{"gene":"CHMP2B","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2005,"finding":"CHMP2B is a component of the endosomal ESCRT-III complex; a splice-site mutation causes aberrant mRNA splicing leading to C-terminal truncation of the protein, disrupting ESCRT-III function and causing frontotemporal dementia.","method":"Genetic mapping, mRNA splicing analysis in patient tissue samples","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — original discovery paper, widely replicated, foundational mechanistic finding","pmids":["16041373"],"is_preprint":false},{"year":2007,"finding":"C-terminally truncated CHMP2B mutants (p.Met178ValfsX2 and p.Gln165X) cause formation of large aberrant endosomal structures when overexpressed in human neuroblastoma cells, establishing that C-truncating mutations disrupt endosome function through a dominant-negative or gain-of-function mechanism.","method":"Overexpression in SK-N-SH cells, immunofluorescence microscopy","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2-3 — replicated across two independent mutations in two independent labs; strong preponderance","pmids":["17956895"],"is_preprint":false},{"year":2010,"finding":"Mutant CHMP2B causes a specific disruption of endosome-lysosome fusion (but not MVB protein sorting) by constitutively binding to MVBs and preventing recruitment of Rab7, a protein required for fusion.","method":"Functional endocytic assays in patient fibroblasts, immunofluorescence, patient brain pathology analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (functional fusion assay, patient fibroblasts, brain pathology), Rab7 recruitment mechanistically defined","pmids":["20223751"],"is_preprint":false},{"year":2010,"finding":"Mutant CHMP2B (CHMP2BIntron5) causes aberrant lysosomal localisation and impairment of autophagy (increased LC3-II levels) when transfected into HEK-293 and COS-7 cells, forming large cytoplasmic vacuoles absent with wild-type CHMP2B.","method":"Transfection of mutant vs. wild-type CHMP2B, CD63 immunostaining, LC3-II western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple readouts in cell lines, consistent with patient data, single lab","pmids":["20352044"],"is_preprint":false},{"year":2010,"finding":"CHMP2B is required for dendritic spine maturation; FTD-linked mutants (CHMP2BIntron5 and CHMP2BΔ10) reduce the proportion of mushroom-shaped large spines in hippocampal neurons and decrease frequency and amplitude of spontaneous excitatory postsynaptic currents. RNAi depletion of endogenous CHMP2B phenocopies mutant overexpression, indicating dominant-negative activity.","method":"Confocal microscopy with 3D reconstruction in cultured hippocampal neurons, electrophysiology (mEPSC recording), RNAi knockdown","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (morphology, electrophysiology, RNAi), functional consequence clearly defined","pmids":["20699355"],"is_preprint":false},{"year":2011,"finding":"Full-length CHMP2B polymerizes into long rigid membrane tubes protruding from the cell surface when VPS4 is depleted; cryo-EM demonstrates CHMP2B forms a tightly packed helical lattice in close association with the inner leaflet of the membrane tube, deforming the lipid bilayer. CHMP4s relocalize to the base of CHMP2B tubes.","method":"VPS4 depletion, overexpression, cryo-electron microscopy, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structural characterization plus functional in cellulo validation","pmids":["21926173"],"is_preprint":false},{"year":2012,"finding":"Transgenic mice expressing C-terminally truncated mutant CHMP2B develop neurodegeneration through a gain-of-function mechanism: progressive p62/ubiquitin-positive (TDP-43-negative) inclusions, gliosis, and axonal swellings with amyloid precursor protein accumulation. Knockout mice and wild-type CHMP2B transgenic mice show none of these changes.","method":"Transgenic and knockout mouse generation, histopathology, immunohistochemistry","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — genetic gain-of-function vs. loss-of-function comparison with specific phenotypic readouts","pmids":["22366797"],"is_preprint":false},{"year":2012,"finding":"Syntaxin 13 (STX13) is a genetic modifier of ESCRT-III dysfunction caused by mutant CHMP2B; knockdown of STX13 or its binding partner Vti1a in mammalian cells causes LC3-positive autophagosome accumulation and blocks autophagic flux; STX13 localizes on LC3-positive phagophores and participates in phagophore maturation into closed autophagosomes.","method":"Drosophila genetic modifier screen, mammalian siRNA knockdown, LC3 immunofluorescence, autophagic flux assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila confirmed by mammalian cell knockdown with multiple functional readouts","pmids":["24095276"],"is_preprint":false},{"year":2012,"finding":"CHMP2B missense mutant T104N accumulates in Rab5- and Rab7-positive endosomes, causes delayed EGFR degradation, shows reduced association with VPS4 ATPase, increased association with Snf7-2 (ESCRT-III core), and causes autophagosome accumulation in post-mitotic neurons.","method":"Overexpression in neurons, immunofluorescence, co-immunoprecipitation, EGFR degradation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple assays but relatively limited functional follow-up","pmids":["22521643"],"is_preprint":false},{"year":2013,"finding":"Expression of CHMP2BIntron5 in Drosophila causes Notch accumulation in enlarged endosomes and upregulation of Notch activity; partial loss of Notch rescues eye deformities, indicating that mutant CHMP2B drives neurodegeneration-associated phenotypes through Notch misregulation in this context.","method":"Drosophila transgenic expression, genetic epistasis (Notch loss-of-function rescue), immunofluorescence","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with rescue, but Drosophila model and context-dependent signaling","pmids":["24158394"],"is_preprint":false},{"year":2015,"finding":"Endogenous Chmp2b concentrates beneath the perisynaptic membrane of dendritic spines (quantitative immuno-EM); Chmp2b depletion reduces dendritic branching and excitatory synapse density in vitro and in vivo and abolishes activity-induced spine enlargement and synaptic potentiation; Chmp2b is stably bound in synaptoneurosome lysates to a large complex containing other CHMP family members and postsynaptic scaffolds.","method":"Quantitative immuno-electron microscopy, co-immunoprecipitation, mass spectrometry, shRNA knockdown, in vivo spine density measurement, LTP electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including ultrastructural localization, biochemical interaction, and functional LTP readout","pmids":["25698751"],"is_preprint":false},{"year":2015,"finding":"Mutant CHMP2B causes lysosomal storage pathology in neurons: transgenic mice expressing FTD-causative mutant CHMP2B at physiological levels develop large neuronal autofluorescent aggregates derived from the endolysosomal system, confirmed by ultrastructural analysis and immuno-gold labelling; similar aggregates are found in patient brains.","method":"Transgenic mouse model, electron microscopy, immuno-gold labelling, patient brain immunofluorescence","journal":"Acta neuropathologica","confidence":"High","confidence_rationale":"Tier 2 — mouse model plus human patient tissue, ultrastructural confirmation, strong preponderance","pmids":["26358247"],"is_preprint":false},{"year":2015,"finding":"TMEM106B associates with CHMP2B-positive endosomal structures; the TMEM106B T185 variant associates more strongly with CHMP2B than S185 and enhances CHMP2B(Intron5)-induced EGFR accumulation, autophagy impairment, and neurotoxicity.","method":"Co-immunoprecipitation, immunofluorescence colocalization, autophagic flux assay, neurotoxicity assay","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-IP plus functional readouts but limited mechanistic depth","pmids":["26651479"],"is_preprint":false},{"year":2018,"finding":"Mutant