Affinage

LINGO1

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 · UniProt Q96FE5

Length
620 aa
Mass
69.9 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LINGO-1 is a CNS single-pass transmembrane LRR-Ig protein that acts as a multivalent negative regulator of neural repair, axonal outgrowth, and myelination (PMID:14966521, PMID:15895088). It is an essential functional component of the NgR1/p75 receptor complex that confers responsiveness to myelin-associated inhibitors such as OMgp and signals through RhoA activation to restrict neurite extension (PMID:14966521). Its ectodomain adopts a bimodular kinked LRR-Ig fold that self-assembles into a ring-shaped tetramer, a quaternary arrangement that scaffolds receptor-complex assembly and whose disruption by the Li81 Fab abolishes biological activity (PMID:17005555, PMID:24756303). In oligodendrocytes LINGO-1 suppresses differentiation and myelination by sustaining RhoA activity (PMID:15895088), blocking ErbB2 translocation into lipid rafts and ErbB2 activation (PMID:24583087), and repressing the actin-severing protein cytoplasmic gelsolin downstream of the receptor (PMID:28193690); it can act simultaneously as ligand and receptor through homophilic trans-interactions that activate RhoA in OPCs (PMID:22514275). Beyond myelin inhibition, LINGO-1 transduces neuronal RhoA signaling through the kinase WNK1, which controls RhoA activation via Rho-GDI1 (PMID:19363035), and it couples to neuronal survival pathways by binding and inhibiting WNK3 to promote apoptosis (PMID:23482566) and by negatively regulating neurotrophin and growth-factor receptors—it complexes with TrkB and EGFR to restrain their signaling and Akt activation (PMID:17726113, PMID:20377621) and drives lysosomal degradation of TrkA/B/C as a negative-feedback mechanism (PMID:26546150). At hippocampal synapses LINGO-1 serves as the NgR1 co-receptor that restricts LTP through the ROCK2-Cofilin pathway (PMID:27166169). LINGO1 also operates as a regulatory subunit of large-conductance Ca2+-activated (BK) channels, where its extracellular domain reduces channel surface expression and its intracellular tail confers current inactivation and Ca2+-dependent gating (PMID:31932443, PMID:40752573). Loss of LINGO-1 function promotes remyelination, axonal survival, and functional recovery across spinal cord injury, EAE, Parkinsonian, and retinal injury models (PMID:17011208, PMID:17906634, PMID:18326721, PMID:17726113), and its transcription is induced by SP1 after injury (PMID:32562344) and repressed by retinoic-acid signaling through RAR-β (PMID:21690307).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 2004 High

    Established LINGO-1 as the missing functional component of the myelin-inhibitory receptor complex, answering how NgR1/p75 transduces inhibitory signals.

    Evidence Co-IP/binding, RhoA activation reconstituted in non-neuronal cells, dominant-negative in primary neurons

    PMID:14966521

    Open questions at the time
    • Stoichiometry of the ternary complex unresolved
    • Did not address localization of the complex
  2. 2005 High

    Extended LINGO-1's role from neurons to oligodendrocytes, showing it cell-autonomously gates differentiation and myelination via RhoA.

    Evidence DN, RNAi, LINGO-1-Fc, KO mice, RhoA assay, coculture myelination

    PMID:15895088

    Open questions at the time
    • Downstream effectors of RhoA in OPCs not defined
    • Ligand on oligodendrocytes unidentified
  3. 2006 High

    Provided the structural basis for LINGO-1 self-assembly, showing a tetrameric ectodomain that could scaffold receptor complex components.

    Evidence X-ray crystallography plus solution biophysics

    PMID:17005555

    Open questions at the time
    • Tetramer relevance in vivo not demonstrated
    • No structure of full receptor complex
  4. 2006 Medium

    Demonstrated therapeutic potential of LINGO-1 antagonism in spinal cord injury through the same RhoA mechanism.

    Evidence LINGO-1-Fc in rat spinal cord hemisection, RhoA assay, behavior

    PMID:17011208

    Open questions at the time
    • Single lab
    • Contributions of neuronal vs glial LINGO-1 not separated
  5. 2007 High

    Showed LINGO-1 acts from both axon and oligodendrocyte and is regulated by NGF/TrkA, refining where the inhibitory signal originates.

    Evidence Synapsin-LINGO-1 transgenic mice, coculture, NGF/TrkA dose-response

    PMID:17202489

    Open questions at the time
    • Trans vs cis signaling not distinguished here
    • Molecular link from TrkA to LINGO-1 transcription not defined
  6. 2007 High

    Broadened LINGO-1 function to neuronal survival, linking its inhibition to EGFR/Akt activation and neuroprotection in Parkinson's models.

