effects of per- and polyfluoroalkyl substances (PFAS).","date":"2022","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36566436","citation_count":33,"is_preprint":false},{"pmid":"19493541","id":"PMC_19493541","title":"Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met.","date":"2009","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19493541","citation_count":33,"is_preprint":false},{"pmid":"32623307","id":"PMC_32623307","title":"Heavy metal ions' poisoning behavior-inspired etched UiO-66/CTS aerogel for Pb(II) and Cd(II) removal from aqueous and apple juice.","date":"2020","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/32623307","citation_count":32,"is_preprint":false},{"pmid":"22091638","id":"PMC_22091638","title":"Dissecting the structure, thermodynamic stability, and aggregation properties of the A25T transthyretin (A25T-TTR) variant involved in leptomeningeal amyloidosis: identifying protein partners that co-aggregate during A25T-TTR fibrillogenesis in cerebrospinal fluid.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22091638","citation_count":30,"is_preprint":false},{"pmid":"18830126","id":"PMC_18830126","title":"Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid.","date":"2009","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18830126","citation_count":30,"is_preprint":false},{"pmid":"36198883","id":"PMC_36198883","title":"Neuropathology of central nervous system involvement in TTR amyloidosis.","date":"2022","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/36198883","citation_count":29,"is_preprint":false},{"pmid":"31923516","id":"PMC_31923516","title":"Fabrication and in-vitro biocompatibility of freeze-dried CTS-nHA and CTS-nBG scaffolds for bone regeneration applications.","date":"2020","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31923516","citation_count":29,"is_preprint":false},{"pmid":"19403647","id":"PMC_19403647","title":"Antibodies to protein tyrosine phosphatase receptor type O (PTPro) increase glomerular albumin permeability (P(alb)).","date":"2009","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19403647","citation_count":29,"is_preprint":false},{"pmid":"29609043","id":"PMC_29609043","title":"Evaluation of HE4 and TTR for diagnosis of ovarian cancer: Comparison with CA-125.","date":"2018","source":"Journal of gynecology obstetrics and human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/29609043","citation_count":28,"is_preprint":false},{"pmid":"29346382","id":"PMC_29346382","title":"6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29346382","citation_count":28,"is_preprint":false},{"pmid":"37928601","id":"PMC_37928601","title":"Lessons from the first-in-human in vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 trial in patients with transthyretin amyloidosis with cardiomyopathy.","date":"2023","source":"Global cardiology science & practice","url":"https://pubmed.ncbi.nlm.nih.gov/37928601","citation_count":28,"is_preprint":false},{"pmid":"9421473","id":"PMC_9421473","title":"CTS1: a p53-derived chimeric tumor suppressor gene with enhanced in vitro apoptotic properties.","date":"1998","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9421473","citation_count":27,"is_preprint":false},{"pmid":"21985967","id":"PMC_21985967","title":"Transcription of Aspergillus nidulans pacC is modulated by alternative RNA splicing of palB.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21985967","citation_count":27,"is_preprint":false},{"pmid":"25135109","id":"PMC_25135109","title":"Regulating drug release from pH- and temperature-responsive electrospun CTS-g-PNIPAAm/poly(ethylene oxide) hydrogel nanofibers.","date":"2014","source":"Biomedical materials (Bristol, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25135109","citation_count":26,"is_preprint":false},{"pmid":"28635949","id":"PMC_28635949","title":"Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/28635949","citation_count":25,"is_preprint":false},{"pmid":"26156087","id":"PMC_26156087","title":"Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia.","date":"2015","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/26156087","citation_count":25,"is_preprint":false},{"pmid":"19624765","id":"PMC_19624765","title":"Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse.","date":"2009","source":"Hepatology research : the official journal of the Japan Society of Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/19624765","citation_count":24,"is_preprint":false},{"pmid":"26437390","id":"PMC_26437390","title":"Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis.","date":"2015","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/26437390","citation_count":23,"is_preprint":false},{"pmid":"30169969","id":"PMC_30169969","title":"Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial.","date":"2018","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/30169969","citation_count":23,"is_preprint":false},{"pmid":"22471984","id":"PMC_22471984","title":"TTR fibril formation inhibitors: is there a SAR?","date":"2012","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22471984","citation_count":22,"is_preprint":false},{"pmid":"8904886","id":"PMC_8904886","title":"A novel human leukaemic cell line, CTS, has a t(6;11) chromosomal translocation and characteristics of pluripotent stem cells.","date":"1996","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/8904886","citation_count":22,"is_preprint":false},{"pmid":"30934952","id":"PMC_30934952","title":"Structural Stabilization of Human Transthyretin by Centella asiatica (L.) Urban Extract: Implications for TTR Amyloidosis.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30934952","citation_count":22,"is_preprint":false},{"pmid":"32578459","id":"PMC_32578459","title":"TTR gene silencing therapy in post liver transplant hereditary ATTR amyloidosis patients.","date":"2020","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/32578459","citation_count":21,"is_preprint":false},{"pmid":"31353960","id":"PMC_31353960","title":"Founder effect of the Glu89Gln TTR mutation in the Bulgarian population.","date":"2019","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/31353960","citation_count":20,"is_preprint":false},{"pmid":"30782931","id":"PMC_30782931","title":"Specific growth rates calculated from CTs in patients with head and neck squamous cell carcinoma: a retrospective study performed in Austria.","date":"2019","source":"BMJ open","url":"https://pubmed.ncbi.nlm.nih.gov/30782931","citation_count":20,"is_preprint":false},{"pmid":"27238058","id":"PMC_27238058","title":"Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey.","date":"2016","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/27238058","citation_count":20,"is_preprint":false},{"pmid":"35730447","id":"PMC_35730447","title":"A natural history analysis of asymptomatic TTR gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS).","date":"2022","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/35730447","citation_count":20,"is_preprint":false},{"pmid":"32954271","id":"PMC_32954271","title":"Clinicopathological correlations of sural nerve biopsies in TTR Val30Met familial amyloid polyneuropathy.","date":"2019","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/32954271","citation_count":20,"is_preprint":false},{"pmid":"12885170","id":"PMC_12885170","title":"The Saccharomyces cerevisiae chitinase, encoded by the CTS1-2 gene, confers antifungal activity against Botrytis cinerea to transgenic tobacco.","date":"2003","source":"Transgenic research","url":"https://pubmed.ncbi.nlm.nih.gov/12885170","citation_count":20,"is_preprint":false},{"pmid":"9260907","id":"PMC_9260907","title":"Interactions of transthyretin (TTR) and retinol-binding protein (RBP) in the uptake of retinol by primary rat hepatocytes.","date":"1997","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/9260907","citation_count":19,"is_preprint":false},{"pmid":"22002655","id":"PMC_22002655","title":"The C2 domain protein Cts1 functions in the calcineurin signaling circuit during high-temperature stress responses in Cryptococcus neoformans.","date":"2011","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/22002655","citation_count":17,"is_preprint":false},{"pmid":"31541162","id":"PMC_31541162","title":"Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31541162","citation_count":17,"is_preprint":false},{"pmid":"22074589","id":"PMC_22074589","title":"Residual HIV-1 DNA Flap-independent nuclear import of cPPT/CTS double mutant viruses does not support spreading infection.","date":"2011","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/22074589","citation_count":17,"is_preprint":false},{"pmid":"7633183","id":"PMC_7633183","title":"TTR exon scanning in peripheral neuropathies.","date":"1995","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/7633183","citation_count":16,"is_preprint":false},{"pmid":"25510352","id":"PMC_25510352","title":"Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation.","date":"2014","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/25510352","citation_count":16,"is_preprint":false},{"pmid":"22471983","id":"PMC_22471983","title":"Methods to evaluate the inhibition of TTR fibrillogenesis induced by small