CHMP2B stably incorporates onto neuronal endolysosomes, rendering them unable to traffic within dendrites. This is mechanistically due to inability of mutant CHMP2B to recruit the ATPase VPS4, which is required for CHMP2B release from endosomal membranes. TMEM106B antisense oligonucleotide treatment rescues both impaired trafficking and increased dendritic branching.","method":"Live imaging of endolysosomal trafficking, CHMP2B-VPS4 interaction assay, antisense oligonucleotide rescue in neurons expressing physiological levels of mutant CHMP2B","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic VPS4 recruitment defect demonstrated, trafficking phenotype, rescue experiment","pmids":["30496365"],"is_preprint":false},{"year":2018,"finding":"CHMP2B polymerization on reconstituted membrane nanotubes acts as a diffusion barrier: CHMP2B (full-length and ΔC) preferentially binds membranes containing PI(4,5)P2, accumulates at nanotube necks, and prevents diffusion of PI(4,5)P2 lipids and membrane-bound proteins across the neck.","method":"In vitro reconstitution in giant unilamellar vesicles, pulled membrane nanotubes, fluorescence microscopy, purified protein binding assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified protein and defined lipid systems","pmids":["29967034"],"is_preprint":false},{"year":2009,"finding":"In a Drosophila model of FTD3, serpin5 (a serine protease inhibitor) suppresses mutant CHMP2B toxicity by acting as a negative regulator of the Toll pathway, blocking proteolytic activation of Spaetzle (Toll receptor ligand) extracellularly; the Toll signaling pathway is identified as a major pathway misregulated by mutant CHMP2B in vivo.","method":"Genome-wide genetic modifier screen in Drosophila, epistasis analysis, gain/loss-of-function genetics","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased genetic screen with epistasis validation, but Drosophila model","pmids":["19581577"],"is_preprint":false},{"year":2021,"finding":"CHMP2B binding to membranes is enhanced by PI(4,5)P2 lipids (unlike CHMP2A which requires CHMP3 and lacks lipid specificity); CHMP2B strongly rigidifies membranes upon polymerization while CHMP2A+CHMP3 does not, demonstrating distinct mechanical properties between ESCRT-III isoforms.","method":"In vitro binding assays with purified proteins and biomimetic membrane systems, membrane mechanics measurements, fluorescence microscopy","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1 — multiple biophysical methods with purified proteins on defined lipid systems","pmids":["33832485"],"is_preprint":false},{"year":2021,"finding":"CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independently of autophagy through modulation of CK1 kinase: CHMP2B negatively regulates ubiquitination and proteasome-mediated turnover of CK1, thereby controlling CK1 protein levels and TDP-43 phosphorylation.","method":"Drosophila genetic screen, mammalian cell knockdown/overexpression, CK1 ubiquitination assay, TDP-43 phosphorylation western blot","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic screen validated in mammalian cells with biochemical ubiquitination assay, multiple orthogonal methods","pmids":["34726688"],"is_preprint":false},{"year":2021,"finding":"Mutant CHMP2B causes a novel synaptopathy: selective retention of presynaptic synaptic vesicle trafficking proteins in aged transgenic mice, increased presynaptic endosomes, defective synaptic vesicle recycling and altered functional SV pools, while postsynaptic proteins are lost.","method":"Transgenic mouse histology, ultrastructural analysis of primary cortical cultures, FM dye SV recycling assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model plus ultrastructure plus functional SV recycling assay, single lab","pmids":["34855215"],"is_preprint":false},{"year":2022,"finding":"Mutant CHMP2BIntron5 associates with spastin with greater affinity than wild-type CHMP2B and colocalizes in p62-positive aggregates; spastin is sequestered from the soluble cytoplasmic fraction to the insoluble fraction in cells and mouse brain neurons expressing CHMP2BIntron5; genetic knockdown of spastin enhances CHMP2BIntron5 toxicity in Drosophila.","method":"Co-immunoprecipitation, immunofluorescence colocalization, subcellular fractionation, Drosophila genetic epistasis","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP, fractionation, in vivo mouse, Drosophila epistasis; single lab","pmids":["36414997"],"is_preprint":false},{"year":2022,"finding":"SIRT6 regulates CHMP2B levels in the heart by decreasing acetylation of FoxO1, promoting its transcriptional activation of Atrogin-1 (a muscle-specific ubiquitin ligase), which subsequently mediates ubiquitin-proteasome degradation of CHMP2B.","method":"Mouse cardiac SIRT6 heterozygous knockout, FoxO1 acetylation assay, Atrogin-1 transcriptional reporter, CHMP2B degradation assay","journal":"Journal of cardiovascular translational research","confidence":"Medium","confidence_rationale":"Tier 2 — identified PTM writer pathway with functional rescue, but single lab cardiac context","pmids":["35235147"],"is_preprint":false},{"year":2020,"finding":"Partial loss of Ik2 (fly TBK1 homologue) enhances mutant CHMP2B toxicity in the fly eye while Ik2 overexpression suppresses it; loss of Spn-F (Ik2 phosphorylation target), dynein light chain (cut up), or Hook (early endosome transport adaptor) also enhances mutant CHMP2B toxicity, implicating early endosome transport as a contributing pathway.","method":"Drosophila genetic epistasis, interactome analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila with interactome validation, but functional mechanism inferred","pmids":["32848189"],"is_preprint":false},{"year":2024,"finding":"CHMP2B promotes CHMP7-mediated nuclear pore complex (NPC) injury in sporadic ALS neurons: sustained CHMP2B-dependent activation is sufficient to cause pathologic CHMP7 nuclear accumulation and POM121 (nucleoporin) reduction; partial knockdown of CHMP2B alleviates NPC injury and downstream TDP-43 dysfunction in sALS iPSC-derived neurons.","method":"iPSC-derived neuron model of sALS, CHMP2B knockdown, super-resolution microscopy, NPC integrity assay, TDP-43 localization","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 — iPSC neuron model with knockdown rescue and defined NPC phenotype, single lab","pmids":["39709457"],"is_preprint":false},{"year":2026,"finding":"Wild-type CHMP2B contains a nuclear export signal (NES) in its C-terminus that mediates CRM1-dependent nuclear export; the FTD3-causative CHMP2BIntron5 mutation removes this NES, causing mislocalization of CHMP2BIntron5 to the nucleus of iPSC-derived cortical neurons. Site-directed mutagenesis of key hydrophobic residues in the NES abolishes nuclear export.","method":"CRM1 inhibition (leptomycin B), site-directed mutagenesis, iPSC-derived cortical neuron localization, functional NES assay","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis plus pharmacological inhibition plus human iPSC-derived neurons, multiple orthogonal approaches","pmids":["41559796"],"is_preprint":false},{"year":2025,"finding":"CHMP2B axonal transport and recruitment to presynaptic boutons is regulated by neuronal activity and requires kinesin-binding protein (KBP); CHMP2BIntron5 shows deficient binding to KBP, resulting in little processive movement or presynaptic localization and instead oscillatory tug-of-war behavior between kinesin and dynein.","method":"Live axonal trafficking imaging in neurons, co-transport analysis, KBP binding assay, neuronal activity manipulation","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging plus binding assay plus activity manipulation, single lab","pmids":["40021219"],"is_preprint":false},{"year":2023,"finding":"CHMP2B T104N mutation causes preferential accumulation in the Golgi body (rather than ESCRT-like cytoplasmic structures), triggers Golgi stress signaling