Affinage

GRN

Progranulin · UniProt P28799

Length
593 aa
Mass
63.5 kDa
Annotated
2026-04-28
100 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Progranulin (GRN) is a secreted glycoprotein that functions as a growth factor, lysosomal regulator, and immunomodulator, with central roles in lysosomal lipid homeostasis, microglial activation, and inflammatory signaling. In the lysosome, progranulin maintains bis(monoacylglycero)phosphate (BMP) levels required for ganglioside and sphingolipid catabolism, and its loss causes ganglioside accumulation and impaired myelin debris clearance by microglia upstream of cathepsin D (PMID:34450028, PMID:36207292, PMID:34433069). Progranulin binds TNFR2 to promote anti-inflammatory macrophage polarization and IL-10-dependent tissue protection, and suppresses NF-κB/IRF3 innate immune signaling by recruiting A20 to deubiquitinate K63-linked polyubiquitin on NEMO via its granulin CDE domains (PMID:25387791, PMID:31585000, PMID:38689292). Heterozygous loss-of-function mutations in GRN cause frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), driven by lysosomal dysfunction, aberrant astrocyte-mediated synaptic degeneration, and dysregulated tau phosphorylation through Gas6-Tyro3-PKCα signaling (PMID:18183624, PMID:36602862, PMID:29382817).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    The initial functional identity of progranulin as an autocrine growth factor was established when antisense suppression of PGRN expression abolished tumorigenicity of teratoma cells in vivo, demonstrating that secreted PGRN is required for tumor growth.

    Evidence Antisense cDNA transfection with in vivo tumor growth assay in syngeneic C3H mice

    PMID:9826678

    Open questions at the time
    • Receptor mediating autocrine signaling not identified
    • No defined downstream signaling pathway
  2. 2001 High

    The mitogenic signaling mechanism was defined when PGRN was shown to activate MAPK and cyclin D1 downstream of estrogen stimulation, establishing PGRN as a mediator of proliferative signaling in breast cancer cells.

    Evidence Neutralizing antibody, antisense KD, PGRN overexpression, MAPK/cyclin D1 assays in MCF-7 cells

    PMID:11134521

    Open questions at the time
    • Direct receptor for PGRN in this context not identified
    • Relevance to non-cancer proliferative settings untested
  3. 2008 High

    The molecular basis of GRN haploinsufficiency in FTLD was clarified when a signal-peptide missense mutation (A9D) was shown to trap progranulin intracellularly, preventing secretion and producing functional haploinsufficiency despite normal mRNA levels—establishing that both null and secretion-defective alleles cause disease.

    Evidence Subcellular fractionation, confocal microscopy, RT-PCR, and Western blot in cells from mutation carriers

    PMID:18183624

    Open questions at the time
    • Whether intracellularly retained PGRN retains any lysosomal function not addressed
    • Scope of secretion-defective mutations in broader FTLD cohorts not surveyed
  4. 2011 Medium

    A link between PGRN deficiency and cell-cycle dysregulation was revealed when patient-derived lymphoblasts showed increased CDK6 and Rb phosphorylation tied to altered TDP-43 localization, suggesting that PGRN loss disrupts TDP-43-mediated transcriptional repression of CDK6.

    Evidence Western blot, flow cytometry cell-cycle analysis, TDP-43 immunofluorescence in patient lymphoblasts

    PMID:21232819

    Open questions at the time
    • Direct regulation of CDK6 by TDP-43 not confirmed by ChIP or reporter assay
    • Relevance to neuronal pathology unclear
  5. 2014 High

    The receptor mediating PGRN's anti-inflammatory signaling was identified as TNFR2, with co-IP confirming physical interaction and TNFR2 neutralizing antibody blocking PGRN-driven M2 macrophage polarization, and genetic models showing TNFR2/IL-10 dependence for colitis protection.

    Evidence Co-IP of PGRN-TNFR2, TNFR2 neutralizing antibody in macrophages, Grn-/- and TNFR2-/- colitis models

    PMID:25387791 PMID:38689292

    Open questions at the time
    • Structural basis of PGRN-TNFR2 interaction not resolved
    • Whether PGRN competes with TNFα for TNFR2 binding in vivo not quantified
  6. 2015 Medium

    PGRN was shown to also signal through TNFR1 in a metabolic context, inducing hepatic insulin resistance via NF-κB-dependent pathways and impaired autophagy, expanding the receptor repertoire beyond TNFR2.

