{"gene":"TMEM230","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2016,"finding":"TMEM230 encodes a transmembrane protein localized to secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking.","method":"Subcellular fractionation, vesicle localization experiments, functional trafficking assays in primary mouse neurons and HEK293 cells with pathogenic TMEM230 variants","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments plus functional trafficking assays; founding paper replicated by subsequent studies","pmids":["27270108"],"is_preprint":false},{"year":2016,"finding":"Expression of pathogenic TMEM230 variants in HEK293 cells increased alpha-synuclein levels, linking impaired vesicular trafficking to alpha-synuclein accumulation.","method":"Overexpression of pathogenic TMEM230 variants in HEK293 cells with alpha-synuclein level measurement","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method (overexpression + western blot), no mechanistic dissection of how trafficking impairment leads to alpha-synuclein increase","pmids":["27270108"],"is_preprint":false},{"year":2017,"finding":"Loss of TMEM230 disrupts retromer cargo CI-M6PR trafficking, impairs autophagic cargo degradation, inhibits extracellular secretion of p62 and immature lysosomal hydrolases from Golgi-derived vesicles, and causes intracellular accumulation of these cargoes. These effects are specifically mediated by loss of the small GTPase Rab8a.","method":"siRNA knockdown of TMEM230, retromer cargo trafficking assays, secretion assays, Rab8a rescue experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (trafficking, secretion, autophagy) in single lab with genetic epistasis placing TMEM230 upstream of Rab8a","pmids":["28115417"],"is_preprint":false},{"year":2017,"finding":"PD-linked TMEM230 variants induce retromer mislocalization, defective cargo trafficking, and impaired autophagy, phenocopying TMEM230 loss-of-function.","method":"Overexpression of PD-linked TMEM230 variants with retromer localization imaging and cargo trafficking assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays in single lab demonstrating variant-specific effects on retromer and autophagy","pmids":["28115417"],"is_preprint":false},{"year":2017,"finding":"Knockdown of LRRK2, which phosphorylates Rab8a, similarly impairs retromer trafficking, secretory autophagy, and Golgi-derived vesicle secretion as TMEM230 knockdown, demonstrating converging roles of TMEM230 and LRRK2 on Rab8a function.","method":"siRNA knockdown of LRRK2, comparison of trafficking and secretion phenotypes with TMEM230 knockdown","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis experiment placing TMEM230 and LRRK2 in the same Rab8a pathway, single lab","pmids":["28115417"],"is_preprint":false},{"year":2018,"finding":"LRRK2 neither interacts with nor phosphorylates TMEM230 in a dopaminergic neuronal cell line. Overexpression of TMEM230 WT or mutants did not clearly alter levels of Rab1A, Rab5, Rab7, Rab8A, or Rab11 proteins.","method":"Co-immunoprecipitation and kinase assay for LRRK2-TMEM230 interaction; western blot for Rab protein levels after TMEM230 overexpression","journal":"Animal cells and systems","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — negative results from direct biochemical assays (Co-IP, kinase assay) in single lab; contradicts indirect inference from Kim et al. 2017 about LRRK2-TMEM230 connection","pmids":["30460091"],"is_preprint":false},{"year":2018,"finding":"PD-linked TMEM230 mutant proteins (R78L and PG5ext) are less stable than wild-type TMEM230 in a dopaminergic neuronal cell line.","method":"Protein stability assays (cycloheximide chase or equivalent) comparing WT and mutant TMEM230 protein levels","journal":"Animal cells and systems","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method, no mechanistic dissection of degradation pathway","pmids":["30460091"],"is_preprint":false},{"year":2021,"finding":"Overexpression of TMEM230 isoform 2 (WT or PD-linked *184Wext*5 mutant) or knockdown of endogenous TMEM230 induces neurodegeneration and impairs retrograde mitochondrial transport in axons of SH-SY5Y cells and mouse primary hippocampal neurons. Mutant TMEM230 causes more severe neurotoxicity and mitochondrial transport impairment than WT.","method":"Overexpression and siRNA knockdown in SH-SY5Y cells and mouse primary neurons; live imaging of mitochondrial transport in axons","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging of axonal transport with both gain- and loss-of-function, single lab with two orthogonal approaches","pmids":["34002226"],"is_preprint":false},{"year":2021,"finding":"TMEM230 is required for