via Arf4 upregulation, and inhibits neuronal process elongation; Arf4 knockdown recovers the neuronal process elongation phenotype.","method":"Transfection in N1E-115 neuronal cell line, immunofluorescence subcellular localization, siRNA knockdown, neurite measurement","journal":"Neurology international","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, cell line model, siRNA rescue with defined pathway","pmids":["37606396"],"is_preprint":false},{"year":2025,"finding":"Truncation mutation of CHMP2B disrupts late endosome-lysosome fusion; CHMP2BIntron5 overexpression upregulates HSP70, which promotes TDP-43 aggregate degradation by enhancing recruitment to juxtanuclear quality control compartments.","method":"Transcriptomic analysis, overexpression in cells, immunofluorescence, TDP-43 aggregation assay","journal":"Neurochemistry international","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic validation of HSP70-TDP-43 link","pmids":["40316175"],"is_preprint":false},{"year":2024,"finding":"CHMP2B and ANXA11 act sequentially in membrane repair: ESCRT-III (including CHMP2B) assembles at sites of membrane damage only after initial membrane sealing by Annexins, and acts to shed damaged membranes from the cell; FTD/ALS-associated mutations in CHMP2B compromise this repair process.","method":"Live cell imaging of membrane damage response, temporal recruitment analysis, loss-of-function with disease mutants","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — temporal live imaging with functional mutant analysis, but preprint","pmids":[],"is_preprint":true}],"current_model":"CHMP2B is a core ESCRT-III subunit that polymerizes into helical filaments on PI(4,5)P2-enriched membranes (scaffolded by VPS4 activity), mediating endosome-lysosome fusion, multivesicular body biogenesis, synaptic vesicle recycling, and membrane repair; FTD/ALS-causative C-terminal truncation mutations constitutively lock CHMP2B onto endolysosomal membranes by abrogating VPS4 recruitment and a nuclear export signal, blocking endolysosomal trafficking, disrupting autophagic flux, impairing dendritic spine maturation and axonal transport, and aberrantly activating signaling pathways (Toll, Notch, CK1-TDP-43), with gain-of-function nuclear mislocalization of CHMP2BIntron5 also contributing to nuclear pore complex injury."},"narrative":{"teleology":[{"year":2005,"claim":"Identification of CHMP2B as an ESCRT-III subunit whose C-terminal truncation through aberrant splicing causes frontotemporal dementia established the first link between ESCRT-III dysfunction and neurodegeneration.","evidence":"Genetic mapping and mRNA splicing analysis in FTD3 patient tissue","pmids":["16041373"],"confidence":"High","gaps":["Mechanism by which C-terminal truncation disrupts ESCRT-III function was unknown","Whether phenotype is loss-of-function or gain-of-function was unresolved"]},{"year":2007,"claim":"Demonstrating that C-terminally truncated CHMP2B mutants cause large aberrant endosomal structures upon overexpression established a dominant-negative or gain-of-function cellular mechanism rather than simple haploinsufficiency.","evidence":"Overexpression of two independent truncation mutants in SK-N-SH neuroblastoma cells with immunofluorescence","pmids":["17956895"],"confidence":"High","gaps":["Which step of endosomal trafficking was specifically disrupted remained unclear","Relevance at physiological expression levels not tested"]},{"year":2009,"claim":"An unbiased Drosophila genetic screen revealed the Toll signaling pathway as a major downstream effector of mutant CHMP2B toxicity, expanding the pathogenic mechanism beyond simple endosomal blockade to signaling misregulation.","evidence":"Genome-wide genetic modifier screen in Drosophila, epistasis with serpin5/Spaetzle","pmids":["19581577"],"confidence":"Medium","gaps":["Whether Toll pathway activation occurs in mammalian neurons was not established","Whether Toll activation is a direct consequence of endosomal trapping or an indirect effect was unclear"]},{"year":2010,"claim":"Multiple studies converged to define the specific trafficking defect: mutant CHMP2B blocks endosome-lysosome fusion by constitutively binding MVBs and preventing Rab7 recruitment, while also impairing autophagic flux and dendritic spine maturation in neurons.","evidence":"Functional endocytic fusion assays in patient fibroblasts (Rab7 mechanism), LC3-II western blots, confocal morphometry and electrophysiology in hippocampal neurons with RNAi phenocopy","pmids":["20223751","20352044","20699355"],"confidence":"High","gaps":["How CHMP2B promotes Rab7 recruitment at the molecular level was not defined","Whether spine maturation defects are caused by endosomal dysfunction or a distinct CHMP2B function was unknown"]},{"year":2011,"claim":"Cryo-EM visualization of CHMP2B helical filaments on membrane tubes upon VPS4 depletion revealed the structural basis of ESCRT-III polymerization and membrane remodeling by CHMP2B.","evidence":"VPS4 depletion, cryo-electron microscopy of membrane tubes in cells","pmids":["21926173"],"confidence":"High","gaps":["Atomic-resolution structure of CHMP2B filament was not obtained","How VPS4 disassembles the filament at the molecular level remained unknown"]},{"year":2012,"claim":"Transgenic mouse studies definitively established a gain-of-function mechanism: mutant CHMP2B mice develop progressive p62/ubiquitin-positive neurodegeneration with axonal transport defects, while knockout and wild-type transgenic mice do not; genetic modifier studies identified syntaxin 13 as an ESCRT-III-dependent regulator of autophagosome maturation.","evidence":"Transgenic and knockout mouse histopathology; Drosophila genetic modifier screen validated by mammalian siRNA knockdown with autophagic flux assays","pmids":["22366797","24095276","22521643"],"confidence":"High","gaps":["Whether p62-positive inclusions are causative or correlative in neurodegeneration was unclear","Whether syntaxin 13 acts directly on CHMP2B or in parallel was not resolved"]},{"year":2013,"claim":"Demonstration that mutant CHMP2B traps Notch in enlarged endosomes and drives ectopic Notch signaling—rescuable by partial Notch loss—provided evidence that receptor signaling deregulation contributes to CHMP2B-mediated neurodegeneration.","evidence":"Drosophila transgenic expression with Notch loss-of-function genetic rescue","pmids":["24158394"],"confidence":"Medium","gaps":["Whether Notch pathway activation occurs in mammalian neurons expressing mutant CHMP2B was not shown","Other trapped signaling receptors were not systematically catalogued"]},{"year":2015,"claim":"Quantitative immuno-EM localized endogenous CHMP2B beneath the perisynaptic membrane of dendritic spines, where it forms a stable complex with other CHMPs and postsynaptic scaffolds; depletion abolished activity-induced spine enlargement and LTP, establishing a direct synaptic function for CHMP2B.","evidence":"Immuno-electron microscopy, co-IP/mass spectrometry from synaptoneurosomes, shRNA knockdown with in vivo spine density and LTP electrophysiology","pmids":["25698751"],"confidence":"High","gaps":["The mechanism by which CHMP2B supports spine enlargement (membrane addition, receptor trafficking, or scaffold organization) was not resolved","Identity of the stable postsynaptic complex was not fully defined"]},{"year":2015,"claim":"Lysosomal storage pathology was confirmed in both transgenic mice expressing mutant CHMP2B at physiological levels and in FTD patient brains, validating the endolysosomal degradation block as an early feature of disease.","evidence":"Transgenic mouse model, electron microscopy, immuno-gold labelling, patient brain immunofluorescence","pmids":["26358247"],"confidence":"High","gaps":["Whether lysosomal storage precedes or follows autophagy impairment was not temporally resolved"]},{"year":2018,"claim":"Two key mechanistic advances defined CHMP2B's biophysical behavior: in