Affinage

TMEM106B

Transmembrane protein 106B · UniProt Q9NUM4

Length
274 aa
Mass
31.1 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM106B is a type II transmembrane protein of late endosomes and lysosomes that serves as a central regulator of lysosomal biology, controlling organelle acidification, positioning, exocytosis, and cargo degradation in neurons, glia, and other cell types. At the lysosomal membrane, TMEM106B maintains acidification through physical interaction with the vacuolar H⁺-ATPase accessory protein AP1, regulates myelin lipid metabolism via interaction with galactosylceramidase, controls anterograde lysosomal transport through MAP6- and Arl8b-dependent pathways, and promotes TFEB-driven lysosomal biogenesis and cathepsin-dependent lysosomal exocytosis (PMID:28728022, PMID:39237682, PMID:24357581, PMID:36619668, PMID:30013069). The luminal domain (residues 120–254) undergoes sequential proteolysis—first by lysosomal cysteine proteases, then by the intramembrane protease SPPL2a—generating a C-terminal fragment that accumulates as amyloid fibrils in an age-dependent manner across neurodegenerative diseases and normal aging, with the FTLD risk variant (T185) promoting higher steady-state protein levels and greater fibril core deposition (PMID:39709600, PMID:24872421, PMID:35344985, PMID:38232138). TMEM106B also functions as an ACE2-independent entry receptor for SARS-CoV-2, with its luminal domain directly engaging the spike receptor-binding motif to facilitate viral membrane fusion (PMID:37421949).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2012 High

    Establishing TMEM106B as a glycosylated type II lysosomal membrane protein whose overexpression impairs endo-lysosomal acidification and degradative function resolved the basic topology and organellar context of a gene previously known only from GWAS.

    Evidence Biochemical fractionation, glycosylation-site mutagenesis, V-ATPase inhibition, overexpression with lysosomal pH and cargo degradation assays in neuronal and non-neuronal cells

    PMID:22511793 PMID:22895706 PMID:23136129

    Open questions at the time
    • No endogenous loss-of-function data yet
    • Mechanism linking TMEM106B to V-ATPase not identified
    • Relevance to human disease beyond GWAS association unresolved
  2. 2013 High

    Identifying MAP6 as a physical interactor and demonstrating that TMEM106B controls dendritic lysosomal transport revealed a direct mechanistic link between TMEM106B and neuronal morphology, explaining how lysosomal positioning defects translate to dendritic arborization phenotypes.

    Evidence Reciprocal co-immunoprecipitation of TMEM106B–MAP6, live lysosomal transport imaging, and MAP6/RILP epistasis rescue in primary neurons

    PMID:24357581

    Open questions at the time
    • Whether MAP6 interaction is direct or bridged remains unclear
    • Axonal transport effects not yet tested
    • No structural basis for the interaction
  3. 2014 High

    Discovery that TMEM106B undergoes regulated intramembrane proteolysis—first by lysosomal proteases, then by SPPL2a—identified a processing pathway that would later prove critical for understanding amyloid fibril generation from the cleaved C-terminal fragment.

    Evidence Cell-based cleavage assays with pharmacological inhibitors and SPPL2a/2b overexpression, domain-deletion mutagenesis

    PMID:24872421

    Open questions at the time
    • Identity of the initial lysosomal protease unresolved
    • Physiological triggers for cleavage unknown
    • Fate and function of the released intracellular domain unclear
  4. 2017 High

    Demonstrating that TMEM106B physically binds the V-ATPase AP1 subunit and that Tmem106b deletion rescues lysosomal and behavioral defects of Grn−/− mice mechanistically connected TMEM106B to lysosomal acidification and established its genetic interaction with progranulin in vivo.

    Evidence Co-immunoprecipitation of TMEM106B–V-ATPase AP1, multi-omics of mouse brain, behavioral rescue in Grn−/−;Tmem106b−/− double-knockout mice

    PMID:28728022

    Open questions at the time
    • Stoichiometry and directness of V-ATPase interaction not resolved
    • Whether rescue reflects restored acidification or another mechanism uncertain
  5. 2018 High

    Showing that TMEM106B overexpression drives TFEB-dependent lysosomal biogenesis and calcium-dependent lysosomal exocytosis of active cathepsins extended its role beyond lysosomal homeostasis to a pro-invasive function in cancer cells.