    Evidence TNFR1 blocking peptide-Fc and siRNA in mouse hepatocytes, glucose/insulin tolerance tests

    PMID:25664864

    Open questions at the time
    • Whether TNFR1 vs TNFR2 engagement is context- or dose-dependent not resolved
    • Relevance to neurodegeneration unclear
  7. 2018 High

    The mechanism linking PGRN loss to synaptic degeneration was elucidated: PGRN deficiency activates Gas6-Tyro3-PLCγ-PKCα signaling, causing tau hyperphosphorylation at Ser203, tau mislocalization to dendritic spines, and spine loss prior to TDP-43 aggregation—and pharmacological blockade of this axis rescued cognitive deficits.

    Evidence Phosphoproteomics, PKC/B-Raf inhibitors, Gas6/Tyro3 knockdown in PGRN-KI (R504X) mice, behavioral testing

    PMID:29382817

    Open questions at the time
    • Whether tau phosphorylation is a primary driver or bystander in human FTLD-GRN not established
    • Relationship between Gas6-Tyro3 axis and lysosomal dysfunction not explored
  8. 2019 High

    A direct mechanism for PGRN's suppression of innate immune signaling was mapped: the granulin CDE domains bind NEMO and recruit deubiquitinase A20 to remove K63-linked polyubiquitin at NEMO K264, suppressing NF-κB and IRF3 activation and type I interferon production during influenza infection.

    Evidence Co-IP, domain mapping, deubiquitination assay, Grn-/- mice challenged with influenza virus

    PMID:31585000

    Open questions at the time
    • Whether NEMO deubiquitination occurs in CNS microglia or only in peripheral immunity not tested
    • Stoichiometry and regulation of PGRN-A20-NEMO complex not determined
  9. 2019 Medium

    Microglial transcriptomic profiling placed PGRN loss as a driver of the neurodegenerative microglial (MGnD) activation state—reciprocal to TREM2 loss—linking PGRN to microglial phenotype switching and brain glucose hypometabolism.

    Evidence Isolated microglia transcriptomics from Grn-/- and Trem2-/- mice, FDG-µPET imaging

    PMID:31122931

    Open questions at the time
    • Causal relationship between microglial activation state and neurodegeneration not directly tested
    • Molecular link between PGRN and TREM2 signaling not established
  10. 2020 High

    Genetic epistasis between PGRN and the lysosomal membrane protein TMEM106B was demonstrated in vivo: double knockout of Grn and Tmem106b caused severe neuronal loss and lysosomal vacuole accumulation exceeding either single KO, establishing TMEM106B as a genetic modifier in PGRN-dependent neurodegeneration.

    Evidence Grn-/-/Tmem106b-/- double-KO mice, histopathology, electron microscopy

    PMID:32852886

    Open questions at the time
    • Biochemical mechanism of PGRN-TMEM106B functional interaction not identified
    • Whether TMEM106B variants modify human GRN disease progression not addressed
  11. 2021 High

    The core lysosomal function of progranulin was defined biochemically: PGRN binds bis(monoacylglycero)phosphate (BMP) in a pH-dependent manner, and its loss causes global BMP deficiency with secondary glucosylsphingosine storage, directly linking progranulin to lysosomal lipid homeostasis.

    Evidence BMP mass spectrometry, pH-dependent binding assay, Grn-/- mice, iPSC-derived microglia, PGRN replacement rescue

    PMID:34450028

    Open questions at the time
    • Whether PGRN stabilizes BMP production or prevents its degradation not resolved
    • Structural basis of PGRN-BMP interaction unknown
  12. 2021 High

    PGRN was positioned upstream of cathepsin D in microglial lysosomal clearance when Grn-/- mice showed myelin debris accumulation in microglial lysosomes, exacerbated by Ctsd co-deletion and accompanied by TDP-43 pathology.

    Evidence Grn-/-, Ctsd/Grn double-KO epistasis, immunofluorescence for myelin debris and TDP-43

    PMID:34433069

    Open questions at the time
    • Whether PGRN directly activates cathepsin D or acts indirectly via BMP not distinguished
    • Applicability to human white-matter pathology not confirmed
  13. 2022 High

    Lysosomal ganglioside accumulation was identified as a hallmark of PGRN deficiency: lipidomics revealed GM1/GM2/GM3 ganglioside storage without reduction in catabolic enzyme levels, establishing that PGRN-dependent BMP maintenance is the rate-limiting factor for ganglioside catabolism.