growth, migration, and substratum adhesion of U87-MG glioblastoma cells. Conditioned media from TMEM230-expressing U87 cells induces sprouting and tubule-like structure formation of HUVECs, indicating TMEM230 promotes pro-angiogenic secretion.","method":"siRNA knockdown of TMEM230 in U87-MG cells with migration, adhesion, and re-passaging assays; conditioned media HUVEC sprouting assay","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional cell assays with defined readouts in single lab","pmids":["34867197"],"is_preprint":false},{"year":2024,"finding":"TMEM230 knockout rats (generated by CRISPR-Cas9) do not exhibit impaired motor function, loss of dopaminergic neurons in the substantia nigra, altered autophagy-related protein expression, altered Rab family protein expression, altered vesicular trafficking protein expression, or glial reactions. This supports a gain-of-toxic-function mechanism for PD-associated TMEM230 mutations rather than loss-of-function.","method":"CRISPR-Cas9 knockout in rats; behavioral motor testing, immunohistochemistry for dopaminergic neurons, western blot for autophagy/Rab/trafficking proteins","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout model with multiple orthogonal readouts, single lab, negative result that informs mechanism","pmids":["39106917"],"is_preprint":false},{"year":2025,"finding":"TMEM230 forms a structural complex with ATP8/ATP11 lipid flippases at human endosomes, identified as a subunit of these flippase complexes.","method":"Cross-linking mass spectrometry of purified early endosomes combined with AlphaFold structural modeling and native gel MS; validated in induced neurons","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — structural interactome with cross-linking MS and AlphaFold validation in neurons, single study, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.02.07.636106"],"is_preprint":true}],"current_model":"TMEM230 is a transmembrane protein of secretory/recycling vesicles (including synaptic vesicles) that functions in vesicle trafficking by regulating retromer cargo sorting, Rab8a-mediated Golgi-derived vesicle secretion, secretory autophagy, and retrograde axonal mitochondrial transport; PD-linked mutations cause gain-of-toxic-function impairment of these trafficking pathways, and a structural interactome study suggests TMEM230 also acts as a subunit of ATP8/11 lipid flippases at endosomes."},"narrative":{"mechanistic_narrative":"TMEM230 is a transmembrane protein of secretory and recycling vesicles, including neuronal synaptic vesicles, that functions in vesicle trafficking, and its disruption is linked to Parkinson's disease through impaired trafficking and alpha-synuclein accumulation [PMID:27270108]. Mechanistically, TMEM230 acts upstream of the small GTPase Rab8a to support retromer-dependent cargo sorting (CI-M6PR), autophagic cargo degradation, and Golgi-derived secretion of p62 and lysosomal hydrolases; loss of TMEM230 mislocalizes the retromer, blocks these routes, and causes intracellular cargo accumulation, with rescue by Rab8a establishing the epistatic relationship [PMID:28115417]. This Rab8a-centered function converges with LRRK2, whose knockdown phenocopies TMEM230 loss in the same trafficking and secretory-autophagy assays [PMID:28115417]. TMEM230 is additionally required for retrograde axonal mitochondrial transport, and both its loss and overexpression of PD-linked variants drive neurodegeneration [PMID:34002226]. Across systems, PD-linked variants behave as gain-of-toxic-function alleles: they phenocopy and exacerbate trafficking and transport defects [PMID:28115417, PMID:34002226], while TMEM230 knockout rats show no motor, dopaminergic, autophagy, or Rab-pathway deficits, arguing against simple loss-of-function pathogenesis [PMID:39106917]. Beyond neurons, TMEM230 supports growth, adhesion, and pro-angiogenic secretion in glioblastoma cells [PMID:34867197].","teleology":[{"year":2016,"claim":"Established TMEM230 as a vesicular transmembrane protein and tied it to disease by showing pathogenic mutants impair synaptic vesicle trafficking, defining its core cellular compartment and a candidate disease mechanism.","evidence":"Subcellular fractionation, vesicle localization, and trafficking assays in primary mouse neurons and HEK293 cells with pathogenic variants","pmids":["27270108"],"confidence":"High","gaps":["Molecular partners mediating vesicle trafficking not identified","Topology and biochemical activity of the protein not defined"]},{"year":2016,"claim":"Connected impaired TMEM230 trafficking to alpha-synuclein accumulation, providing a plausible link between the vesicular defect and PD pathology.","evidence":"Overexpression