vitro reconstitution showed CHMP2B preferentially binds PI(4,5)P2-containing membranes and acts as a diffusion barrier at membrane necks, while neuronal studies demonstrated that mutant CHMP2B fails to recruit VPS4, locking it onto endolysosomes and blocking their trafficking in dendrites.","evidence":"Purified protein reconstitution on GUVs and pulled nanotubes; live imaging of endolysosomal trafficking in neurons with VPS4 interaction assay and ASO rescue","pmids":["29967034","30496365"],"confidence":"High","gaps":["Whether the diffusion barrier function operates at endosomal necks in vivo was not tested","How TMEM106B ASO rescue mechanistically restores trafficking was not fully elucidated"]},{"year":2021,"claim":"CHMP2B was shown to regulate TDP-43 phosphorylation through a non-autophagic pathway by controlling CK1 kinase stability via ubiquitin-proteasome turnover, and independently, mutant CHMP2B was found to cause presynaptic synaptopathy with selective synaptic vesicle recycling defects; biophysical comparison showed CHMP2B uniquely rigidifies membranes compared to CHMP2A/CHMP3.","evidence":"Drosophila genetic screen validated in mammalian cells with CK1 ubiquitination assay; transgenic mouse histology with FM dye SV recycling; purified protein membrane mechanics measurements","pmids":["34726688","34855215","33832485"],"confidence":"High","gaps":["Whether CK1 regulation is a direct binding interaction or mediated through endosomal signaling was not established","Relative contribution of pre- vs. postsynaptic dysfunction to neurodegeneration was unclear"]},{"year":2022,"claim":"Mutant CHMP2BIntron5 was found to sequester spastin (an endosomal microtubule-severing enzyme) into insoluble p62-positive aggregates, providing a mechanism for cytoskeletal disruption downstream of ESCRT-III dysfunction.","evidence":"Co-immunoprecipitation, subcellular fractionation in cells and mouse brain, Drosophila genetic epistasis","pmids":["36414997"],"confidence":"Medium","gaps":["Whether spastin sequestration contributes to axonal transport defects was not directly tested","Stoichiometry of the CHMP2B-spastin interaction was not defined"]},{"year":2024,"claim":"CHMP2B was identified as a driver of nuclear pore complex injury in sporadic ALS: sustained CHMP2B activity promotes pathologic CHMP7 nuclear accumulation and nucleoporin POM121 loss, and partial CHMP2B knockdown rescues NPC integrity and TDP-43 mislocalization in sALS iPSC neurons.","evidence":"iPSC-derived sALS neuron model, CHMP2B knockdown, super-resolution NPC imaging, TDP-43 localization","pmids":["39709457"],"confidence":"Medium","gaps":["How CHMP2B activates CHMP7 nuclear accumulation mechanistically was not resolved","Whether this pathway operates in FTD3 patient neurons was not tested"]},{"year":2025,"claim":"CHMP2B axonal transport was shown to depend on kinesin-binding protein (KBP) and to be regulated by neuronal activity; the CHMP2BIntron5 mutant loses KBP binding, resulting in aberrant bidirectional tug-of-war transport and failure to reach presynaptic boutons.","evidence":"Live axonal trafficking imaging, co-transport analysis, KBP binding assay, neuronal activity manipulation","pmids":["40021219"],"confidence":"Medium","gaps":["Whether KBP interaction is direct or scaffolded was not resolved","Whether restoring presynaptic localization is sufficient to rescue synaptic defects was not tested"]},{"year":2026,"claim":"Discovery of a CRM1-dependent nuclear export signal in the CHMP2B C-terminus explained why the FTD3-causative CHMP2BIntron5 truncation mislocalizes to the nucleus, adding a nuclear gain-of-function mechanism to the cytoplasmic endolysosomal trafficking defect.","evidence":"CRM1 inhibition (leptomycin B), site-directed mutagenesis of NES residues, iPSC-derived cortical neuron localization","pmids":["41559796"],"confidence":"High","gaps":["Nuclear targets or chromatin effects of mislocalized CHMP2BIntron5 were not identified","Whether nuclear CHMP2B contributes to NPC injury independently of CHMP7 was not tested"]},{"year":null,"claim":"Key unresolved questions include: the atomic structure of CHMP2B filaments, the physiological function of CHMP2B at synapses (membrane remodeling vs. signaling scaffold), the relative pathogenic contributions of endolysosomal blockade, nuclear mislocalization, and signaling deregulation in human FTD/ALS, and whether CHMP2B's membrane repair function is relevant to neurodegeneration.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of CHMP2B filaments exists","Relative contribution of nuclear vs. cytoplasmic gain-of-function to disease is unknown","Membrane repair role has not been validated in neurons in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[14,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,14,16]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2,8,13]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[23]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,18]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,7,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,10,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15]}],"complexes":["ESCRT-III"],"partners":["VPS4","CHMP7","CHMP4B","TMEM106B","SPAST","KBP","STX13","CK1"],"other_free_text":[]},"mechanistic_narrative":"CHMP2B is a subunit of the ESCRT-III complex that polymerizes into helical filaments on PI(4,5)P2-enriched membranes, forming a diffusion barrier at membrane necks and rigidifying the lipid bilayer; its disassembly requires recruitment of the VPS4 ATPase via the CHMP2B C-terminus [PMID:21926173, PMID:29967034, PMID:33832485]. CHMP2B functions in endosome-lysosome fusion, multivesicular body biogenesis, autophagic flux, synaptic vesicle recycling, dendritic spine maturation, and nuclear pore complex homeostasis, and it regulates CK1-dependent TDP-43 phosphorylation independently of autophagy [PMID:20223751, PMID:25698751, PMID:34726688, PMID:39709457]. Its C-terminus also harbors a CRM1-dependent nuclear export signal whose loss in the FTD3-causative CHMP2BIntron5 truncation mutant causes nuclear mislocalization; C-terminal truncation mutations lock CHMP2B onto endolysosomal membranes by abolishing VPS4 recruitment, producing gain-of-function endolysosomal trafficking failure, lysosomal storage pathology, and progressive neurodegeneration [PMID:16041373, PMID:30496365, PMID:41559796, PMID:22366797]. Mutations in CHMP2B cause chromosome 3-linked frontotemporal dementia (FTD3) and have been implicated in ALS-associated nuclear pore complex injury [PMID:16041373, PMID:39709457]."},"prefetch_data":{"uniprot":{"accession":"Q9UQN3","full_name":"Charged multivesicular body protein 2b","aliases":["CHMP2.5","Chromatin-modifying protein 2b","CHMP2b","Vacuolar protein sorting-associated protein 2-2","Vps2-2","hVps2-2"],"length_aa":213,"mass_kda":23.9,"function":"Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4","subcellular_location":"Cytoplasm, cytosol; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UQN3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHMP2B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000083937","cell_line_id":"CID000774","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"CADPS","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000774","total_profiled":1310},"omim":[{"mim_id":"609983","title":"VACUOLAR PROTEIN SORTING 4 HOMOLOG B; 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tau","date":"2024-12-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.27.630547","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.06.602309","title":"Non canonical activation of the ESCRT machinery is required for division of<i>Leishmania donovani</i>parasitophorous vacuoles and parasite persistence","date":"2024-07-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.06.602309","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37554,"output_tokens":6417,"usd":0.104458},"stage2":{"model":"claude-opus-4-6","input_tokens":10044,"output_tokens":4118,"usd":0.229755},"total_usd":0.334213,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"CHMP2B is a component of the endosomal ESCRT-III complex; a splice-site mutation causes aberrant mRNA splicing leading to C-terminal truncation of the protein, disrupting ESCRT-III function and causing frontotemporal dementia.