    Evidence Lipidomics in PGRN-deficient cells, Grn-/- mouse brains, and human FTD-GRN frontal lobe tissue

    PMID:36207292

    Open questions at the time
    • Whether ganglioside accumulation is directly neurotoxic or a marker of broader lysosomal failure not tested
    • Therapeutic reversal of gangliosidosis by PGRN replacement not demonstrated
  14. 2022 High

    PGRN was established as a genetic modifier of GBA1/glucocerebrosidase pathway disease: Grn-/-/Gba9v/9v double-mutant mice showed exacerbated neuronopathic Gaucher pathology, and a BBB-penetrant PGRN-derived peptide rescued neurobehavioral and neuropathological deficits.

    Evidence Double-mutant mouse model, ND7 peptide treatment, behavioral/neuropathological assays, patient fibroblast rescue

    PMID:36574647

    Open questions at the time
    • Mechanism by which PGRN/granulins modulate GCase activity not defined
    • Whether PGRN replacement benefits human Gaucher or PD patients unknown
  15. 2023 High

    Progranulin-deficient astrocytes were shown to be active drivers of neurodegeneration: they upregulate APOE and GJA1 while losing the glutamate transporter SLC1A2, promoting synaptic degeneration and TDP-43 proteinopathy in neuron co-cultures and cortical organoids.

    Evidence Single-cell RNA-seq, iPSC-derived astrocyte transplantation into cortical organoids, mouse/human comparative transcriptomics

    PMID:36602862

    Open questions at the time
    • Whether astrocyte toxicity is cell-autonomous or secondary to impaired lysosomal lipid handling not resolved
    • Relative contribution of astrocyte vs microglial dysfunction to human FTLD-GRN pathology not quantified
  16. 2023 High

    A post-transcriptional mechanism for boosting PGRN levels was validated: ASOs displacing miR-29b from the GRN 3′ UTR increased progranulin translation dose-dependently in iPSC neurons and humanized mice, confirmed by FRET competition and polysome profiling.

    Evidence FRET-based miRNA binding competition assay, polysome profiling, iPSC-derived neurons, humanized GRN mouse model

    PMID:37981208

    Open questions at the time
    • Long-term safety and efficacy of miR-29b-blocking ASOs in vivo not established
    • Whether this approach achieves therapeutically relevant PGRN increases in human brain not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of progranulin-BMP interaction, whether PGRN directly activates cathepsin D or acts via BMP, how lysosomal and signaling functions are coordinately regulated, and whether PGRN replacement can reverse established neurodegeneration in humans.
  • No structure of progranulin bound to BMP or TNFR2
  • Relative pathogenic contributions of lysosomal, microglial, and astrocytic dysfunction to FTLD-GRN not dissected in humans
  • Whether processed granulins versus full-length PGRN have distinct lysosomal vs signaling roles not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4 GO:0005764 lysosome 4
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3
Partners
CTSDGAS6NEMOTARDBPTMEM106BTNFAIP3TNFRSF1BTYRO3