of pathogenic variants in HEK293 cells with alpha-synuclein measurement","pmids":["27270108"],"confidence":"Medium","gaps":["No mechanistic dissection of how trafficking impairment raises alpha-synuclein","Single overexpression/western readout"]},{"year":2017,"claim":"Placed TMEM230 mechanistically upstream of Rab8a, defining its role in retromer cargo sorting, secretory autophagy, and Golgi-derived secretion, and showing PD variants phenocopy loss-of-function.","evidence":"siRNA knockdown, retromer/secretion/autophagy assays, Rab8a rescue, and variant overexpression","pmids":["28115417"],"confidence":"High","gaps":["Direct physical interaction between TMEM230 and Rab8a not shown","Mechanism of retromer recruitment unresolved"]},{"year":2017,"claim":"Showed LRRK2 and TMEM230 converge on Rab8a function, embedding TMEM230 in a known PD signaling axis.","evidence":"siRNA knockdown of LRRK2 with comparison of trafficking and secretion phenotypes to TMEM230 knockdown","pmids":["28115417"],"confidence":"Medium","gaps":["Epistasis is phenotypic, not biochemical","Order of action of LRRK2, TMEM230, and Rab8a not resolved"]},{"year":2018,"claim":"Challenged a direct LRRK2-TMEM230 link by failing to detect interaction, phosphorylation, or Rab-level changes, refining how the two proteins relate.","evidence":"Co-IP and kinase assay for LRRK2-TMEM230, western blot for Rab levels after TMEM230 overexpression in dopaminergic cells","pmids":["30460091"],"confidence":"Medium","gaps":["Negative result; does not exclude indirect functional convergence","Single cell line and method"]},{"year":2018,"claim":"Identified reduced stability of PD-linked TMEM230 mutant proteins as a possible contributor to their pathogenicity.","evidence":"Protein stability assays comparing WT and R78L/PG5ext mutants in dopaminergic cells","pmids":["30460091"],"confidence":"Low","gaps":["Degradation pathway not identified","Single lab, single method, no in vivo validation"]},{"year":2021,"claim":"Extended TMEM230 function to retrograde axonal mitochondrial transport and showed both loss and mutant overexpression cause neurodegeneration, broadening its role beyond secretory trafficking.","evidence":"Overexpression and knockdown in SH-SY5Y and mouse primary neurons with live axonal mitochondrial transport imaging","pmids":["34002226"],"confidence":"Medium","gaps":["Molecular link between TMEM230 and mitochondrial transport machinery unknown","Relationship to the Rab8a/retromer role unclear"]},{"year":2021,"claim":"Demonstrated a non-neuronal role for TMEM230 in glioblastoma growth, adhesion, and pro-angiogenic secretion, indicating its trafficking function has broader cellular consequences.","evidence":"siRNA knockdown in U87-MG cells with migration/adhesion assays and conditioned-media HUVEC sprouting assay","pmids":["34867197"],"confidence":"Medium","gaps":["Secreted pro-angiogenic factors not identified","Mechanistic link to the Rab8a secretory pathway not established"]},{"year":2024,"claim":"Argued against simple loss-of-function pathogenesis by showing TMEM230 knockout rats lack PD-relevant motor, dopaminergic, autophagy, and Rab-pathway phenotypes, supporting a gain-of-toxic-function model for mutations.","evidence":"CRISPR-Cas9 knockout rats with motor testing, dopaminergic immunohistochemistry, and western blots for autophagy/Rab/trafficking proteins","pmids":["39106917"],"confidence":"Medium","gaps":["Possible compensation in knockout not excluded","Does not directly test toxicity of mutant alleles in vivo"]},{"year":2025,"claim":"Proposed TMEM230 as a structural subunit of ATP8/ATP11 lipid flippase complexes at endosomes, offering a candidate biochemical activity underlying its trafficking role.","evidence":"Cross-linking mass spectrometry of purified endosomes, AlphaFold modeling, and native gel MS, validated in induced neurons (preprint)","pmids":["bio_10.1101_2025.02.07.636106"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Functional contribution of TMEM230 to flippase activity not demonstrated","Link to Rab8a/retromer trafficking not established"]},{"year":null,"claim":"The direct biochemical activity of TMEM230 and the molecular mechanism connecting it to Rab8a, the retromer, mitochondrial transport, and putative flippase function remain unresolved.","evidence":"No single study integrates the trafficking, mitochondrial, and structural findings into one molecular mechanism","pmids":[],"confidence":"Low","gaps":["No defined enzymatic or binding activity tying together all phenotypes","Topology and direct partners largely uncharacterized","How PD mutations exert gain-of-toxic-function