ligands.","date":"2012","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22471983","citation_count":15,"is_preprint":false},{"pmid":"28335735","id":"PMC_28335735","title":"Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis.","date":"2017","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/28335735","citation_count":15,"is_preprint":false},{"pmid":"32456532","id":"PMC_32456532","title":"DISCOVERY: prevalence of transthyretin (TTR) mutations in a US-centric patient population suspected of having cardiac amyloidosis.","date":"2020","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/32456532","citation_count":15,"is_preprint":false},{"pmid":"38626647","id":"PMC_38626647","title":"Targeting TNF-α-induced expression of TTR and RAGE in rheumatoid arthritis: Apigenin's mediated therapeutic approach.","date":"2024","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/38626647","citation_count":14,"is_preprint":false},{"pmid":"30274077","id":"PMC_30274077","title":"Self-assembling peptide and nHA/CTS composite scaffolds promote bone regeneration through increasing seed cell adhesion.","date":"2018","source":"Materials science & engineering. C, Materials for biological applications","url":"https://pubmed.ncbi.nlm.nih.gov/30274077","citation_count":14,"is_preprint":false},{"pmid":"24779883","id":"PMC_24779883","title":"In silico analysis of TTR gene (coding and non-coding regions, and interactive network) and its implications in transthyretin-related amyloidosis.","date":"2014","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/24779883","citation_count":14,"is_preprint":false},{"pmid":"34500767","id":"PMC_34500767","title":"Chitosan (CTS) Alleviates Heat-Induced Leaf Senescence in Creeping Bentgrass by Regulating Chlorophyll Metabolism, Antioxidant Defense, and the Heat Shock Pathway.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34500767","citation_count":14,"is_preprint":false},{"pmid":"22149423","id":"PMC_22149423","title":"Technetium pyrophosphate myocardial uptake and peripheral neuropathy in a rare variant of familial transthyretin (TTR) amyloidosis (Ser23Asn): a case report and literature review.","date":"2011","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/22149423","citation_count":14,"is_preprint":false},{"pmid":"32733418","id":"PMC_32733418","title":"A Novel Factor Essential for Unconventional Secretion of Chitinase Cts1.","date":"2020","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32733418","citation_count":13,"is_preprint":false},{"pmid":"31554435","id":"PMC_31554435","title":"Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy.","date":"2019","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/31554435","citation_count":13,"is_preprint":false},{"pmid":"17980738","id":"PMC_17980738","title":"Oculoleptomeningeal amyloidosis in a patient with a TTR Val30Gly mutation in the transthyretin gene.","date":"2007","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/17980738","citation_count":13,"is_preprint":false},{"pmid":"31659433","id":"PMC_31659433","title":"Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses.","date":"2019","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31659433","citation_count":13,"is_preprint":false},{"pmid":"27382986","id":"PMC_27382986","title":"Impairment of autophagy by TTR V30M aggregates: in vivo reversal by TUDCA and curcumin.","date":"2016","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/27382986","citation_count":12,"is_preprint":false},{"pmid":"25382970","id":"PMC_25382970","title":"Curcumin could reduce the monomer of TTR with Tyr114Cys mutation via autophagy in cell model of familial amyloid polyneuropathy.","date":"2014","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/25382970","citation_count":12,"is_preprint":false},{"pmid":"10830726","id":"PMC_10830726","title":"Cancer gene therapy mediated by CTS1, a p53 derivative: advantage over wild-type p53 in growth inhibition of human tumors overexpressing MDM2.","date":"2000","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/10830726","citation_count":12,"is_preprint":false},{"pmid":"34862928","id":"PMC_34862928","title":"Metformin-loaded β-TCP/CTS/SBA-15 composite scaffolds promote alveolar bone regeneration in a rat model of periodontitis.","date":"2021","source":"Journal of materials science. Materials in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34862928","citation_count":12,"is_preprint":false},{"pmid":"22311483","id":"PMC_22311483","title":"[Identification of a TTR gene mutation in a family with hereditary vitreous amyloidosis].","date":"2012","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22311483","citation_count":12,"is_preprint":false},{"pmid":"16276348","id":"PMC_16276348","title":"PCTAIRE3: a putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells.","date":"2006","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/16276348","citation_count":12,"is_preprint":false},{"pmid":"26975390","id":"PMC_26975390","title":"The transcription factor Ace2 and its paralog Swi5 regulate ethanol production during static fermentation through their targets Cts1 and Rps4a in Saccharomyces cerevisiae.","date":"2016","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/26975390","citation_count":11,"is_preprint":false},{"pmid":"34337097","id":"PMC_34337097","title":"Development of a Quantitative Antigen Assay to Detect Coccidioidal Chitinase-1 (CTS1) in Human Serum.","date":"2021","source":"Open forum infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34337097","citation_count":11,"is_preprint":false},{"pmid":"23390551","id":"PMC_23390551","title":"Inhibition of TTR aggregation-induced cell death--a new role for serum amyloid P component.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23390551","citation_count":11,"is_preprint":false},{"pmid":"22928869","id":"PMC_22928869","title":"Familial amyloidosis with polyneuropathy associated with TTR Ser50Arg mutation.","date":"2012","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/22928869","citation_count":11,"is_preprint":false},{"pmid":"27884058","id":"PMC_27884058","title":"Efficiency of silencing RNA for removal of transthyretin V30M in a TTR leptomeningeal animal model.","date":"2016","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis","url":"https://pubmed.ncbi.nlm.nih.gov/27884058","citation_count":11,"is_preprint":false},{"pmid":"23000319","id":"PMC_23000319","title":"Studies on the peptidase activity of transthyretin (TTR).","date":"2012","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/23000319","citation_count":11,"is_preprint":false},{"pmid":"7581026","id":"PMC_7581026","title":"Does gene palB regulate the transcription or the post-translational modification of Pi-repressible phosphatases of Aspergillus nidulans?","date":"1995","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/7581026","citation_count":10,"is_preprint":false},{"pmid":"31720756","id":"PMC_31720756","title":"Non-genetic factors and polymorphisms in genes CYP2C9 and VKORC1: predictive algorithms for TTR in Brazilian patients on warfarin.","date":"2019","source":"European journal of clinical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31720756","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50336,"output_tokens":3578,"usd":0.102339,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11290,"output_tokens":3845,"usd":0.076287,"stage2_stop_reason":"end_turn"},"total_usd":0.178626,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"TTR forms two thyroxine (T4) binding sites at the center of the dimer-dimer interface and contains retinol-binding protein (holo-RBP) binding sites on both faces of the tetramer, as revealed by nearly 200 X-ray crystal structures of TTR and its complexes.\",\n      \"method\": \"X-ray crystallography (structural studies of TTR and complexes)\",\n      \"journal\": \"Current medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — based on nearly 200 independent X-ray crystal structures across multiple labs providing atomic-level structural validation of ligand binding sites\",\n      \"pmids\": [\"22471981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TTR amyloid fibril formation proceeds via dissociation of the native tetramer into non-native monomers, which then associate into soluble oligomers and protofibrils that evolve into mature amyloid deposits; tetramer dissociation is the rate-limiting step.\",\n      \"method\": \"In vitro aggregation assays, structural studies, biophysical characterization\",\n      \"journal\": \"Current medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic model established by multiple independent structural and biochemical studies summarized across nearly 200 crystal structures and in vitro reconstitution experiments\",\n      \"pmids\": [\"22471981\", \"10940233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TTR T119M and R104H variants confer increased resistance to tetramer dissociation into monomers compared to wild-type TTR, as shown by stability assays; the His104 substitution increases tetramer stability in compound heterozygotes despite lower T4 binding affinity, indicating that tetramer stability and T4 binding affinity are not necessarily correlated.