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PCDGF/progranulin (GRN) mediates estrogen (E2) mitogenic signaling in MCF-7 breast cancer cells by stimulating MAPK activity and cyclin D1 expression; neutralizing antibody or antisense inhibition of PGRN blocked E2-induced DNA synthesis, and PGRN overexpression conferred estrogen-independent proliferation and tamoxifen resistance. Neutralizing antibody, antisense transfection, PGRN overexpression, MAPK activity assay, cyclin D1 Western blot in MCF-7 cells Proceedings of the National Academy of Sciences of the United States of America High 11134521
1998 Autocrine production of PCDGF/progranulin (GRN) is required for tumorigenicity of PC teratoma cells; inhibition of PGRN expression by antisense cDNA transfection dramatically reduced in vivo tumor formation in syngeneic mice, and PGRN expression level positively correlated with tumorigenic potential. Antisense cDNA transfection, in vivo tumor growth assay in syngeneic C3H mice, Northern/Western blot Proceedings of the National Academy of Sciences of the United States of America High 9826678
2008 A missense mutation in the GRN signal peptide (p.A9D) prevents progranulin secretion, trapping the protein in an intracellular compartment, resulting in functional haploinsufficiency despite normal total GRN mRNA levels; a splice-site mutation (IVS6-2A>G) causes exon 7 skipping and reduces GRN mRNA and protein by ~50%. Subcellular fractionation, confocal microscopy, RT-PCR, Western blot in patient mutation carriers Human mutation High 18183624
2019 Progranulin (PGRN) directly interacts with TNF receptors (TNFR2), and this interaction mediates PGRN's anti-inflammatory and protective functions; PGRN-deficient mice are highly susceptible to experimental colitis, whereas recombinant PGRN protects via IL-10 and TNFR2-dependent pathways. Co-immunoprecipitation (PGRN-TNFR2), genetic knockout mice (PGRN-/-, TNFR2-/-, IL-10-/-), DSS/TNBS colitis models, bone marrow chimeras, T cell transfer colitis Scientific reports High 25387791
2018 PGRN deficiency in a knock-in mouse (PGRN-KI, R504X) leads to activation of Gas6-Tyro3-PLCγ-PKCα signaling, causing tau phosphorylation at Ser203, tau mislocalization to dendritic spines, and spine loss preceding TDP43 aggregation; targeting Gas6/Tyro3 or PKC/MAPK signaling rescues spine loss and cognitive impairment. Phosphoproteomics, PKC inhibitor/B-Raf inhibitor treatment, knockdown of Gas6/Tyro3 axis in PGRN-KI mice, behavioral testing, spine analysis Nature communications High 29382817
2021 PGRN is a lysosomal protein that interacts with bis(monoacylglycero)phosphate (BMP) in a pH-dependent manner; PGRN loss in mice causes global BMP deficiency and secondary glucosylsphingosine storage, implicating PGRN in lysosomal phospholipid homeostasis and proteolysis/lipolysis. BMP mass spectrometry, pH-dependent binding assay, Grn-/- mouse biochemistry, primary macrophage and iPSC-derived microglia functional assays, PTV:PGRN replacement rescue Cell High 34450028
2022 PGRN-deficient human cells and Grn-/- mouse brains accumulate gangliosides (including GM1, GM2, GM3); granulins are required to maintain bis(monoacylglycero)phosphate (BMP) levels needed for lysosomal ganglioside catabolism, indicating that PGRN loss causes gangliosidosis without reducing ganglioside-catabolizing enzyme levels. Lipidomics of PGRN-deficient cells and mouse brains, lysosomal enzyme activity assays, BMP quantification, human FTD-GRN frontal lobe analysis Nature communications High 36207292
2021 Grn knockout mice accumulate myelin debris in microglial lysosomes in white matter; PGRN insufficiency in microglia impairs lysosomal-mediated clearance of myelin debris, and double-KO of Grn and cathepsin D (Ctsd) augments myelin debris accumulation and neuronal TDP-43 pathology, placing PGRN upstream of cathepsin D in microglial lysosomal clearance. Grn KO mice, Ctsd/Grn double-KO epistasis, immunofluorescence for myelin debris and TDP-43, microgliosis quantification Cell reports High 34433069