not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,10]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]}],"complexes":["ATP8/ATP11 lipid flippase complex"],"partners":["RAB8A","LRRK2","ATP8","ATP11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96A57","full_name":"Transmembrane protein 230","aliases":[],"length_aa":120,"mass_kda":13.2,"function":"Involved in trafficking and recycling of synaptic vesicles","subcellular_location":"Membrane; Golgi apparatus, trans-Golgi network; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle; Early endosome; Recycling endosome; Late endosome; Cytoplasmic vesicle, autophagosome","url":"https://www.uniprot.org/uniprotkb/Q96A57/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM230","classification":"Not Classified","n_dependent_lines":240,"n_total_lines":1208,"dependency_fraction":0.1986754966887417},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"GPR107","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMEM230","total_profiled":1310},"omim":[{"mim_id":"617019","title":"TRANSMEMBRANE PROTEIN 230; TMEM230","url":"https://www.omim.org/entry/617019"},{"mim_id":"616361","title":"PARKINSON DISEASE 21; PARK21","url":"https://www.omim.org/entry/616361"},{"mim_id":"614334","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 13; DNAJC13","url":"https://www.omim.org/entry/614334"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM230"},"hgnc":{"alias_symbol":["HSPC274"],"prev_symbol":["C20orf30"]},"alphafold":{"accession":"Q96A57","domains":[{"cath_id":"1.20.58","chopping":"43-108","consensus_level":"high","plddt":90.1094,"start":43,"end":108}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96A57","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96A57-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96A57-F1-predicted_aligned_error_v6.png","plddt_mean":81.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM230","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM230"},"sequence":{"accession":"Q96A57","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96A57.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96A57/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96A57"}},"corpus_meta":[{"pmid":"27270108","id":"PMC_27270108","title":"Identification of TMEM230 mutations in familial Parkinson's disease.","date":"2016","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27270108","citation_count":140,"is_preprint":false},{"pmid":"28115417","id":"PMC_28115417","title":"The Parkinson's disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer trafficking.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28115417","citation_count":48,"is_preprint":false},{"pmid":"27814995","id":"PMC_27814995","title":"TMEM230 mutation analysis in Parkinson's disease in a Chinese population.","date":"2016","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/27814995","citation_count":28,"is_preprint":false},{"pmid":"27818000","id":"PMC_27818000","title":"Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population.","date":"2016","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/27818000","citation_count":26,"is_preprint":false},{"pmid":"33212219","id":"PMC_33212219","title":"Controversy of TMEM230 Associated with Parkinson's Disease.","date":"2020","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33212219","citation_count":13,"is_preprint":false},{"pmid":"34867197","id":"PMC_34867197","title":"Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy.","date":"2021","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34867197","citation_count":12,"is_preprint":false},{"pmid":"28568905","id":"PMC_28568905","title":"TMEM230: How does it fit in the etiology and pathogenesis of Parkinson's disease?","date":"2017","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/28568905","citation_count":11,"is_preprint":false},{"pmid":"34002226","id":"PMC_34002226","title":"Mutant-TMEM230-induced neurodegeneration and impaired axonal mitochondrial transport.","date":"2021","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34002226","citation_count":11,"is_preprint":false},{"pmid":"30175983","id":"PMC_30175983","title":"The Role of TMEM230 Gene in Parkinson's Disease.","date":"2018","source":"Journal of Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/30175983","citation_count":10,"is_preprint":false},{"pmid":"28457580","id":"PMC_28457580","title":"TMEM230 in Parkinson's disease.","date":"2017","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/28457580","citation_count":9,"is_preprint":false},{"pmid":"28527219","id":"PMC_28527219","title":"TMEM230 Accumulation in Granulovacuolar Degeneration Bodies and Dystrophic Neurites of Alzheimer's