\",\n      \"method\": \"In vitro stability assays (resistance to dissociation), thyroxine binding studies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assays in a single lab with two orthogonal methods (stability and binding), but single study\",\n      \"pmids\": [\"10772944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"TTR Met119 variant increases T4 binding to TTR due to higher TTR protein concentration rather than an increased association constant; plasma retinol binding protein (RBP), which is almost entirely bound by TTR, is elevated in Met119 carriers, confirming TTR's role in RBP transport.\",\n      \"method\": \"Serum dialysis with stepwise saturation of iodothyronine binding sites, isoelectric focusing, cyanogen bromide peptide mapping, DNA restriction analysis\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (serum dialysis, protein analysis, DNA analysis) in a single study demonstrating mechanism of T4 and RBP binding\",\n      \"pmids\": [\"8102146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TTR facilitates retinol uptake from the RBP-TTR complex into primary rat hepatocytes (both parenchymal and non-parenchymal cells); retinol uptake from the RBP-TTR complex was approximately twofold greater than from RBP alone, and excess free TTR inhibited this uptake, suggesting TTR acts as a positive regulator in RBP-bound retinol delivery, possibly via a membrane receptor.\",\n      \"method\": \"Primary rat hepatocyte cell culture with [3H]retinol-RBP and [3H]retinol-RBP-TTR complexes; HPLC analysis; competition/inhibition experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional cell uptake assay with multiple conditions and competition experiments, single lab\",\n      \"pmids\": [\"9260907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TTR modulates Aβ deposition in vivo: APPswe/PS1deltaE9 transgenic mice hemizygous for TTR deletion (TTR+/-) showed significantly elevated detergent-soluble and formic acid-soluble Aβ levels and accelerated Aβ deposition in hippocampus and cortex compared to TTR+/+ controls, establishing that TTR plays a critical role in modulating Aβ deposition in vivo.\",\n      \"method\": \"Genetic ablation (TTR knockout crossed with AD model mice), biochemical Aβ quantification, histological assessment of amyloid deposition\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function (hemizygous KO) with defined quantitative phenotypic readouts (soluble/insoluble Aβ levels and deposition) using two orthogonal methods\",\n      \"pmids\": [\"17596449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TTR expression in neurons (but not hepatocytes or cardiomyocytes) is regulated by heat shock factor 1 (HSF1): HSF1 occupies TTR promoter heat shock elements in APP23 mouse hippocampus, primary hippocampal neurons, and SH-SY5Y cells (demonstrated by ChIP), and HSF1 overexpression increases TTR transcription and protein production in neurons, an effect blocked by shHSF1 antisense. This neuron-specific regulation is not observed in liver or cardiac cell lines.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), HSF1 overexpression/knockdown (shRNA), heat shock and celastrol treatments, in vivo and in vitro experiments\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP assay directly demonstrating HSF1 occupancy of TTR promoter, combined with gain- and loss-of-function experiments, multiple cell types and in vivo model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24849358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The A25T-TTR mutant tetramer is 3 kcal/mol less thermodynamically stable than L55P-TTR as assessed by pressure-induced dissociation; A25T-TTR forms mature amyloid fibrils after 15 days at 37°C (pH 7.3). In cerebrospinal fluid, A25T-TTR rapidly co-aggregates with 19 partner proteins including clusterin, apolipoprotein E, complement proteins, and blood coagulation proteins.\",\n      \"method\": \"X-ray crystallography, pressure-induced dissociation (stability assay), in vitro fibrillation assay, proteomics/mass spectrometry of co-aggregated proteins\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — X-ray structure, thermodynamic stability assay, in vitro fibrillation, and proteomics in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"22091638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TTR has peptidase (proteolytic) activity: it cleaves FRET peptides at multiple sites without strict sequence specificity, is inhibited by metal chelators (ortho-phenanthroline, EDTA) but not classical protease inhibitors, and pH/temperature profiling with proton inventory suggests a carboxylate and an ammonium group (possibly from lysine) are involved in catalysis, supporting a metalloprotease mechanism.