2023 Progranulin-deficient astrocytes (from Grn-/- mice and FTLD-GRN patients) upregulate GJA1, AQP4, and APOE and downregulate glutamate transporter SLC1A2; these progranulin-deficient astrocytes promote synaptic degeneration, neuronal stress, and TDP-43 proteinopathy in neuron co-cultures and cortical organoids with iPSC-derived astrocytes. Single-cell RNA-seq, astrocyte-neuron co-cultures, iPSC-derived astrocyte transplantation into cortical organoids, comparative mouse/human transcriptomics The Journal of clinical investigation High 36602862
2019 Progranulin (PGRN) directly interacts with NF-κB essential modulator (NEMO) via its Grn CDE domains during influenza virus infection, recruiting A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264, thereby suppressing NF-κB and IRF3 signaling and inhibiting type I interferon production. Co-immunoprecipitation (PGRN-NEMO interaction), domain mapping (Grn CDE domains), deubiquitination assay (A20 recruitment, K63-Ub chains on NEMO K264), PGRN KD and Grn-/- mice, in vivo challenge with influenza PLoS pathogens High 31585000
2013 PGRN haploinsufficiency in lymphoblasts from FTLD-TDP (c.709-1G>A) mutation carriers activates noncanonical Wnt5a signaling; PGRN-deficient cells show increased cellular and secreted Wnt5a, enhanced phospho-CaMKII, and ERK1/2 activation via Ca2+/PKC-dependent, pertussis toxin-sensitive mechanism; exogenous PGRN or control conditioned medium normalized these responses. ERK1/2 and CaMKII phosphorylation assays, Wnt5a ELISA, pertussis toxin treatment, exogenous PGRN rescue, PGRN knockdown in SH-SY5Y cells Neurobiology of aging Medium 24139281
2011 PGRN deficit in lymphoblasts from PGRN mutation (c.709-1G>A) carriers increases CDK6 levels and retinoblastoma protein phosphorylation, causing G1/S regulatory failure; this is associated with altered subcellular TDP-43 distribution and loss of TDP-43-mediated repression of CDK6 expression. CDK6 and phospho-Rb Western blot, cell cycle analysis (flow cytometry), TDP-43 localization (immunofluorescence), patient-derived lymphoblasts Neurobiology of aging Medium 21232819
2014 PGRN promotes macrophage M2 polarization through direct binding to TNFR2; co-immunoprecipitation confirmed PGRN-TNFR2 physical interaction, and TNFR2-blocking neutralizing antibody abrogated PGRN-mediated increases in M2 markers (CD206, IL-10, Arg-1) in RAW264.7 macrophages and bone marrow-derived macrophages. Co-immunoprecipitation (PGRN-TNFR2), TNFR2 neutralizing antibody, flow cytometry for M1/M2 markers, ELISA for cytokines, multiplex IHC Journal of translational medicine Medium 38689292
2015 PGRN induces hepatic insulin resistance via TNFR1, activating NF-κB-dependent pathways; TNFR1 blocking peptide-Fc fusion protein or TNFR1 siRNA reversed PGRN-induced defective autophagy and impaired insulin signaling in hepatocytes in vivo and in vitro. In vivo mouse PGRN treatment, TNFR1 blocking peptide-Fc, TNFR1 siRNA, glucose/insulin tolerance tests, insulin signaling Western blots Molecular endocrinology (Baltimore, Md.) Medium 25664864
2020 Loss of both TMEM106B and PGRN in mice results in severe neuronal loss, glial activation, and enlarged lysosomes in microglia and astrocytes, with greatly enhanced accumulation of lysosomal vacuoles in the axon initial segment of motor neurons; TMEM106B deficiency alone causes lysosomal vacuole accumulation at the axon initial segment, identifying TMEM106B as a lysosomal membrane protein that genetically interacts with PGRN in neurodegeneration. Grn-/-/Tmem106b-/- double-KO mice, histopathology, electron microscopy, immunofluorescence for lysosomal markers and neuronal markers EMBO reports High 32852886