    Evidence TMEM106B overexpression in lung cancer cells with cathepsin activity assays, TFEB target analysis, calcium chelation, and in vivo metastasis models

    PMID:30013069

    Open questions at the time
    • Direct TMEM106B–TFEB regulatory mechanism not defined
    • Whether endogenous TMEM106B levels drive exocytosis in non-cancer contexts unclear
  6. 2020 High

    Studies in Tmem106b−/− mice demonstrated that loss of TMEM106B impairs axonal lysosomal distribution, myelination, cathepsin D levels, and lysosomal exocytosis in oligodendrocytes, establishing bidirectional dosage sensitivity and cell-type-specific functions including interaction with galactosylceramidase (later confirmed) and cathepsin D.

    Evidence Tmem106b−/− mice with live axonal transport imaging, PLP/MOG quantification, TMEM106B–cathepsin D co-immunoprecipitation, lysosomal exocytosis assays, D252N mutant characterization

    PMID:32160553 PMID:32572497 PMID:36619668

    Open questions at the time
    • Whether myelination defect is cell-autonomous to oligodendrocytes vs. neuronal contribution unclear
    • Arl8b-dependent rescue awaits in vivo validation
    • Role of cathepsin D interaction in myelination not directly tested
  7. 2022 High

    Three independent cryo-EM studies revealed that residues 120–254 of TMEM106B form amyloid fibrils in human brains across neurodegenerative diseases and in normal aging, fundamentally redefining TMEM106B from a lysosomal regulator to an amyloid-forming protein whose aggregation is age-dependent and disease-nonspecific.

    Evidence Cryo-EM structure determination at atomic resolution from post-mortem brain extracts of FTLD-TDP, PSP, DLB, and aged controls, with immunogold and mass spectrometry validation

    PMID:35247328 PMID:35344984 PMID:35344985

    Open questions at the time
    • Whether fibril formation is pathogenic, protective, or bystander remains unknown
    • Mechanism initiating fibril nucleation from the cleaved fragment undefined
    • No animal model recapitulating TMEM106B amyloid formation
  8. 2023 High

    Structural and functional evidence established TMEM106B as an ACE2-independent receptor for SARS-CoV-2, with its luminal domain directly engaging the spike receptor-binding motif, explaining its identification as a proviral host factor and expanding its function beyond lysosomal biology.

    Evidence X-ray crystallography and cryo-EM of TMEM106B LD–spike complex, monoclonal antibody blocking of infection, pseudovirus entry in ACE2-negative cells, syncytium formation assay

    PMID:33686287 PMID:37421949

    Open questions at the time
    • In vivo contribution of TMEM106B-mediated entry relative to ACE2 pathway not quantified
    • Whether TMEM106B-mediated entry involves endosomal route exclusively is unresolved
  9. 2024 High

    Identification of lysosomal cysteine proteases as the enzymes performing initial luminal domain shedding, together with the finding that TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism, completed two long-standing mechanistic gaps in TMEM106B processing and myelination pathways.

    Evidence Pharmacological inhibition of protease classes across cellular and mouse models; co-immunoprecipitation of TMEM106B–galactosylceramidase with lipidomics and enzyme activity assays in Tmem106b−/− brain

    PMID:39237682 PMID:39709600

    Open questions at the time
    • Specific cysteine protease identity (e.g., cathepsin B vs. L) not resolved
    • Whether galactosylceramidase interaction is direct or within a larger complex unknown
  10. 2024 High

    Crossing Tmem106b−/− and T185S knock-in mice with P301S tau models demonstrated that TMEM106B loss exacerbates tau-driven neurodegeneration while the protective coding variant preserves neuronal function without affecting tau pathology, positioning TMEM106B as a downstream modifier of tauopathy outcome.