Disease.","date":"2017","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/28527219","citation_count":9,"is_preprint":false},{"pmid":"28455698","id":"PMC_28455698","title":"TMEM230 Mutations Are Rare in Han Chinese Patients with Autosomal Dominant Parkinson's Disease.","date":"2017","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/28455698","citation_count":9,"is_preprint":false},{"pmid":"28766910","id":"PMC_28766910","title":"Lack of TMEM230 mutations in patients with familial and sporadic Parkinson's disease in a Taiwanese population.","date":"2017","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28766910","citation_count":9,"is_preprint":false},{"pmid":"30460091","id":"PMC_30460091","title":"Characterization of Parkinson's disease-related pathogenic TMEM230 mutants.","date":"2018","source":"Animal cells and systems","url":"https://pubmed.ncbi.nlm.nih.gov/30460091","citation_count":8,"is_preprint":false},{"pmid":"28709721","id":"PMC_28709721","title":"Screening for TMEM230 mutations in young-onset Parkinson's disease.","date":"2017","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/28709721","citation_count":8,"is_preprint":false},{"pmid":"29305083","id":"PMC_29305083","title":"Genetic analysis of TMEM230 in Japanese patients with familial Parkinson's disease.","date":"2017","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/29305083","citation_count":8,"is_preprint":false},{"pmid":"28446760","id":"PMC_28446760","title":"Genetic analysis of the TMEM230 gene in Chinese Han patients with Parkinson's disease.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28446760","citation_count":7,"is_preprint":false},{"pmid":"29771939","id":"PMC_29771939","title":"TMEM230 in Parkinson's disease in a southern Spanish population.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29771939","citation_count":7,"is_preprint":false},{"pmid":"27872751","id":"PMC_27872751","title":"Novel gene (TMEM230) linked to Parkinson's disease.","date":"2016","source":"Journal of clinical movement disorders","url":"https://pubmed.ncbi.nlm.nih.gov/27872751","citation_count":5,"is_preprint":false},{"pmid":"40141059","id":"PMC_40141059","title":"Glycosylation Regulation by TMEM230 in Aging and Autoimmunity.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40141059","citation_count":4,"is_preprint":false},{"pmid":"38612777","id":"PMC_38612777","title":"Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38612777","citation_count":4,"is_preprint":false},{"pmid":"38960477","id":"PMC_38960477","title":"Transmembrane protein TMEM230, regulator of metalloproteins and motor proteins in gliomas and gliosis.","date":"2024","source":"Advances in protein chemistry and structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/38960477","citation_count":3,"is_preprint":false},{"pmid":"39106917","id":"PMC_39106917","title":"Absence of motor impairments or pathological changes in TMEM230 knockout rats.","date":"2024","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/39106917","citation_count":1,"is_preprint":false},{"pmid":"40744139","id":"PMC_40744139","title":"Genetic analysis of TMEM230 variants in Han Chinese patients with Parkinson's disease.","date":"2025","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/40744139","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.07.636106","title":"EndoMAP.v1, a Structural Protein Complex Landscape of Human Endosomes","date":"2025-02-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.07.636106","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12711,"output_tokens":2551,"usd":0.038199,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9718,"output_tokens":3317,"usd":0.065757,"stage2_stop_reason":"end_turn"},"total_usd":0.103956,"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\": 2016,\n      \"finding\": \"TMEM230 encodes a transmembrane protein localized to secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking.\",\n      \"method\": \"Subcellular fractionation, vesicle localization experiments, functional trafficking assays in primary mouse neurons and HEK293 cells with pathogenic TMEM230 variants\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments plus functional trafficking assays; founding paper replicated by subsequent studies\",\n      \"pmids\": [\"27270108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Expression of pathogenic TMEM230 variants in HEK293 cells increased alpha-synuclein levels, linking impaired vesicular trafficking to alpha-synuclein accumulation.