2019 Loss of Grn in mice shifts microglia from a homeostatic state to the microglial neurodegenerative phenotype (MGnD), with suppression of homeostatic genes, reciprocally opposite to the effect of Trem2 loss; both Grn-/- and Trem2-/- result in reduced brain glucose metabolism despite opposite microglial activation states. Isolated microglia transcriptomics from Grn-/- and Trem2-/- mice, FDG-µPET brain imaging EMBO molecular medicine Medium 31122931
2012 GRN promoter methylation is increased in sporadic FTLD patients relative to controls, with a negative correlation between GRN promoter methylation and GRN mRNA levels in peripheral blood mononuclear cells, identifying promoter methylation as a mechanism that can reduce GRN expression. Bisulfite pyrosequencing of GRN promoter, RT-PCR for GRN mRNA, correlation analysis in patient cohort Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology Medium 22797721
2020 Transcription factor REST (repressor element 1 silencing transcription factor) directly binds the PGRN promoter and represses PGRN expression; REST knockdown increases PGRN levels and promotes BV2 microglia-like cell migration, while REST overexpression suppresses migration, placing REST as an inhibitory transcriptional regulator of PGRN. Dual luciferase reporter assay (REST binding to PGRN promoter), siRNA KD and REST overexpression in BV2 cells, transwell migration assay, PGRN siRNA Neural plasticity Medium 33299399
2023 Antisense oligonucleotides (ASOs) targeting the miR-29b binding site in the 3' UTR of GRN mRNA increase progranulin protein translation in a dose-dependent manner in neuroglioma cells, iPSC-derived neurons, and a humanized GRN mouse model; mechanism was confirmed by FRET competition assays showing ASO displacement of miR-29b from GRN 3'UTR and polysome profiling demonstrating increased translation. FRET-based miRNA binding competition assay, polysome profiling, Western blot for progranulin protein, iPSC-derived neurons, humanized GRN mouse model The Journal of biological chemistry High 37981208
2024 Progranulin (PGRN) mediates liver pathology caused by ADAR1 deficiency by promoting interferon signaling and recruiting EGFR+ macrophages into the liver; the PGRN-EGFR axis drives hepatic inflammation in ADAR1-deficient hepatocytes, and this signaling is repressed in ADAR1-high tumors to facilitate immune evasion. Liver-specific Adar KO and Ifih1;Adar double-KO mouse models, PGRN expression analysis in hepatocytes, macrophage recruitment assays, EGFR co-localization Cell reports Medium 38935501
2021 PGRN deficiency reduces parkin protein levels in fibroblasts from FTLD patients with four different PGRN mutations, and parkin knockdown is also observed upon PGRN silencing in control fibroblasts; this is accompanied by decreases in parkin targets MFN2 and VDAC1. TDP-43 overexpression rescues PRKN levels during transient PGRN silencing but not in stable PGRN-mutant fibroblasts, and TDP-43 silencing reduces PRKN, suggesting TDP-43 loss-of-function contributes to parkin downregulation downstream of PGRN deficiency. Western blot for parkin/MFN2/VDAC1 in patient fibroblasts, PGRN siRNA in control fibroblasts, TDP-43 overexpression/knockdown rescue experiments Frontiers in molecular neuroscience Medium 34054428
2022 PGRN deficiency exacerbates GBA1 mutation-associated disease in Grn-/-/Gba9v/9v mice, including neurobehavioral deficits, neuroinflammation (microgliosis, astrogliosis), and impaired autophagy; a BBB-penetrant PGRN-derived peptide (ND7) ameliorated neuronopathic Gaucher disease and PD-like pathology in vivo, identifying PGRN as a modifier of GCase/GBA1 pathway. Double-mutant mouse model (Grn-/-/Gba9v/9v), ND7 peptide BBB penetration and treatment, neuropathology, behavioral assays, patient fibroblast ex vivo rescue Proceedings of the National Academy of Sciences of the United States of America High 36574647