    Evidence Tmem106b−/− × PS19 and T186S knock-in × PS19 crosses with behavioral, histological, synaptic, and transcriptomic analyses

    PMID:38526616 PMID:38526799

    Open questions at the time
    • Molecular mechanism by which T185S variant confers neuroprotection not defined
    • Whether the effect is mediated by reduced fibril formation, improved lysosomal function, or both is unresolved
    • Relevance to sporadic human tauopathies awaits further validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Critical open questions include whether TMEM106B amyloid fibril formation is a cause or consequence of neurodegeneration, the identity of the specific cysteine protease(s) initiating luminal domain shedding, the structural basis of TMEM106B interactions with V-ATPase and MAP6, and how TMEM106B dosage is sensed to trigger TFEB-dependent lysosomal biogenesis.
  • No causal link established between TMEM106B fibrils and neurodegeneration
  • No reconstituted in vitro system for fibril nucleation from membrane-bound TMEM106B
  • Structural basis for most protein–protein interactions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0001618 virus receptor activity 2
Localization
GO:0005764 lysosome 7 GO:0005768 endosome 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9612973 Autophagy 2
Partners
ATP6V0A1CHMP2BCTSDGALCMAP6SPPL2A

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 TMEM106B is a type II integral membrane protein with a highly glycosylated luminal domain, localizing to late endosomes and lysosomes; N-glycosylation is partially required for transport beyond the ER to late compartments; inhibition of vacuolar H+-ATPase significantly increases TMEM106B protein levels. Differential membrane extraction, sequential mutagenesis of N-glycosylation sites, subcellular fractionation, pharmacological inhibition of V-ATPase The Journal of biological chemistry High 22511793
2012 TMEM106B overexpression causes enlargement and poor acidification of endo-lysosomes, impairs mannose-6-phosphate-receptor trafficking, and colocalizes with progranulin in late endo-lysosomes; overexpression increases intracellular progranulin levels; microRNA-132 and microRNA-212 repress TMEM106B expression through shared binding sites in the TMEM106B 3'UTR. Overexpression in neuronal cells, live-cell imaging of lysosomes, miRNA microarray screen, luciferase reporter assay for 3'UTR binding, progranulin protein quantification The Journal of neuroscience : the official journal of the Society for Neuroscience High 22895706
2012 TMEM106B localizes to late endosome/lysosome compartments and its protein levels are regulated by lysosomal activities; ectopic TMEM106B expression induces lysosomal morphological changes and delays degradation of endocytic cargoes; overexpression elevates intracellular progranulin levels, possibly by attenuating lysosomal degradation. Subcellular fractionation, immunofluorescence colocalization, overexpression with endocytic cargo degradation assays, progranulin protein measurement Human molecular genetics High 23136129
2013 TMEM106B knockdown in primary neurons impairs lysosomal trafficking and reduces dendritic arborization; TMEM106B physically interacts with microtubule-associated protein 6 (MAP6); MAP6 knockdown rescues the dendritic phenotype of TMEM106B knockdown; TMEM106B/MAP6 interaction controls dendritic lysosomal transport by acting as a brake on retrograde transport; expression of dominant-negative RILP (Rab7-interacting lysosomal protein) also rescues dendrite loss in TMEM106B knockdown neurons. shRNA knockdown in primary neurons, live imaging of lysosomal transport, co-immunoprecipitation (TMEM106B–MAP6 interaction), genetic epistasis via MAP6 knockdown and dominant-negative RILP The EMBO journal High 24357581
2013 The disease-risk variant T185 TMEM106B protein is degraded more slowly than the protective S185 variant, likely due to differences in N-glycosylation at residue N183, resulting in higher steady-state protein levels for the risk isoform. Cycloheximide chase experiments, overexpression of T185 vs. S185 variants, ELISA for protein levels, glycosylation analysis Journal of neurochemistry Medium 23742080