\",\n      \"method\": \"Fluorescence resonance energy transfer (FRET) peptide cleavage assay, inhibitor studies, pH-profile and proton inventory analysis\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with multiple substrates, inhibitor panel, and mechanistic pH/temperature profiling in a single study\",\n      \"pmids\": [\"23000319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Serum amyloid P component (SAP) binds to early aggregates of amyloidogenic TTR mutants (not just mature fibrils) and prevents TTR aggregate-induced cell death in vitro. In a Drosophila model of TTR amyloidosis, SAP overexpression almost completely reduced TTR-induced abnormal wing posture and protected retinal structure, establishing SAP as a protective factor that attenuates TTR aggregate toxicity in vivo.\",\n      \"method\": \"In vitro binding assay, cell viability assay, Drosophila transgenic model with genetic cross, retinal histology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (in vitro binding, cell death assay, in vivo Drosophila genetic model, retinal analysis) in a single lab\",\n      \"pmids\": [\"23390551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TTR V30M aggregates partially impair the autophagic machinery in cell culture (p62 accumulation without blocking early steps such as autophagosome formation or LC3 turnover); in TTR V30M transgenic mice, TUDCA and curcumin reverse p62 accumulation in the GI tract, demonstrating that autophagy impairment is a cellular consequence of TTR V30M aggregates that can be pharmacologically modulated.\",\n      \"method\": \"Cell culture with TTR V30M aggregates, p62 accumulation assay, LC3 turnover assay, autophagosome counting; in vivo transgenic mouse model with TUDCA/curcumin treatment\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo methods (cell culture, autophagy flux assays, transgenic mouse model) in a single lab\",\n      \"pmids\": [\"27382986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The human TTR (prealbumin/PALB) gene was mapped to chromosome region 18q11.2-q12.1 using human genomic probes in somatic cell hybrids and in situ hybridization.\",\n      \"method\": \"Somatic cell hybrid analysis, in situ hybridization\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal methods (somatic cell hybrids and in situ hybridization) used to map the gene, foundational chromosomal localization\",\n      \"pmids\": [\"3028932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TTR stabilizers (tafamidis, diflunisal) act at the dimer-dimer interface to prevent tetramer dissociation into monomers, which is the initiating step for amyloid fibril formation; treatment with stabilizers was associated with decreased death/orthotopic heart transplant in TTR cardiac amyloidosis patients.\",\n      \"method\": \"Mechanistic model from structural studies; retrospective clinical cohort study with Cox proportional hazards modeling\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural mechanism well established; clinical evidence is retrospective single-center cohort, not an experimental mechanistic study per se\",\n      \"pmids\": [\"29615436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Systemically administered TTR siRNA (NTLA-2001/inotersen) reduces blood TTR protein levels and promotes clearance of TTR non-fibrillar deposits in meninges and brain blood vessels in V30M TTR transgenic mice; however, despite striking blood TTR reduction, CSF TTR levels were unaffected, indicating that choroid plexus-derived CSF TTR is produced independently of hepatic plasma TTR.\",\n      \"method\": \"siRNA systemic administration in transgenic mice, immunohistochemistry of meningeal/vascular TTR deposits, measurement of blood and CSF TTR levels\",\n      \"journal\": \"Amyloid\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo gene silencing experiment with quantitative protein-level outcomes in multiple compartments, single lab\",\n      \"pmids\": [\"27884058\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TTR is a homotetrameric plasma and CSF protein that transports thyroxine (T4) via two binding sites at the dimer-dimer interface and facilitates retinol delivery as a complex with retinol-binding protein (RBP); tetramer dissociation into non-native monomers is the rate-limiting step for amyloid fibril formation underlying TTR amyloidoses, and this process is inhibited by small-molecule kinetic stabilizers that bind at the T4 sites; TTR also possesses metallopeptidase activity and sequesters Aβ peptides in vivo, reducing Aβ deposition; in neurons (but not hepatocytes), TTR expression is upregulated by the stress-responsive transcription factor HSF1 via direct occupancy of TTR promoter heat shock elements.