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
2008 Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. The Lancet. Neurology 186 18771956
2021 Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell 175 34450028
2007 Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. Journal of neuropathology and experimental neurology 163 17278999
2018 LncRNA H19/miR-29b-3p/PGRN Axis Promoted Epithelial-Mesenchymal Transition of Colorectal Cancer Cells by Acting on Wnt Signaling. Molecules and cells 160 29754471
2001 Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor). Proceedings of the National Academy of Sciences of the United States of America 123 11134521
2008 Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). Archives of neurology 122 18413467
2009 Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN. Neurology 111 19255408
2017 MiR-29b-3p promotes chondrocyte apoptosis and facilitates the occurrence and development of osteoarthritis by targeting PGRN. Journal of cellular and molecular medicine 109 28609022
2019 Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism. EMBO molecular medicine 93 31122931
2015 Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort. Brain : a journal of neurology 91 26674655
2016 Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia. Molecular neurodegeneration 88 27341800
2020 Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO reports 82 32852886
2012 Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Parkinsonism & related disorders 82 22818528
2022 Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis. Nature communications 75 36207292
2015 Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations. Amyotrophic lateral sclerosis & frontotemporal degeneration 75 26473392
1998 Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor). Proceedings of the National Academy of Sciences of the United States of America 73 9826678
2020 Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms. Brain : a journal of neurology 71 31855245
2008 Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Human mutation 70 18183624
2014 PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Scientific reports 67 25387791
2013 Plasma phosphorylated TDP-43 levels are elevated in patients with frontotemporal dementia carrying a C9orf72 repeat expansion or a GRN mutation. Journal of neurology, neurosurgery, and psychiatry 67 24309270
2021 Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD. Cell reports 66 34433069
2009 Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta neuropathologica 60 19649643
2022 Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex. Nature neuroscience 58 35879464
2016 PGRN Suppresses Inflammation and Promotes Autophagy in Keratinocytes Through the Wnt/β-Catenin Signaling Pathway. Inflammation 54 27239673
2021 Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications. Journal of neurology, neurosurgery, and psychiatry 49 34349004
2011 Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN. Neurology 48 21753165
2007 Clinicopathologic correlation in PGRN mutations. Neurology 48 17522386
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
2016 Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study. NeuroImage. Clinical 47 27625986
2008 Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiology of aging 47 18314228
2014 Circulating PGRN is significantly associated with systemic insulin sensitivity and autophagic activity in metabolic syndrome. Endocrinology 46 24971611
2016 PGRN Is Associated with Late-Onset Alzheimer's Disease: a Case-Control Replication Study and Meta-analysis. Molecular neurobiology 45 26820675
2015 PGRN promotes migration and invasion of epithelial ovarian cancer cells through an epithelial mesenchymal transition program and the activation of cancer associated fibroblasts. Experimental and molecular pathology 44 26607602
2020 Downregulation of LncRNA OIP5-AS1 Induced by IL-1β Aggravates Osteoarthritis via Regulating miR-29b-3p/PGRN. Cartilage 42 32037864
2020 Adeno-associated virus serotype 1-based gene therapy for FTD caused by GRN mutations. Annals of clinical and translational neurology 42 32937039
2015 PGRN induces impaired insulin sensitivity and defective autophagy in hepatic insulin resistance. Molecular endocrinology (Baltimore, Md.) 42 25664864
2023 Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta neuropathologica communications 41 36967384
2013 Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia. Neurobiology of aging 38 24387985
2008 Progranulin (PGRN) expression in ALS: an immunohistochemical study. Journal of the neurological sciences 38 18848708
2019 miR-138 activates NF-κB signaling and PGRN to promote rheumatoid arthritis via regulating HDAC4. Biochemical and biophysical research communications 37 31492495
2016 Analyses MAPT, GRN, and C9orf72 mutations in Chinese patients with frontotemporal dementia. Neurobiology of aging 37 27311648
2024 PGRN is involved in macrophage M2 polarization regulation through TNFR2 in periodontitis. Journal of translational medicine 36 38689292
2012 Progranulin gene (GRN) promoter methylation is increased in patients with sporadic frontotemporal lobar degeneration. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 36 22797721
2009 "Frontotemporoparietal" dementia: clinical phenotype associated with the c.709-1G>A PGRN mutation. Neurology 35 19858458
2023 Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations. The Journal of clinical investigation 34 36602862
2019 NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas. Journal of cellular biochemistry 34 31710121
2021 Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant. Neurology 33 33980708
2021 Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia. Journal of neurology, neurosurgery, and psychiatry 32 33452053
2019 Upregulation of microRNA-140-3p inhibits epithelial-mesenchymal transition, invasion, and metastasis of hepatocellular carcinoma through inactivation of the MAPK signaling pathway by targeting GRN. Journal of cellular biochemistry 32 31044454
2019 A PSCA/PGRN-NF-κB-Integrin-α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential. Molecular cancer research : MCR 32 31722969
2018 Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. NeuroImage. Clinical 32 29845007
2021 Evidence for GRN connecting multiple neurodegenerative diseases. Brain communications 31 34693284