2014 TMEM106B undergoes regulated intramembrane proteolysis: it is first processed by lysosomal proteases to an N-terminal fragment containing the transmembrane and intracellular domains, which is then cleaved by the GxGD aspartyl proteases SPPL2a (and to a lesser extent SPPL2b) to generate a small intracellular domain that is rapidly degraded. Cell-based cleavage assays, pharmacological inhibition of lysosomal proteases, overexpression of SPPL2a/SPPL2b, domain-deletion mutagenesis The Journal of biological chemistry High 24872421
2015 TMEM106B physically associates with CHMP2B (an ESCRT-III component); the disease-risk T185 variant localizes more to Rab7-positive late endosomes and shows greater association with CHMP2B compared to the protective S185 variant; T185 slightly enhances autophagic flux impairment and EGFR accumulation caused by mutant CHMP2B. Co-immunoprecipitation, immunofluorescence colocalization with Rab5/Rab7 markers, autophagic flux assay, EGFR degradation assay Molecular brain Medium 26651479
2016 Increased TMEM106B expression causes a vacuolar phenotype in neurons and other cell types, impairs lysosomal acidification and degradative function, and increases cytotoxicity; a lysosomal sorting motif in TMEM106B is required for these effects (abrogation of lysosomal sorting rescues defects); TMEM106B-induced lysosomal defects are dependent on C9orf72, as C9orf72 knockdown rescues them. TMEM106B overexpression with lysosomal pH measurements, cell viability assays, mutagenesis of sorting motif, C9orf72 siRNA knockdown epistasis Human molecular genetics High 27126638
2017 TMEM106B physically binds vacuolar-ATPase accessory protein 1 (AP1); TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification; Grn-/- and Tmem106b-/- mice have opposite effects on lysosomal enzyme levels, and Tmem106b deletion from Grn-/- mice normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration. Co-immunoprecipitation (TMEM106B–V-ATPase AP1), transcriptomic and proteomic analyses of mouse brain, behavioral phenotyping, lysosomal pH measurements in neurons Neuron High 28728022
2018 TMEM106B overexpression in lung cancer cells promotes synthesis of enlarged vesicular lysosomes laden with active cathepsins in a TFEB-dependent manner, and induces calcium-dependent lysosomal exocytosis, releasing active cathepsins necessary for cancer cell invasion and metastasis. TMEM106B overexpression in lung cancer cell lines, lysosomal morphology analysis, cathepsin activity assays, TFEB transcriptional target analysis, calcium chelation experiments, in vivo metastasis assays, pharmacological cathepsin inhibition Nature communications High 30013069
2018 The cytoplasmic domain of TMEM106B (residues 1–~74) is intrinsically disordered with no well-defined tertiary structure, though several segments have dynamic/nascent secondary structures and restricted backbone motions, consistent with its ability to transiently interact with diverse binding partners. CD spectroscopy, multi-dimensional NMR spectroscopy, bioinformatics analysis PloS one Medium 30332472
2018 TMEM106B knockdown with antisense oligonucleotides rescues impaired endolysosomal trafficking and increased dendritic branching caused by physiological levels of mutant CHMP2B in neurons, demonstrating that reducing TMEM106B restores endosomal health in a frontotemporal dementia context. Antisense oligonucleotide (ASO) knockdown in primary neurons expressing mutant CHMP2B, live imaging of endolysosomal trafficking, dendritic morphology analysis Brain : a journal of neurology Medium 30496365
2020 TMEM106B deficiency in mice causes accumulation of enlarged LAMP1-positive vacuoles at the distal end and within the axon initial segment of motor neurons, increased retrograde axonal transport of lysosomes, lipofuscin and autophagosome accumulation, and impaired facial-nerve-dependent motor performance. Tmem106b-/- mouse model, live-cell imaging of lysosomal transport, LAMP1 immunofluorescence, electron microscopy, behavioral motor testing Cell reports High 32160553