\",\n      \"method\": \"Overexpression of pathogenic TMEM230 variants in HEK293 cells with alpha-synuclein level measurement\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (overexpression + western blot), no mechanistic dissection of how trafficking impairment leads to alpha-synuclein increase\",\n      \"pmids\": [\"27270108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of TMEM230 disrupts retromer cargo CI-M6PR trafficking, impairs autophagic cargo degradation, inhibits extracellular secretion of p62 and immature lysosomal hydrolases from Golgi-derived vesicles, and causes intracellular accumulation of these cargoes. These effects are specifically mediated by loss of the small GTPase Rab8a.\",\n      \"method\": \"siRNA knockdown of TMEM230, retromer cargo trafficking assays, secretion assays, Rab8a rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (trafficking, secretion, autophagy) in single lab with genetic epistasis placing TMEM230 upstream of Rab8a\",\n      \"pmids\": [\"28115417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PD-linked TMEM230 variants induce retromer mislocalization, defective cargo trafficking, and impaired autophagy, phenocopying TMEM230 loss-of-function.\",\n      \"method\": \"Overexpression of PD-linked TMEM230 variants with retromer localization imaging and cargo trafficking assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays in single lab demonstrating variant-specific effects on retromer and autophagy\",\n      \"pmids\": [\"28115417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of LRRK2, which phosphorylates Rab8a, similarly impairs retromer trafficking, secretory autophagy, and Golgi-derived vesicle secretion as TMEM230 knockdown, demonstrating converging roles of TMEM230 and LRRK2 on Rab8a function.\",\n      \"method\": \"siRNA knockdown of LRRK2, comparison of trafficking and secretion phenotypes with TMEM230 knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis experiment placing TMEM230 and LRRK2 in the same Rab8a pathway, single lab\",\n      \"pmids\": [\"28115417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LRRK2 neither interacts with nor phosphorylates TMEM230 in a dopaminergic neuronal cell line. Overexpression of TMEM230 WT or mutants did not clearly alter levels of Rab1A, Rab5, Rab7, Rab8A, or Rab11 proteins.\",\n      \"method\": \"Co-immunoprecipitation and kinase assay for LRRK2-TMEM230 interaction; western blot for Rab protein levels after TMEM230 overexpression\",\n      \"journal\": \"Animal cells and systems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — negative results from direct biochemical assays (Co-IP, kinase assay) in single lab; contradicts indirect inference from Kim et al. 2017 about LRRK2-TMEM230 connection\",\n      \"pmids\": [\"30460091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PD-linked TMEM230 mutant proteins (R78L and PG5ext) are less stable than wild-type TMEM230 in a dopaminergic neuronal cell line.\",\n      \"method\": \"Protein stability assays (cycloheximide chase or equivalent) comparing WT and mutant TMEM230 protein levels\",\n      \"journal\": \"Animal cells and systems\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method, no mechanistic dissection of degradation pathway\",\n      \"pmids\": [\"30460091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Overexpression of TMEM230 isoform 2 (WT or PD-linked *184Wext*5 mutant) or knockdown of endogenous TMEM230 induces neurodegeneration and impairs retrograde mitochondrial transport in axons of SH-SY5Y cells and mouse primary hippocampal neurons. Mutant TMEM230 causes more severe neurotoxicity and mitochondrial transport impairment than WT.\",\n      \"method\": \"Overexpression and siRNA knockdown in SH-SY5Y cells and mouse primary neurons; live imaging of mitochondrial transport in axons\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging of axonal transport with both gain- and loss-of-function, single lab with two orthogonal approaches\",\n      \"pmids\": [\"34002226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM230 is required for growth, migration, and substratum adhesion of U87-MG glioblastoma cells. Conditioned media from TMEM230-expressing U87 cells induces sprouting and tubule-like structure formation of HUVECs, indicating TMEM230 promotes pro-angiogenic secretion.\",\n      \"method\": \"siRNA knockdown of TMEM230 in U87-MG cells with migration, adhesion, and re-passaging assays; conditioned media HUVEC sprouting assay\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional cell assays with defined readouts in single lab\",\n      \"pmids\": [\"34867197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM230 knockout rats (generated by CRISPR-Cas9) do not exhibit impaired motor function, loss of dopaminergic neurons in the substantia nigra, altered autophagy-related protein expression, altered Rab family protein expression, altered vesicular trafficking protein expression, or glial reactions. This supports a gain-of-toxic-function mechanism for PD-associated TMEM230 mutations rather than loss-of-function.