2017 Genetic Features of MAPT, GRN, C9orf72 and CHCHD10 Gene Mutations in Chinese Patients with Frontotemporal Dementia. Current Alzheimer research 31 28462717
2021 PGRN exacerbates the progression of non-small cell lung cancer via PI3K/AKT/Bcl-2 antiapoptotic signaling. Genes & diseases 29 36157487
2019 Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling. PLoS pathogens 29 31585000
2014 Suppression of Ov-grn-1 encoding granulin of Opisthorchis viverrini inhibits proliferation of biliary epithelial cells. Experimental parasitology 29 25450776
2008 Novel progranulin mutation: screening for PGRN mutations in a Portuguese series of FTD/CBS cases. Movement disorders : official journal of the Movement Disorder Society 29 18464284
2018 Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology. Nature communications 27 29382817
2017 Modifiers of GRN-Associated Frontotemporal Lobar Degeneration. Trends in molecular medicine 27 28890134
2023 Progranulin (PGRN) as a regulator of inflammation and a critical factor in the immunopathogenesis of cardiovascular diseases. Journal of inflammation (London, England) 26 36658641
2020 Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency. Molecular neurodegeneration 26 32178712
2020 A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression. Cancer research 25 33323378
2011 Expression, refolding and purification of Ov-GRN-1, a granulin-like growth factor from the carcinogenic liver fluke, that causes proliferation of mammalian host cells. Protein expression and purification 25 21757010
2022 Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini. PLoS pathogens 23 36137145
2016 Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients. PloS one 23 27632209
2015 Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner. Cell cycle (Georgetown, Tex.) 23 26039714
2013 PGRN haploinsufficiency increased Wnt5a signaling in peripheral cells from frontotemporal lobar degeneration-progranulin mutation carriers. Neurobiology of aging 23 24139281
2011 Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G>A PGRN mutation associated with FTLD-TDP dementia. Neurobiology of aging 22 21232819
2021 Neuropathological and behavioral characterization of aged Grn R493X progranulin-deficient frontotemporal dementia knockin mice. Acta neuropathologica communications 21 33795008
2021 Circ_GRN Promotes the Proliferation, Migration, and Inflammation of Vascular Smooth Muscle Cells in Atherosclerosis Through miR-214-3p/FOXO1 Axis. Journal of cardiovascular pharmacology 21 33818550
2018 Clinical variability and onset age modifiers in an extended Belgian GRN founder family. Neurobiology of aging 21 29653316
2015 The Role of PGRN in Alzheimer's Disease. Molecular neurobiology 21 26215834
2010 Intra-familial clinical heterogeneity due to FTLD-U with TDP-43 proteinopathy caused by a novel deletion in progranulin gene (PGRN). Journal of Alzheimer's disease : JAD 20 20930269
2018 Using ATAC-seq and RNA-seq to increase resolution in GRN connectivity. Methods in cell biology 19 30948003
2024 GRouNdGAN: GRN-guided simulation of single-cell RNA-seq data using causal generative adversarial networks. Nature communications 18 38744843
2022 Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations. Brain : a journal of neurology 17 34918030
2020 GRN, NOTCH3, FN1, and PINK1 expression in eutopic endometrium - potential biomarkers in the detection of endometriosis - a pilot study. Journal of assisted reproduction and genetics 16 33029756
2019 The role of progranulin (PGRN) in the modulation of anti-inflammatory response in asthma. Central-European journal of immunology 16 31114443
2017 C5a/C5aR pathway accelerates renal ischemia-reperfusion injury by downregulating PGRN expression. International immunopharmacology 16 29031143
2021 Elevated serum and urine levels of progranulin (PGRN) as a predictor of microglia activation in the early phase of traumatic brain injury: a further link with the development of neurodegenerative diseases. Folia neuropathologica 15 33969679
2020 Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations. Parkinsonism & related disorders 15 32961397
2020 Repressor Element 1 Silencing Transcription Factor (REST) Governs Microglia-Like BV2 Cell Migration via Progranulin (PGRN). Neural plasticity 15 33299399
2016 Identification of biological pathways regulated by PGRN and GRN peptide treatments using transcriptome analysis. The European journal of neuroscience 15 27307215
2015 Profiling of ubiquitination pathway genes in peripheral cells from patients with frontotemporal dementia due to C9ORF72 and GRN mutations. International journal of molecular sciences 15 25580532
2024 A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors. Alzheimer's research & therapy 14 38539243
2022 PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases. Proceedings of the National Academy of Sciences of the United States of America 14 36574647
2021 Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency. Frontiers in molecular neuroscience 14 34054428
2019 Interaction between PGRN gene and the early trauma on clinical characteristics in patients with obsessive-compulsive disorder. Journal of affective disorders 14 31818769
2019 Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study. Neurobiology of aging 14 31918955
2024 Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver. Cell reports 13 38935501
2023 Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations. Acta neuropathologica communications 13 37118844
2023 The Role of Progranulin (PGRN) in the Pathogenesis of Ischemic Stroke. Cellular and molecular neurobiology 13 37561339
2023 Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation. The Journal of biological chemistry 13 37981208
2021 CSF sTREM2 is elevated in a subset in GRN-related frontotemporal dementia. Neurobiology of aging 13 33896652
2020 Elevated levels of extracellular vesicles in progranulin-deficient mice and FTD-GRN Patients. Annals of clinical and translational neurology 13 33197149
2018 Thyrotropin Regulates eNOS Expression in the Endothelium by PGRN Through Akt Pathway. Frontiers in endocrinology 13 30026730
2023 Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression. Neurobiology of disease 12 37003407
2022 Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration. Neurology 12 35790423
2021 Inference of dynamic spatial GRN models with multi-GPU evolutionary computation. Briefings in bioinformatics 12 33834216