    Evidence KO mice, MPTP/6-OHDA, antagonists, p-Akt blot, EGFR binding assay

    PMID:17726113

    Open questions at the time
    • Direct mechanism of EGFR inhibition not structurally resolved
    • Relationship to RhoA pathway unclear
  7. 2007 High

    Established LINGO-1 as a negative regulator of remyelination in vivo, validating it as a demyelinating-disease target.

    Evidence Lingo1 KO and anti-LINGO-1 antibody in EAE, MR DTI, electron microscopy

    PMID:17906634

    Open questions at the time
    • Cellular source of relevant LINGO-1 in EAE not pinpointed
    • Antibody mechanism of action not detailed
  8. 2008 High

    Defined the neuroprotective signaling logic in retinal ganglion cells, placing LINGO-1 upstream of a RhoA/JNK vs PI3K/Akt switch.

    Evidence Ocular hypertension model, LINGO-1-Fc/mAb, RhoA/JNK/Akt blots, kinase inhibitors

    PMID:18326721

    Open questions at the time
    • How LINGO-1 bifurcates RhoA and Akt arms unclear
    • Receptor partner in RGCs not identified
  9. 2009 High

    Identified WNK1 as an intracellular effector linking LINGO-1 to RhoA activation via Rho-GDI1.

    Evidence Yeast two-hybrid, FRET, co-IP, RNAi, DN, RhoA and neurite assays

    PMID:19363035

    Open questions at the time
    • Direct biochemical contact between LINGO-1 tail and WNK1 not mapped
    • Kinase substrate landscape unresolved
  10. 2009 Medium

    Showed N-glycosylation on the LRR concave surface is required for LINGO-1 surface trafficking.

    Evidence High-throughput mammalian expression, mutagenesis, surface expression assay

    PMID:19254717

    Open questions at the time
    • Single study
    • Functional consequence beyond surface expression untested
  11. 2010 Medium

    Identified LINGO-1/TrkB complex as a brake on BDNF-dependent RGC survival, extending negative regulation to neurotrophin receptors.

    Evidence Co-IP, p-TrkB blot, anti-BDNF blockade, ocular hypertension model

    PMID:20377621

    Open questions at the time
    • Direct vs indirect TrkB binding unresolved
    • Single lab in vivo
  12. 2011 Medium

    Defined the molecular determinants of NgR1-LINGO-1 association, implicating gangliosides and the NgR1 stalk.

    Evidence Cell-free solid-phase binding with ganglioside manipulation

    PMID:21872576

    Open questions at the time
    • Cell-free system only
    • Physiological relevance of ganglioside bridging untested in neurons
  13. 2011 Medium

    Identified RA-RAR-β as a transcriptional repressor of Lingo-1, explaining how retinoic acid overcomes myelin inhibition.

    Evidence RAR-β gain/loss, promoter reporter, neurite assay, dorsal column injury

    PMID:21690307

    Open questions at the time
    • RAR-β binding site on promoter not mapped
    • Single lab
  14. 2011 Low

    Mapped self- and APP-interaction to ectodomain regions outside the LRR and TM/cytoplasmic domains.

    Evidence Deletional mutagenesis and binding assays

    PMID:22133804

    Open questions at the time
    • Single lab deletion-mapping with limited follow-up
    • Functional significance of APP binding untested
  15. 2012 High

    Established LINGO-1 as a homophilic trans-acting ligand/receptor that activates RhoA in OPCs.

    Evidence Recombinant ectodomain binding, surface-bound LINGO-1 coculture, RhoA assay

    PMID:22514275

    Open questions at the time
    • Trans-interaction interface not structurally defined
    • Single lab
  16. 2013 High

    Showed LINGO-1 promotes neuronal apoptosis by binding and inhibiting WNK3 through its intracellular domain.

    Evidence Co-IP, in vitro kinase assay, shRNA, DN WNK3, serum-deprivation apoptosis

    PMID:23482566

    Open questions at the time
    • WNK3 anti-apoptotic substrates unidentified
    • Relationship to WNK1/RhoA arm unclear
  17. 2014 High

    Demonstrated LINGO-1 gates oligodendrocyte differentiation by blocking ErbB2 entry into lipid rafts.

    Evidence Co-IP, lipid raft fractionation, p-ErbB2 blot, KO oligodendrocytes, pharmacology

    PMID:24583087

    Open questions at the time
    • Mechanism of raft exclusion unresolved
    • Single lab
  18. 2014 High

    Resolved how a therapeutic antibody works structurally, showing Li81 disrupts LINGO-1 oligomerization to block function.