\",\n      \"method\": \"Genetic mapping, mRNA splicing analysis in patient tissue samples\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery paper, widely replicated, foundational mechanistic finding\",\n      \"pmids\": [\"16041373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C-terminally truncated CHMP2B mutants (p.Met178ValfsX2 and p.Gln165X) cause formation of large aberrant endosomal structures when overexpressed in human neuroblastoma cells, establishing that C-truncating mutations disrupt endosome function through a dominant-negative or gain-of-function mechanism.\",\n      \"method\": \"Overexpression in SK-N-SH cells, immunofluorescence microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2-3 — replicated across two independent mutations in two independent labs; strong preponderance\",\n      \"pmids\": [\"17956895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mutant CHMP2B causes a specific disruption of endosome-lysosome fusion (but not MVB protein sorting) by constitutively binding to MVBs and preventing recruitment of Rab7, a protein required for fusion.\",\n      \"method\": \"Functional endocytic assays in patient fibroblasts, immunofluorescence, patient brain pathology analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (functional fusion assay, patient fibroblasts, brain pathology), Rab7 recruitment mechanistically defined\",\n      \"pmids\": [\"20223751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mutant CHMP2B (CHMP2BIntron5) causes aberrant lysosomal localisation and impairment of autophagy (increased LC3-II levels) when transfected into HEK-293 and COS-7 cells, forming large cytoplasmic vacuoles absent with wild-type CHMP2B.\",\n      \"method\": \"Transfection of mutant vs. wild-type CHMP2B, CD63 immunostaining, LC3-II western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple readouts in cell lines, consistent with patient data, single lab\",\n      \"pmids\": [\"20352044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHMP2B is required for dendritic spine maturation; FTD-linked mutants (CHMP2BIntron5 and CHMP2BΔ10) reduce the proportion of mushroom-shaped large spines in hippocampal neurons and decrease frequency and amplitude of spontaneous excitatory postsynaptic currents. RNAi depletion of endogenous CHMP2B phenocopies mutant overexpression, indicating dominant-negative activity.\",\n      \"method\": \"Confocal microscopy with 3D reconstruction in cultured hippocampal neurons, electrophysiology (mEPSC recording), RNAi knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (morphology, electrophysiology, RNAi), functional consequence clearly defined\",\n      \"pmids\": [\"20699355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Full-length CHMP2B polymerizes into long rigid membrane tubes protruding from the cell surface when VPS4 is depleted; cryo-EM demonstrates CHMP2B forms a tightly packed helical lattice in close association with the inner leaflet of the membrane tube, deforming the lipid bilayer. CHMP4s relocalize to the base of CHMP2B tubes.\",\n      \"method\": \"VPS4 depletion, overexpression, cryo-electron microscopy, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural characterization plus functional in cellulo validation\",\n      \"pmids\": [\"21926173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Transgenic mice expressing C-terminally truncated mutant CHMP2B develop neurodegeneration through a gain-of-function mechanism: progressive p62/ubiquitin-positive (TDP-43-negative) inclusions, gliosis, and axonal swellings with amyloid precursor protein accumulation. Knockout mice and wild-type CHMP2B transgenic mice show none of these changes.\",\n      \"method\": \"Transgenic and knockout mouse generation, histopathology, immunohistochemistry\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain-of-function vs. loss-of-function comparison with specific phenotypic readouts\",\n      \"pmids\": [\"22366797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Syntaxin 13 (STX13) is a genetic modifier of ESCRT-III dysfunction caused by mutant CHMP2B; knockdown of STX13 or its binding partner Vti1a in mammalian cells causes LC3-positive autophagosome accumulation and blocks autophagic flux; STX13 localizes on LC3-positive phagophores and participates in phagophore maturation into closed autophagosomes.\",\n      \"method\": \"Drosophila genetic modifier screen, mammalian siRNA knockdown, LC3 immunofluorescence, autophagic flux assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila confirmed by mammalian cell knockdown with multiple functional readouts\",\n      \"pmids\": [\"24095276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CHMP2B missense mutant T104N accumulates in Rab5- and Rab7-positive endosomes, causes delayed EGFR degradation, shows reduced association with VPS4 ATPase, increased association with Snf7-2 (ESCRT-III core), and causes autophagosome accumulation in post-mitotic neurons.\",\n      \"method\": \"Overexpression in neurons, immunofluorescence, co-immunoprecipitation, EGFR degradation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple assays but relatively limited functional follow-up\",\n      \"pmids\": [\"22521643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Expression of CHMP2BIntron5 in Drosophila causes Notch accumulation in enlarged endosomes and upregulation of Notch activity; partial loss of Notch rescues eye deformities, indicating that mutant CHMP2B drives neurodegeneration-associated phenotypes through Notch misregulation in this context.\",\n      \"method\": \"Drosophila transgenic expression, genetic epistasis (Notch loss-of-function rescue), immunofluorescence\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with rescue, but Drosophila model and context-dependent signaling\",\n      \"pmids\": [\"24158394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endogenous Chmp2b concentrates beneath the perisynaptic membrane of dendritic spines (quantitative immuno-EM); Chmp2b depletion reduces dendritic branching and excitatory synapse density in vitro and in vivo and abolishes activity-induced spine enlargement and synaptic potentiation; Chmp2b is stably bound in synaptoneurosome lysates to a large complex containing other CHMP family members and postsynaptic scaffolds.\",\n      \"method\": \"Quantitative immuno-electron microscopy, co-immunoprecipitation, mass spectrometry, shRNA knockdown, in vivo spine density measurement, LTP electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including ultrastructural localization, biochemical interaction, and functional LTP readout\",\n      \"pmids\": [\"25698751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mutant CHMP2B causes lysosomal storage pathology in neurons: transgenic mice expressing FTD-causative mutant CHMP2B at physiological levels develop large neuronal autofluorescent aggregates derived from the endolysosomal system, confirmed by ultrastructural analysis and immuno-gold labelling; similar aggregates are found in patient brains.