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TTR is a homotetrameric transport protein that carries thyroxine (T4) through two binding sites at the center of the dimer-dimer interface and binds retinol-binding protein (holo-RBP) on both faces of the tetramer [#0], functioning as a positive regulator of RBP-bound retinol delivery into cells [#3, #4]. The same dimer-dimer interface that forms the T4 sites is the locus of TTR's pathological behavior: amyloid fibril formation proceeds through rate-limiting dissociation of the native tetramer into non-native monomers that assemble into oligomers, protofibrils, and mature deposits [#1], and destabilizing mutations such as A25T accelerate this cascade in proportion to their loss of tetramer stability [#7]. This mechanistic link is exploited therapeutically by small-molecule kinetic stabilizers (tafamidis, diflunisal) that occupy the T4 sites at the dimer-dimer interface to block dissociation [#12], while stabilizing variants such as T119M and R104H confer intrinsic resistance to dissociation, showing tetramer stability is separable from T4 binding affinity [#2]. Beyond transport, TTR possesses metal-dependent peptidase activity that cleaves peptides without strict sequence specificity through a metalloprotease mechanism [#8], and it modulates amyloid-beta in vivo, with TTR haploinsufficiency accelerating Abeta deposition in an Alzheimer model [#5]. TTR expression is compartment-specific: neuronal TTR is transcriptionally induced by the stress-responsive factor HSF1 acting directly at promoter heat shock elements, a regulation absent in hepatocytes and cardiomyocytes [#6], and choroid plexus-derived CSF TTR is produced independently of hepatic plasma TTR [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Establishing the chromosomal locus of human TTR provided the genetic foundation for linking the gene to inherited amyloid disease.\",\n      \"evidence\": \"somatic cell hybrid analysis and in situ hybridization mapping to 18q11.2-q12.1\",\n      \"pmids\": [\"3028932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Localization alone established no protein function or disease mechanism\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Resolving whether a TTR variant alters T4 handling distinguished concentration effects from intrinsic affinity changes and confirmed TTR's physiological role in RBP transport.\",\n      \"evidence\": \"serum dialysis, isoelectric focusing, peptide mapping and DNA analysis of Met119 carriers\",\n      \"pmids\": [\"8102146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the structural basis of the binding sites\", \"Single variant in human carriers\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing TTR enhances cellular retinol uptake from the RBP-TTR complex established TTR as an active facilitator rather than a passive carrier in retinol delivery.\",\n      \"evidence\": \"primary rat hepatocyte uptake assays with labeled retinol complexes and competition experiments\",\n      \"pmids\": [\"9260907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The putative membrane receptor mediating uptake was not identified\", \"Demonstrated in rat hepatocytes only\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that stabilizing variants resist dissociation while differing in T4 affinity showed tetramer stability and ligand binding are mechanistically separable, a key principle for stabilizer design.\",\n      \"evidence\": \"in vitro dissociation-resistance stability assays and T4 binding studies of T119M and R104H\",\n      \"pmids\": [\"10772944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vitro study\", \"Did not establish in vivo protection from amyloidosis\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking the thermodynamic instability of A25T-TTR to fibril formation and CSF co-aggregation defined how destabilizing mutations drive the amyloid cascade and engage partner proteins.\",\n      \"evidence\": \"X-ray crystallography, pressure-induced dissociation, in vitro fibrillation, and proteomics of co-aggregates\",\n      \"pmids\": [\"22091638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of co-aggregation with the 19 partner proteins not established\", \"Relevance of CSF co-aggregation to in vivo disease unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Crystallographic resolution of the T4 and holo-RBP binding sites and consolidation of the dissociation-driven amyloid model unified TTR's transport and pathological mechanisms onto the dimer-dimer interface.