\",\n      \"method\": \"CRISPR-Cas9 knockout in rats; behavioral motor testing, immunohistochemistry for dopaminergic neurons, western blot for autophagy/Rab/trafficking proteins\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout model with multiple orthogonal readouts, single lab, negative result that informs mechanism\",\n      \"pmids\": [\"39106917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM230 forms a structural complex with ATP8/ATP11 lipid flippases at human endosomes, identified as a subunit of these flippase complexes.\",\n      \"method\": \"Cross-linking mass spectrometry of purified early endosomes combined with AlphaFold structural modeling and native gel MS; validated in induced neurons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — structural interactome with cross-linking MS and AlphaFold validation in neurons, single study, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.07.636106\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TMEM230 is a transmembrane protein of secretory/recycling vesicles (including synaptic vesicles) that functions in vesicle trafficking by regulating retromer cargo sorting, Rab8a-mediated Golgi-derived vesicle secretion, secretory autophagy, and retrograde axonal mitochondrial transport; PD-linked mutations cause gain-of-toxic-function impairment of these trafficking pathways, and a structural interactome study suggests TMEM230 also acts as a subunit of ATP8/11 lipid flippases at endosomes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM230 is a transmembrane protein of secretory and recycling vesicles, including neuronal synaptic vesicles, that functions in vesicle trafficking, and its disruption is linked to Parkinson's disease through impaired trafficking and alpha-synuclein accumulation [#0, #1]. Mechanistically, TMEM230 acts upstream of the small GTPase Rab8a to support retromer-dependent cargo sorting (CI-M6PR), autophagic cargo degradation, and Golgi-derived secretion of p62 and lysosomal hydrolases; loss of TMEM230 mislocalizes the retromer, blocks these routes, and causes intracellular cargo accumulation, with rescue by Rab8a establishing the epistatic relationship [#2]. This Rab8a-centered function converges with LRRK2, whose knockdown phenocopies TMEM230 loss in the same trafficking and secretory-autophagy assays [#4]. TMEM230 is additionally required for retrograde axonal mitochondrial transport, and both its loss and overexpression of PD-linked variants drive neurodegeneration [#7]. Across systems, PD-linked variants behave as gain-of-toxic-function alleles: they phenocopy and exacerbate trafficking and transport defects [#3, #7], while TMEM230 knockout rats show no motor, dopaminergic, autophagy, or Rab-pathway deficits, arguing against simple loss-of-function pathogenesis [#9]. Beyond neurons, TMEM230 supports growth, adhesion, and pro-angiogenic secretion in glioblastoma cells [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established TMEM230 as a vesicular transmembrane protein and tied it to disease by showing pathogenic mutants impair synaptic vesicle trafficking, defining its core cellular compartment and a candidate disease mechanism.\",\n      \"evidence\": \"Subcellular fractionation, vesicle localization, and trafficking assays in primary mouse neurons and HEK293 cells with pathogenic variants\",\n      \"pmids\": [\"27270108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating vesicle trafficking not identified\", \"Topology and biochemical activity of the protein not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected impaired TMEM230 trafficking to alpha-synuclein accumulation, providing a plausible link between the vesicular defect and PD pathology.\",\n      \"evidence\": \"Overexpression of pathogenic variants in HEK293 cells with alpha-synuclein measurement\",\n      \"pmids\": [\"27270108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanistic dissection of how trafficking impairment raises alpha-synuclein\", \"Single overexpression/western readout\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed TMEM230 mechanistically upstream of Rab8a, defining its role in retromer cargo sorting, secretory autophagy, and Golgi-derived secretion, and showing PD variants phenocopy loss-of-function.