2020 TMEM106B deficiency in mice causes myelination defects with reduced PLP and MOG protein levels; TMEM106B physically interacts with the lysosomal protease cathepsin D and is required to maintain cathepsin D levels in oligodendrocytes; TMEM106B deficiency results in lysosome clustering in the perinuclear region and decreased lysosome exocytosis and cell-surface PLP levels; the disease-causing D252N mutation abolishes lysosome enlargement and acidification induced by wild-type TMEM106B, instead stimulating perinuclear lysosomal clustering. Tmem106b-/- mouse, co-immunoprecipitation (TMEM106B–cathepsin D), lysosomal pH assay, lysosome exocytosis assay, surface PLP quantification, D252N mutant overexpression Brain : a journal of neurology High 32572497
2020 Loss of TMEM106B in mice causes a block late in autophagy by disrupting autophagosome-to-autolysosome maturation, coinciding with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes via Rab7A-dependent reduced Arl8b-mediated anterograde transport; increasing Arl8b activity restores lysosomal distribution and rescues autophagy. TMEM106B knockdown in cell models and C9ALS/FTD-derived iAstrocytes, autophagy flux assays, lysosomal pH measurements, cathepsin activity assays, Rab7A/Arl8b overexpression rescue experiments Frontiers in cellular neuroscience Medium 36619668
2021 TMEM106B is required as a proviral host factor for SARS-CoV-2 infection; TMEM106B overexpression enhances SARS-CoV-2 and pseudovirus infection, suggesting a role in viral entry into human cell lines and primary lung cells. Genome-wide CRISPR knockout screen with SARS-CoV-2, TMEM106B overexpression in cell lines, pseudovirus infection assay, single-cell RNA-seq of patient airway cells Nature genetics High 33686287
2021 The luminal domain of TMEM106B belongs to the late embryogenesis abundant-2 (LEA-2) domain superfamily, which has a conserved lipid-binding groove, predicting that TMEM106B may function as a lipid transfer protein in the lumen of late endocytic organelles. Computational homology detection using PSI-BLAST, HMMER, HHpred, and trRosetta structural prediction Proteins Low 34347309
2022 Cryo-EM structure determination showed that residues 120–254 of TMEM106B form amyloid filaments in human brains across multiple neurodegenerative diseases and in normal aging; three distinct TMEM106B fold conformers were identified; filaments correlate with a 29-kDa sarkosyl-insoluble C-terminal fragment and form in an age-dependent manner. Cryogenic electron microscopy structure determination from post-mortem human brain extracts, sarkosyl fractionation, immunoblotting with C-terminal antibody Nature High 35344985
2022 Cryo-EM of amyloid fibrils extracted from FTLD-TDP brains showed they are composed of a 135-residue C-terminal fragment of TMEM106B, not TDP-43; TDP-43 was detected as non-fibrillar aggregates by immunogold labelling. Cryo-electron microscopy structure determination from FTLD-TDP brain extracts, immunogold labelling for TDP-43 Nature High 35344984
2022 A 135 amino acid C-terminal fragment of TMEM106B forms amyloid fibrils (solved at 2.7 Å resolution) as a common finding in FTLD-TDP, PSP, and DLB, demonstrating homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cryoelectron microscopy and mass spectrometry from postmortem human brain tissue from multiple disease groups Cell High 35247328
2022 TMEM106B deficiency impairs cerebellar myelination with reduced PLP and MOG levels, and causes loss of synapses between Purkinje and deep cerebellar nuclei neurons in young mice; aged TMEM106B-deficient mice show loss of Purkinje neurons in the anterior cerebellar lobe; TMEM106B deficiency causes distinct cell-type-specific lysosomal phenotypes. Tmem106b-/- mouse model, immunofluorescence, electron microscopy, synapse quantification, behavioral analysis Acta neuropathologica communications High 35287730
2023 TMEM106B serves as an ACE2-independent receptor for SARS-CoV-2 entry: the luminal domain (LD) of TMEM106B directly engages the receptor-binding motif of SARS-CoV-2 spike protein; spike substitution E484D enhances TMEM106B binding and TMEM106B-mediated entry; TMEM106B-specific monoclonal antibodies block SARS-CoV-2 infection; TMEM106B promotes spike-mediated syncytium formation, suggesting a role in viral membrane fusion. X-ray crystallography and cryo-EM of TMEM106B LD–spike complex, HDX-MS, monoclonal antibody blocking assays, pseudovirus entry in ACE2-negative cells, syncytium formation assay Cell High 37421949