\",\n      \"method\": \"Transgenic mouse model, electron microscopy, immuno-gold labelling, patient brain immunofluorescence\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mouse model plus human patient tissue, ultrastructural confirmation, strong preponderance\",\n      \"pmids\": [\"26358247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMEM106B associates with CHMP2B-positive endosomal structures; the TMEM106B T185 variant associates more strongly with CHMP2B than S185 and enhances CHMP2B(Intron5)-induced EGFR accumulation, autophagy impairment, and neurotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, autophagic flux assay, neurotoxicity assay\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP plus functional readouts but limited mechanistic depth\",\n      \"pmids\": [\"26651479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutant CHMP2B stably incorporates onto neuronal endolysosomes, rendering them unable to traffic within dendrites. This is mechanistically due to inability of mutant CHMP2B to recruit the ATPase VPS4, which is required for CHMP2B release from endosomal membranes. TMEM106B antisense oligonucleotide treatment rescues both impaired trafficking and increased dendritic branching.\",\n      \"method\": \"Live imaging of endolysosomal trafficking, CHMP2B-VPS4 interaction assay, antisense oligonucleotide rescue in neurons expressing physiological levels of mutant CHMP2B\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic VPS4 recruitment defect demonstrated, trafficking phenotype, rescue experiment\",\n      \"pmids\": [\"30496365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHMP2B polymerization on reconstituted membrane nanotubes acts as a diffusion barrier: CHMP2B (full-length and ΔC) preferentially binds membranes containing PI(4,5)P2, accumulates at nanotube necks, and prevents diffusion of PI(4,5)P2 lipids and membrane-bound proteins across the neck.\",\n      \"method\": \"In vitro reconstitution in giant unilamellar vesicles, pulled membrane nanotubes, fluorescence microscopy, purified protein binding assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified protein and defined lipid systems\",\n      \"pmids\": [\"29967034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In a Drosophila model of FTD3, serpin5 (a serine protease inhibitor) suppresses mutant CHMP2B toxicity by acting as a negative regulator of the Toll pathway, blocking proteolytic activation of Spaetzle (Toll receptor ligand) extracellularly; the Toll signaling pathway is identified as a major pathway misregulated by mutant CHMP2B in vivo.\",\n      \"method\": \"Genome-wide genetic modifier screen in Drosophila, epistasis analysis, gain/loss-of-function genetics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genetic screen with epistasis validation, but Drosophila model\",\n      \"pmids\": [\"19581577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHMP2B binding to membranes is enhanced by PI(4,5)P2 lipids (unlike CHMP2A which requires CHMP3 and lacks lipid specificity); CHMP2B strongly rigidifies membranes upon polymerization while CHMP2A+CHMP3 does not, demonstrating distinct mechanical properties between ESCRT-III isoforms.\",\n      \"method\": \"In vitro binding assays with purified proteins and biomimetic membrane systems, membrane mechanics measurements, fluorescence microscopy\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods with purified proteins on defined lipid systems\",\n      \"pmids\": [\"33832485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independently of autophagy through modulation of CK1 kinase: CHMP2B negatively regulates ubiquitination and proteasome-mediated turnover of CK1, thereby controlling CK1 protein levels and TDP-43 phosphorylation.\",\n      \"method\": \"Drosophila genetic screen, mammalian cell knockdown/overexpression, CK1 ubiquitination assay, TDP-43 phosphorylation western blot\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic screen validated in mammalian cells with biochemical ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"34726688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutant CHMP2B causes a novel synaptopathy: selective retention of presynaptic synaptic vesicle trafficking proteins in aged transgenic mice, increased presynaptic endosomes, defective synaptic vesicle recycling and altered functional SV pools, while postsynaptic proteins are lost.\",\n      \"method\": \"Transgenic mouse histology, ultrastructural analysis of primary cortical cultures, FM dye SV recycling assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model plus ultrastructure plus functional SV recycling assay, single lab\",\n      \"pmids\": [\"34855215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mutant CHMP2BIntron5 associates with spastin with greater affinity than wild-type CHMP2B and colocalizes in p62-positive aggregates; spastin is sequestered from the soluble cytoplasmic fraction to the insoluble fraction in cells and mouse brain neurons expressing CHMP2BIntron5; genetic knockdown of spastin enhances CHMP2BIntron5 toxicity in Drosophila.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, subcellular fractionation, Drosophila genetic epistasis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP, fractionation, in vivo mouse, Drosophila epistasis; single lab\",\n      \"pmids\": [\"36414997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT6 regulates CHMP2B levels in the heart by decreasing acetylation of FoxO1, promoting its transcriptional activation of Atrogin-1 (a muscle-specific ubiquitin ligase), which subsequently mediates ubiquitin-proteasome degradation of CHMP2B.\",\n      \"method\": \"Mouse cardiac SIRT6 heterozygous knockout, FoxO1 acetylation assay, Atrogin-1 transcriptional reporter, CHMP2B degradation assay\",\n      \"journal\": \"Journal of cardiovascular translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identified PTM writer pathway with functional rescue, but single lab cardiac context\",\n      \"pmids\": [\"35235147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Partial loss of Ik2 (fly TBK1 homologue) enhances mutant CHMP2B toxicity in the fly eye while Ik2 overexpression suppresses it; loss of Spn-F (Ik2 phosphorylation target), dynein light chain (cut up), or Hook (early endosome transport adaptor) also enhances mutant CHMP2B toxicity, implicating early endosome transport as a contributing pathway.\",\n      \"method\": \"Drosophila genetic epistasis, interactome analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila with interactome validation, but functional mechanism inferred\",\n      \"pmids\": [\"32848189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHMP2B promotes CHMP7-mediated nuclear pore complex (NPC) injury in sporadic ALS neurons: sustained CHMP2B-dependent activation is sufficient to cause pathologic CHMP7 nuclear accumulation and POM121 (nucleoporin) reduction; partial knockdown of CHMP2B alleviates NPC injury and downstream TDP-43 dysfunction in sALS iPSC-derived neurons.\",\n      \"method\": \"iPSC-derived neuron model of sALS, CHMP2B knockdown, super-resolution microscopy, NPC integrity assay, TDP-43 localization\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — iPSC neuron model with knockdown rescue and defined NPC phenotype, single lab\",\n      \"pmids\": [\"39709457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Wild-type CHMP2B contains a nuclear export signal (NES) in its C-terminus that mediates CRM1-dependent nuclear export; the FTD3-causative CHMP2BIntron5 mutation removes this NES, causing mislocalization of CHMP2BIntron5 to the nucleus of iPSC-derived cortical neurons. Site-directed mutagenesis of key hydrophobic residues in the NES abolishes nuclear export.\",\n      \"method\": \"CRM1 inhibition (leptomycin B), site-directed mutagenesis, iPSC-derived cortical neuron localization, functional NES assay\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus pharmacological inhibition plus human iPSC-derived neurons, multiple orthogonal approaches\",\n      \"pmids\": [\"41559796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHMP2B axonal transport and recruitment to presynaptic boutons is regulated by neuronal activity and requires kinesin-binding protein (KBP); CHMP2BIntron5 shows deficient binding to KBP, resulting in little processive movement or presynaptic localization and instead oscillatory tug-of-war behavior between kinesin and dynein.