\",\n      \"evidence\": \"siRNA knockdown, retromer/secretion/autophagy assays, Rab8a rescue, and variant overexpression\",\n      \"pmids\": [\"28115417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between TMEM230 and Rab8a not shown\", \"Mechanism of retromer recruitment unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed LRRK2 and TMEM230 converge on Rab8a function, embedding TMEM230 in a known PD signaling axis.\",\n      \"evidence\": \"siRNA knockdown of LRRK2 with comparison of trafficking and secretion phenotypes to TMEM230 knockdown\",\n      \"pmids\": [\"28115417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epistasis is phenotypic, not biochemical\", \"Order of action of LRRK2, TMEM230, and Rab8a not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Challenged a direct LRRK2-TMEM230 link by failing to detect interaction, phosphorylation, or Rab-level changes, refining how the two proteins relate.\",\n      \"evidence\": \"Co-IP and kinase assay for LRRK2-TMEM230, western blot for Rab levels after TMEM230 overexpression in dopaminergic cells\",\n      \"pmids\": [\"30460091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not exclude indirect functional convergence\", \"Single cell line and method\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified reduced stability of PD-linked TMEM230 mutant proteins as a possible contributor to their pathogenicity.\",\n      \"evidence\": \"Protein stability assays comparing WT and R78L/PG5ext mutants in dopaminergic cells\",\n      \"pmids\": [\"30460091\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Degradation pathway not identified\", \"Single lab, single method, no in vivo validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended TMEM230 function to retrograde axonal mitochondrial transport and showed both loss and mutant overexpression cause neurodegeneration, broadening its role beyond secretory trafficking.\",\n      \"evidence\": \"Overexpression and knockdown in SH-SY5Y and mouse primary neurons with live axonal mitochondrial transport imaging\",\n      \"pmids\": [\"34002226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between TMEM230 and mitochondrial transport machinery unknown\", \"Relationship to the Rab8a/retromer role unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a non-neuronal role for TMEM230 in glioblastoma growth, adhesion, and pro-angiogenic secretion, indicating its trafficking function has broader cellular consequences.\",\n      \"evidence\": \"siRNA knockdown in U87-MG cells with migration/adhesion assays and conditioned-media HUVEC sprouting assay\",\n      \"pmids\": [\"34867197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secreted pro-angiogenic factors not identified\", \"Mechanistic link to the Rab8a secretory pathway not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Argued against simple loss-of-function pathogenesis by showing TMEM230 knockout rats lack PD-relevant motor, dopaminergic, autophagy, and Rab-pathway phenotypes, supporting a gain-of-toxic-function model for mutations.\",\n      \"evidence\": \"CRISPR-Cas9 knockout rats with motor testing, dopaminergic immunohistochemistry, and western blots for autophagy/Rab/trafficking proteins\",\n      \"pmids\": [\"39106917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Possible compensation in knockout not excluded\", \"Does not directly test toxicity of mutant alleles in vivo\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed TMEM230 as a structural subunit of ATP8/ATP11 lipid flippase complexes at endosomes, offering a candidate biochemical activity underlying its trafficking role.\",\n      \"evidence\": \"Cross-linking mass spectrometry of purified endosomes, AlphaFold modeling, and native gel MS, validated in induced neurons (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.07.636106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Functional contribution of TMEM230 to flippase activity not demonstrated\", \"Link to Rab8a/retromer trafficking not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical activity of TMEM230 and the molecular mechanism connecting it to Rab8a, the retromer, mitochondrial transport, and putative flippase function remain unresolved.\",\n      \"evidence\": \"No single study integrates the trafficking, mitochondrial, and structural findings into one molecular mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined enzymatic or binding activity tying together all phenotypes\", \"Topology and direct partners largely uncharacterized\", \"How PD mutations exert gain-of-toxic-function not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"ATP8/ATP11 lipid flippase complex\"\n    ],\n    \"partners\": [\n      \"RAB8A\",\n      \"LRRK2\",\n      \"ATP8\",\n      \"ATP11\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}