2023 TMEM106B deficiency in mice reduces microglia proliferation and activation, increases microglial apoptosis in response to demyelination, increases lysosomal pH and decreases lysosomal enzyme activities in microglia, and significantly decreases TREM2 protein levels; microglial-specific ablation of TMEM106B produces similar phenotypes and myelination defects. Tmem106b-/- mouse, microglial-specific conditional KO mouse, lysosomal pH assay, TREM2 western blot, immunohistochemistry for microglia markers, demyelination challenge Science advances High 37146150
2024 TMEM106B physically interacts with galactosylceramidase (co-immunoprecipitation); TMEM106B deficiency significantly increases galactosylceramidase activity and decreases levels of galactosylceramide and sulfatide (major myelin lipids) in mouse brain, indicating that TMEM106B regulates myelin lipid metabolism through interaction with galactosylceramidase. Lipidomic analysis of Tmem106b-/- mouse brain, co-immunoprecipitation of TMEM106B and galactosylceramidase, galactosylceramidase enzyme activity assay Communications biology High 39237682
2024 Lysosomal cysteine-type proteases perform the initial cleavage of TMEM106B's luminal domain (generating the C-terminal fragment capable of fibril formation) and also perform additional C-terminal trimming; this shedding occurs physiologically and is detectable in cellular and mouse models. Antibody development against luminal domain, pharmacological inhibition of specific protease classes, cellular and TMEM106B-related mouse models, human autopsy tissue immunoblotting Cell reports High 39709600
2024 TMEM106B deletion in a P301S tau mouse model accelerates cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration; the T185S coding variant (knock-in) protects against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology itself, demonstrating that TMEM106B acts downstream of tau aggregation to preserve neuronal function. Tmem106b-/- and T186S knock-in mice crossed with P301S tau transgenic mice, behavioral testing, tau pathology quantification, synaptic protein analysis, transcriptomics Acta neuropathologica High 38526616
2024 TMEM106B C-terminal fragment core accumulation in FTLD-TDP postmortem brain is associated with TDP-43 dysfunction; carriers of the risk genotype (rs3173615) show higher TMEM106B core deposition, while protective allele carriers show minimal core deposition and an increase in dimeric full-length TMEM106B; interactome data implicate TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function. Novel antibody targeting TMEM106B filament core, immunoblotting of postmortem FTLD-TDP samples stratified by rs3173615 genotype, interactome proteomics Science translational medicine Medium 38232138
2024 TMEM106B loss in Tmem106b-/- PS19 (P301S tau) mice enhances accumulation of pathological tau in neuronal soma in the hippocampus, causes severe neuronal loss, and exacerbates abnormalities in neuronal cytoskeleton, autophagy-lysosome activities, and glial activation compared to PS19 alone. Tmem106b-/- × PS19 double-mutant mice, tau immunohistochemistry and pathology scoring, lysosomal/autophagy marker analysis, neuronal counting, glial activation assays Acta neuropathologica High 38526799
2022 TMEM106B C-terminal fragment aggregates form amyloid inclusions (confirmed by luminescent conjugated oligothiophene staining) predominantly in astrocytes in the brain parenchyma, and also in dorsal root ganglia and spinal cord non-neuronal cells; by in situ immunoelectron microscopy, TMEM106B assemblies are found in structures resembling endosomes and lysosomes; a second cleavage beyond residue 120 is indicated by antibody staining at residues 263–274. Immunohistochemistry with TMEM106B-specific antibodies, luminescent conjugated oligothiophene (LCO) staining, transmission immuno-electron microscopy, tissue distribution analysis Acta neuropathologica communications Medium 38886865