\",\n      \"method\": \"Live axonal trafficking imaging in neurons, co-transport analysis, KBP binding assay, neuronal activity manipulation\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging plus binding assay plus activity manipulation, single lab\",\n      \"pmids\": [\"40021219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHMP2B T104N mutation causes preferential accumulation in the Golgi body (rather than ESCRT-like cytoplasmic structures), triggers Golgi stress signaling via Arf4 upregulation, and inhibits neuronal process elongation; Arf4 knockdown recovers the neuronal process elongation phenotype.\",\n      \"method\": \"Transfection in N1E-115 neuronal cell line, immunofluorescence subcellular localization, siRNA knockdown, neurite measurement\",\n      \"journal\": \"Neurology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, cell line model, siRNA rescue with defined pathway\",\n      \"pmids\": [\"37606396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Truncation mutation of CHMP2B disrupts late endosome-lysosome fusion; CHMP2BIntron5 overexpression upregulates HSP70, which promotes TDP-43 aggregate degradation by enhancing recruitment to juxtanuclear quality control compartments.\",\n      \"method\": \"Transcriptomic analysis, overexpression in cells, immunofluorescence, TDP-43 aggregation assay\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic validation of HSP70-TDP-43 link\",\n      \"pmids\": [\"40316175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHMP2B and ANXA11 act sequentially in membrane repair: ESCRT-III (including CHMP2B) assembles at sites of membrane damage only after initial membrane sealing by Annexins, and acts to shed damaged membranes from the cell; FTD/ALS-associated mutations in CHMP2B compromise this repair process.\",\n      \"method\": \"Live cell imaging of membrane damage response, temporal recruitment analysis, loss-of-function with disease mutants\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — temporal live imaging with functional mutant analysis, but preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CHMP2B is a core ESCRT-III subunit that polymerizes into helical filaments on PI(4,5)P2-enriched membranes (scaffolded by VPS4 activity), mediating endosome-lysosome fusion, multivesicular body biogenesis, synaptic vesicle recycling, and membrane repair; FTD/ALS-causative C-terminal truncation mutations constitutively lock CHMP2B onto endolysosomal membranes by abrogating VPS4 recruitment and a nuclear export signal, blocking endolysosomal trafficking, disrupting autophagic flux, impairing dendritic spine maturation and axonal transport, and aberrantly activating signaling pathways (Toll, Notch, CK1-TDP-43), with gain-of-function nuclear mislocalization of CHMP2BIntron5 also contributing to nuclear pore complex injury.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CHMP2B is a subunit of the ESCRT-III complex that polymerizes into helical filaments on PI(4,5)P2-enriched membranes, forming a diffusion barrier at membrane necks and rigidifying the lipid bilayer; its disassembly requires recruitment of the VPS4 ATPase via the CHMP2B C-terminus [PMID:21926173, PMID:29967034, PMID:33832485]. CHMP2B functions in endosome-lysosome fusion, multivesicular body biogenesis, autophagic flux, synaptic vesicle recycling, dendritic spine maturation, and nuclear pore complex homeostasis, and it regulates CK1-dependent TDP-43 phosphorylation independently of autophagy [PMID:20223751, PMID:25698751, PMID:34726688, PMID:39709457]. Its C-terminus also harbors a CRM1-dependent nuclear export signal whose loss in the FTD3-causative CHMP2BIntron5 truncation mutant causes nuclear mislocalization; C-terminal truncation mutations lock CHMP2B onto endolysosomal membranes by abolishing VPS4 recruitment, producing gain-of-function endolysosomal trafficking failure, lysosomal storage pathology, and progressive neurodegeneration [PMID:16041373, PMID:30496365, PMID:41559796, PMID:22366797]. Mutations in CHMP2B cause chromosome 3-linked frontotemporal dementia (FTD3) and have been implicated in ALS-associated nuclear pore complex injury [PMID:16041373, PMID:39709457].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of CHMP2B as an ESCRT-III subunit whose C-terminal truncation through aberrant splicing causes frontotemporal dementia established the first link between ESCRT-III dysfunction and neurodegeneration.\",\n      \"evidence\": \"Genetic mapping and mRNA splicing analysis in FTD3 patient tissue\",\n      \"pmids\": [\"16041373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which C-terminal truncation disrupts ESCRT-III function was unknown\", \"Whether phenotype is loss-of-function or gain-of-function was unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that C-terminally truncated CHMP2B mutants cause large aberrant endosomal structures upon overexpression established a dominant-negative or gain-of-function cellular mechanism rather than simple haploinsufficiency.\",\n      \"evidence\": \"Overexpression of two independent truncation mutants in SK-N-SH neuroblastoma cells with immunofluorescence\",\n      \"pmids\": [\"17956895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which step of endosomal trafficking was specifically disrupted remained unclear\", \"Relevance at physiological expression levels not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"An unbiased Drosophila genetic screen revealed the Toll signaling pathway as a major downstream effector of mutant CHMP2B toxicity, expanding the pathogenic mechanism beyond simple endosomal blockade to signaling misregulation.\",\n      \"evidence\": \"Genome-wide genetic modifier screen in Drosophila, epistasis with serpin5/Spaetzle\",\n      \"pmids\": [\"19581577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Toll pathway activation occurs in mammalian neurons was not established\", \"Whether Toll activation is a direct consequence of endosomal trapping or an indirect effect was unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Multiple studies converged to define the specific trafficking defect: mutant CHMP2B blocks endosome-lysosome fusion by constitutively binding MVBs and preventing Rab7 recruitment, while also impairing autophagic flux and dendritic spine maturation in neurons.\",\n      \"evidence\": \"Functional endocytic fusion assays in patient fibroblasts (Rab7 mechanism), LC3-II western blots, confocal morphometry and electrophysiology in hippocampal neurons with RNAi phenocopy\",\n      \"pmids\": [\"20223751\", \"20352044\", \"20699355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHMP2B promotes Rab7 recruitment at the molecular level was not defined\", \"Whether spine maturation defects are caused by endosomal dysfunction or a distinct CHMP2B function was unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cryo-EM visualization of CHMP2B helical filaments on membrane tubes upon VPS4 depletion revealed the structural basis of ESCRT-III polymerization and membrane remodeling by CHMP2B.\",\n      \"evidence\": \"VPS4 depletion, cryo-electron microscopy of membrane tubes in cells\",\n      \"pmids\": [\"21926173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of CHMP2B filament was not obtained\", \"How VPS4 disassembles the filament at the molecular level remained unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Transgenic mouse studies definitively established a gain-of-function mechanism: mutant CHMP2B mice develop progressive p62/ubiquitin-positive neurodegeneration with axonal transport defects, while knockout and wild-type transgenic mice do not; genetic modifier studies identified syntaxin 13 as an ESCRT-III-dependent regulator of autophagosome maturation.