\",\n      \"evidence\": \"synthesis of nearly 200 X-ray crystal structures of TTR and complexes, plus in vitro aggregation and biophysical characterization\",\n      \"pmids\": [\"22471981\", \"10940233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures do not capture transient oligomeric/protofibril intermediates\", \"Did not address tissue-specific regulation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying intrinsic metal-dependent peptidase activity revealed a catalytic function for TTR beyond ligand transport.\",\n      \"evidence\": \"FRET peptide cleavage assays, metal chelator inhibition, and pH/proton-inventory mechanistic profiling\",\n      \"pmids\": [\"23000319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological substrates not identified\", \"Catalytic metal and active-site residues not definitively assigned\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic ablation experiments established that TTR modulates Abeta deposition in vivo, extending its role to Alzheimer-relevant proteostasis.\",\n      \"evidence\": \"TTR hemizygous knockout crossed with APPswe/PS1deltaE9 mice, biochemical Abeta quantification and histology\",\n      \"pmids\": [\"17596449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which TTR limits Abeta deposition not resolved\", \"Relationship to TTR's own aggregation propensity unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that SAP binds early TTR aggregates and rescues toxicity in vitro and in flies identified a protective modifier of TTR aggregate toxicity.\",\n      \"evidence\": \"in vitro binding and cell viability assays plus a Drosophila TTR amyloidosis model with retinal histology\",\n      \"pmids\": [\"23390551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SAP-mediated protection not defined\", \"Human relevance of the fly model phenotype not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying HSF1 as a direct, neuron-specific transcriptional activator of TTR explained compartment-restricted TTR induction under stress.\",\n      \"evidence\": \"ChIP for HSF1 occupancy of TTR promoter heat shock elements with HSF1 gain/loss-of-function across neuronal cells and APP23 mice\",\n      \"pmids\": [\"24849358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating HSF1 at the TTR promoter not defined\", \"Functional outcome of elevated neuronal TTR not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking TTR V30M aggregates to selective autophagy impairment defined a cellular pathology that is pharmacologically reversible.\",\n      \"evidence\": \"p62 accumulation and LC3 turnover assays in cells plus TUDCA/curcumin treatment in V30M transgenic mice\",\n      \"pmids\": [\"27382986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular step in autophagy targeted by aggregates not pinpointed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connecting interface-binding kinetic stabilizers to improved clinical outcomes validated the dissociation model as a therapeutic target in cardiac amyloidosis.\",\n      \"evidence\": \"structural mechanism of tafamidis/diflunisal at the dimer-dimer interface combined with a retrospective clinical cohort\",\n      \"pmids\": [\"29615436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical evidence is retrospective single-center\", \"Not a prospective mechanistic intervention study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systemic TTR knockdown that cleared peripheral deposits but left CSF TTR unchanged established that choroid plexus CSF TTR is produced independently of hepatic plasma TTR.\",\n      \"evidence\": \"systemic TTR siRNA in V30M transgenic mice with immunohistochemistry and blood/CSF TTR measurement\",\n      \"pmids\": [\"27884058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether CSF TTR contributes to or protects against CNS amyloid\", \"Single transgenic model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological substrates of TTR's metalloprotease activity and the molecular mechanism by which TTR limits Abeta and engages aggregate-modifying partners remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous peptidase substrate identified\", \"Mechanism of TTR-Abeta interaction in vivo not defined\", \"Receptor mediating RBP-TTR retinol uptake unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 7, 12]}\n    ],\n    \"complexes\": [\"TTR homotetramer\", \"RBP-TTR complex\"],\n    \"partners\": [\"RBP4\", \"APP\", \"APCS\", \"HSF1\", \"CLU\", \"APOE\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}