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 214 21178100
2012 TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 200 22895706
2021 Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2. Nature genetics 187 33686287
2012 The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Human molecular genetics 169 23136129
2022 Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature 158 35344985
2011 Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Archives of neurology 145 21220649
2013 The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. The EMBO journal 144 24357581
2017 Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron 142 28728022
2014 TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta neuropathologica 137 24385136
2022 Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43. Nature 135 35344984
2012 Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. The Journal of biological chemistry 133 22511793
2022 Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell 125 35247328
2014 TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta neuropathologica 122 24442578
2023 TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. Cell 114 37421949
2018 TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. Nature communications 113 30013069
2011 TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain : a journal of neurology 111 21354975
2017 Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes. Cell systems 108 28330615
2010 Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta neuropathologica 105 21104415
2013 TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. Journal of neurochemistry 99 23742080
2016 What we know about TMEM106B in neurodegeneration. Acta neuropathologica 91 27543298
2021 Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders. Acta neuropathologica 85 33386471
2020 Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO reports 82 32852886
2015 The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology 80 25653292
2021 rs1990622 variant associates with Alzheimer's disease and regulates TMEM106B expression in human brain tissues. BMC medicine 76 33461566
2017 A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain : a journal of neurology 74 29186371
2015 Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. Journal of neuropathology and experimental neurology 66 25470345
2020 The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons. Cell reports 65 32160553
2019 The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion. Acta neuropathologica 65 31456032
2016 Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Human molecular genetics 60 27126638
2022 Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging. Acta neuropathologica 56 36527486
2020 Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice. EMBO reports 53 32929860
2020 Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies. Brain : a journal of neurology 52 32504082
2018 Variation in TMEM106B in chronic traumatic encephalopathy. Acta neuropathologica communications 49 30390709
2017 Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study. Brain : a journal of neurology 49 28460069
2020 Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice. EMBO reports 48 32761777
2021 Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study. Acta neuropathologica communications 47 34526147
2020 A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination. Brain : a journal of neurology 46 32572497
2019 Long noncoding MAGI2-AS3 promotes colorectal cancer progression through regulating miR-3163/TMEM106B axis. Journal of cellular physiology 41 31709544
2017 Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta neuropathologica communications 41 28126008
2014 Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). The Journal of biological chemistry 41 24872421
2014 TMEM106B expression is reduced in Alzheimer's disease brains. Alzheimer's research & therapy 40 24684749
2014 Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions. Neurobiology of aging 38 25085782
2014 Effect of TMEM106B polymorphism on functional network connectivity in asymptomatic GRN mutation carriers. JAMA neurology 37 24343233
2018 Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown. Brain : a journal of neurology 35 30496365
2015 TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3-linked CHMP2B, a complex of ESCRT-III. Molecular brain 35 26651479
2015 Identification of a novel TMEM106B-ROS1 fusion variant in lung adenocarcinoma by comprehensive genomic profiling. Lung cancer (Amsterdam, Netherlands) 33 25851827
2013 Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain. Acta neuropathologica communications 33 24252750
2023 TMEM106B aggregation in neurodegenerative diseases: linking genetics to function. Molecular neurodegeneration 30 37563705
2023 The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus. Molecular neurodegeneration 30 37726834
2017 A novel, potentially targetable TMEM106B-BRAF fusion in pleomorphic xanthoastrocytoma. Cold Spring Harbor molecular case studies 29 28299358
2018 Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency. Molecular neurodegeneration 28 29929528
2024 TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia. Science translational medicine 27 38232138
2022 Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease. Acta neuropathologica 27 36056242
2021 TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels. Alzheimer's & dementia : the journal of the Alzheimer's Association 27 33991015