\",\n      \"evidence\": \"Transgenic and knockout mouse histopathology; Drosophila genetic modifier screen validated by mammalian siRNA knockdown with autophagic flux assays\",\n      \"pmids\": [\"22366797\", \"24095276\", \"22521643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p62-positive inclusions are causative or correlative in neurodegeneration was unclear\", \"Whether syntaxin 13 acts directly on CHMP2B or in parallel was not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that mutant CHMP2B traps Notch in enlarged endosomes and drives ectopic Notch signaling—rescuable by partial Notch loss—provided evidence that receptor signaling deregulation contributes to CHMP2B-mediated neurodegeneration.\",\n      \"evidence\": \"Drosophila transgenic expression with Notch loss-of-function genetic rescue\",\n      \"pmids\": [\"24158394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Notch pathway activation occurs in mammalian neurons expressing mutant CHMP2B was not shown\", \"Other trapped signaling receptors were not systematically catalogued\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantitative immuno-EM localized endogenous CHMP2B beneath the perisynaptic membrane of dendritic spines, where it forms a stable complex with other CHMPs and postsynaptic scaffolds; depletion abolished activity-induced spine enlargement and LTP, establishing a direct synaptic function for CHMP2B.\",\n      \"evidence\": \"Immuno-electron microscopy, co-IP/mass spectrometry from synaptoneurosomes, shRNA knockdown with in vivo spine density and LTP electrophysiology\",\n      \"pmids\": [\"25698751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The mechanism by which CHMP2B supports spine enlargement (membrane addition, receptor trafficking, or scaffold organization) was not resolved\", \"Identity of the stable postsynaptic complex was not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Lysosomal storage pathology was confirmed in both transgenic mice expressing mutant CHMP2B at physiological levels and in FTD patient brains, validating the endolysosomal degradation block as an early feature of disease.\",\n      \"evidence\": \"Transgenic mouse model, electron microscopy, immuno-gold labelling, patient brain immunofluorescence\",\n      \"pmids\": [\"26358247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lysosomal storage precedes or follows autophagy impairment was not temporally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two key mechanistic advances defined CHMP2B's biophysical behavior: in vitro reconstitution showed CHMP2B preferentially binds PI(4,5)P2-containing membranes and acts as a diffusion barrier at membrane necks, while neuronal studies demonstrated that mutant CHMP2B fails to recruit VPS4, locking it onto endolysosomes and blocking their trafficking in dendrites.\",\n      \"evidence\": \"Purified protein reconstitution on GUVs and pulled nanotubes; live imaging of endolysosomal trafficking in neurons with VPS4 interaction assay and ASO rescue\",\n      \"pmids\": [\"29967034\", \"30496365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the diffusion barrier function operates at endosomal necks in vivo was not tested\", \"How TMEM106B ASO rescue mechanistically restores trafficking was not fully elucidated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CHMP2B was shown to regulate TDP-43 phosphorylation through a non-autophagic pathway by controlling CK1 kinase stability via ubiquitin-proteasome turnover, and independently, mutant CHMP2B was found to cause presynaptic synaptopathy with selective synaptic vesicle recycling defects; biophysical comparison showed CHMP2B uniquely rigidifies membranes compared to CHMP2A/CHMP3.\",\n      \"evidence\": \"Drosophila genetic screen validated in mammalian cells with CK1 ubiquitination assay; transgenic mouse histology with FM dye SV recycling; purified protein membrane mechanics measurements\",\n      \"pmids\": [\"34726688\", \"34855215\", \"33832485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CK1 regulation is a direct binding interaction or mediated through endosomal signaling was not established\", \"Relative contribution of pre- vs. postsynaptic dysfunction to neurodegeneration was unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mutant CHMP2BIntron5 was found to sequester spastin (an endosomal microtubule-severing enzyme) into insoluble p62-positive aggregates, providing a mechanism for cytoskeletal disruption downstream of ESCRT-III dysfunction.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation in cells and mouse brain, Drosophila genetic epistasis\",\n      \"pmids\": [\"36414997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether spastin sequestration contributes to axonal transport defects was not directly tested\", \"Stoichiometry of the CHMP2B-spastin interaction was not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CHMP2B was identified as a driver of nuclear pore complex injury in sporadic ALS: sustained CHMP2B activity promotes pathologic CHMP7 nuclear accumulation and nucleoporin POM121 loss, and partial CHMP2B knockdown rescues NPC integrity and TDP-43 mislocalization in sALS iPSC neurons.\",\n      \"evidence\": \"iPSC-derived sALS neuron model, CHMP2B knockdown, super-resolution NPC imaging, TDP-43 localization\",\n      \"pmids\": [\"39709457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CHMP2B activates CHMP7 nuclear accumulation mechanistically was not resolved\", \"Whether this pathway operates in FTD3 patient neurons was not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CHMP2B axonal transport was shown to depend on kinesin-binding protein (KBP) and to be regulated by neuronal activity; the CHMP2BIntron5 mutant loses KBP binding, resulting in aberrant bidirectional tug-of-war transport and failure to reach presynaptic boutons.\",\n      \"evidence\": \"Live axonal trafficking imaging, co-transport analysis, KBP binding assay, neuronal activity manipulation\",\n      \"pmids\": [\"40021219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KBP interaction is direct or scaffolded was not resolved\", \"Whether restoring presynaptic localization is sufficient to rescue synaptic defects was not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovery of a CRM1-dependent nuclear export signal in the CHMP2B C-terminus explained why the FTD3-causative CHMP2BIntron5 truncation mislocalizes to the nucleus, adding a nuclear gain-of-function mechanism to the cytoplasmic endolysosomal trafficking defect.\",\n      \"evidence\": \"CRM1 inhibition (leptomycin B), site-directed mutagenesis of NES residues, iPSC-derived cortical neuron localization\",\n      \"pmids\": [\"41559796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear targets or chromatin effects of mislocalized CHMP2BIntron5 were not identified\", \"Whether nuclear CHMP2B contributes to NPC injury independently of CHMP7 was not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the atomic structure of CHMP2B filaments, the physiological function of CHMP2B at synapses (membrane remodeling vs. signaling scaffold), the relative pathogenic contributions of endolysosomal blockade, nuclear mislocalization, and signaling deregulation in human FTD/ALS, and whether CHMP2B's membrane repair function is relevant to neurodegeneration.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of CHMP2B filaments exists\", \"Relative contribution of nuclear vs. cytoplasmic gain-of-function to disease is unknown\", \"Membrane repair role has not been validated in neurons in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [14, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 14, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2, 8, 13]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 10, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"ESCRT-III\"\n    ],\n    \"partners\": [\n      \"VPS4\",\n      \"CHMP7\",\n      \"CHMP4B\",\n      \"TMEM106B\",\n      \"SPAST\",\n      \"KBP\",\n      \"STX13\",\n      \"CK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}