2017 Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2. Neurobiology of aging 27 28131462
2022 TMEM106B deficiency impairs cerebellar myelination and synaptic integrity with Purkinje cell loss. Acta neuropathologica communications 25 35287730
2023 C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes. Brain : a journal of neurology 24 37100087
2021 TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy. Acta neuropathologica 23 34152475
2020 Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non-motor dysfunction. Brain pathology (Zurich, Switzerland) 23 33016371
2011 TMEM106B a novel risk factor for frontotemporal lobar degeneration. Journal of molecular neuroscience : MN 22 21614538
2018 Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity. Acta neuropathologica communications 20 29855382
2023 TMEM106B regulates microglial proliferation and survival in response to demyelination. Science advances 19 37146150
2021 TMEM106B in humans and Vac7 and Tag1 in yeast are predicted to be lipid transfer proteins. Proteins 17 34347309
2022 TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis. International journal of molecular sciences 16 36012536
2021 A novel temporal-predominant neuro-astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS-TDP. Brain pathology (Zurich, Switzerland) 15 33314436
2024 TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy. Acta neuropathologica 14 38526616
2024 Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice. Acta neuropathologica 13 38526799
2024 TMEM106B-mediated SARS-CoV-2 infection allows for robust ACE2-independent infection in vitro but not in vivo. Cell reports 13 39480813
2023 Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family. Frontiers in neurology 13 37077569
2021 Loss of Tmem106b leads to cerebellum Purkinje cell death and motor deficits. Brain pathology (Zurich, Switzerland) 12 33709463
2024 Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism. Communications biology 11 39237682
2022 Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation. Frontiers in cellular neuroscience 11 36619668
2020 Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders. Brain communications 11 33796852
2017 Association analysis of polymorphisms in VMAT2 and TMEM106B genes for Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy. Journal of the neurological sciences 11 28477711
2024 A common Alu insertion in the 3'UTR of TMEM106B is associated with risk of dementia. Alzheimer's & dementia : the journal of the Alzheimer's Association 10 38924247
2024 A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP. Neurology. Genetics 10 39911968
2023 Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration. Acta neuropathologica communications 10 36707901
2020 A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay. Brain & development 10 32595021
2024 Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems. Acta neuropathologica communications 9 38886865
2023 AAV-GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106bGrn mice. iScience 9 37519899
2018 TMEM106B, a risk factor for FTLD and aging, has an intrinsically disordered cytoplasmic domain. PloS one 7 30332472
2015 Association of TMEM106B rs1990622 marker and frontotemporal dementia: evidence for a recessive effect and meta-analysis. Journal of Alzheimer's disease : JAD 7 25096617
2024 Physiological and pathological functions of TMEM106B in neurodegenerative diseases. Cellular and molecular life sciences : CMLS 6 38710967
2024 TMEM106B Knockdown Exhibits a Neuroprotective Effect in Parkinson's Disease via Decreasing Inflammation and Iron Deposition. Molecular neurobiology 6 39044012
2024 TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy in transgenic Caenorhabditis elegans. Alzheimer's & dementia : the journal of the Alzheimer's Association 6 39711302
2023 The identification of high-performing antibodies for transmembrane protein 106B (TMEM106B) for use in Western blot, immunoprecipitation, and immunofluorescence. F1000Research 6 37545650
2020 Progranulin and TMEM106B: when two become wan. EMBO reports 6 32985120
2017 TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD-3). Neurobiology of aging 6 28888721
2025 The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases. Molecular neurodegeneration 5 40713630
2024 Novel Omicron Variants Enhance Anchored Recognition of TMEM106B: A New Pathway for SARS-CoV-2 Cellular Invasion. The journal of physical chemistry letters 5 38206837
2023 TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury. Cells 5 37443768
2023 A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated with Increased Risk for FTLD-TDP. medRxiv : the preprint server for health sciences 5 37461476
2023 Unveiling TMEM106B: SARS-CoV-2's secret entrance to the cell. Cell 5 37541193
2023 Antibody-recognizing residues 188-211 of TMEM106B exhibit immunohistochemical reactivity with the TMEM106B C-terminal fragment. Frontiers in neuroscience 5 37937069
2023 TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models. iScience 5 37965143
2025 TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43Q331K knock-in mouse model. Communications biology 4 40011708
2024 Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration. Neurology 4 39321401
2024 TMEM106B amyloid filaments in the Biondi bodies of ependymal cells. Acta neuropathologica 4 39503754
2024 Physiological shedding and C-terminal proteolytic processing of TMEM106B. Cell reports 4 39709600
2022 Severe Epilepsy and Movement Disorder May Be Early Symptoms of TMEM106B-Related Hypomyelinating Leukodystrophy. Neurology. Genetics 4 36046422