    Evidence LINGO-1-Fab co-crystal, binding studies, oligodendrocyte differentiation assay

    PMID:24756303

    Open questions at the time
    • In vivo correlation of quaternary rearrangement not shown
  19. 2014 Medium

    Established constitutive cis-dimerization of LINGO-1 and that conformational modulators can tune EGFR-inhibitory activity.

    Evidence Co-IP, BRET saturation, small-molecule screen, EGFR/Erk blots

    PMID:25257685

    Open questions at the time
    • Reconciliation of cis-dimer with tetramer model unaddressed
    • Single lab
  20. 2015 Medium

    Challenged the surface ternary-complex model by showing LINGO-1 is predominantly intracellular and competes with NgR for p75NTR.

    Evidence Fractionation, immunofluorescence, C-terminus mutagenesis, co-IP competition, N-glycan analysis

    PMID:25666623

    Open questions at the time
    • Physiological site of LINGO-1/p75 signaling unresolved
    • Single lab contradicting prior model
  21. 2015 Medium

    Identified LINGO-1-driven lysosomal degradation of Trk receptors as a negative-feedback brake on neurotrophin signaling.

    Evidence Co-IP, lysosomal inhibitors, recycling endosome colocalization, deletion mutant in PC12

    PMID:26546150

    Open questions at the time
    • Ubiquitin/sorting machinery not identified
    • Single lab
  22. 2015 Low

    Linked LINGO-1 and paralogs to reduced amyloidogenic APP processing via lysosomal degradation.

    Evidence Cell-based APP processing assay, lysosomal pathway analysis

    PMID:25758563

    Open questions at the time
    • Limited mechanistic detail; abstract-level only
    • No in vivo validation
  23. 2017 High

    Placed cytoplasmic gelsolin downstream of LINGO-1 as an actin-severing effector in OPC differentiation and remyelination.

    Evidence Anti-LINGO-1 antibody, cGSN siRNA/overexpression in vitro and in vivo, epistasis rescue

    PMID:28193690

    Open questions at the time
    • Connection from RhoA to cGSN regulation not detailed
    • Single lab
  24. 2017 High

    Defined LINGO-1 as the NgR1 co-receptor restricting hippocampal LTP via ROCK2-Cofilin, excluding p75NTR involvement.

    Evidence Hippocampal slice electrophysiology, Lingo1 and p75NTR loss-of-function, pathway biochemistry

    PMID:27166169

    Open questions at the time
    • Receptor partner replacing p75 in synaptic context unclear
    • Single lab
  25. 2020 High

    Revealed an entirely distinct role for LINGO1 as a regulatory subunit of BK channels controlling inactivation and surface expression.

    Evidence Co-IP from human brain, patch-clamp of coexpressed channels, surface expression assay

    PMID:31932443

    Open questions at the time
    • Native neuronal context of BK regulation not demonstrated
    • Stoichiometry of LINGO1:BK unresolved
  26. 2020 Medium

    Identified SP1 as the injury-induced transcription factor driving LINGO-1 expression in retinal ganglion cells.

    Evidence Promoter luciferase, SP1 overexpression qRT-PCR, in vivo SP1 shRNA, optic nerve crush

    PMID:32562344

    Open questions at the time
    • Upstream signal activating SP1 not defined
    • Single lab
  27. 2021 Medium

    Showed LINGO-1 controls neural stem cell differentiation by modulating miR-15b-3p and Wnt5a translation.

    Evidence shRNA in NSPCs, miRNA-seq, Western/RT-qPCR, NSPC transplantation in SCI mice

    PMID:34187584

    Open questions at the time
    • Mechanism linking LINGO-1 to miR-15b-3p levels unknown
    • Single lab
  28. 2025 High

    Dissected the BK-regulatory structure-function, attributing surface inhibition to the ectodomain and inactivation/gating to the intracellular tail.

    Evidence LINGO1/LINGO2 chimera domain swaps, patch-clamp, surface expression

    PMID:40752573

    Open questions at the time
    • Atomic interface with BK channel unresolved
    • LRR-independent mechanism not explained mechanistically
  29. 2025 Medium

    Integrated LINGO1 into postoperative/aging cognitive decline via dual RhoA/ROCK1 activation and EGFR/PI3K/Akt suppression.

    Evidence AAV knockdown in aged mice, pathway Western blots, behavior

    PMID:39781463

    Open questions at the time
    • Causality between tau phosphorylation and LINGO1 not directly tested
    • Single lab
  30. 2025 Medium

    Showed LINGO-1 negatively regulates CB1R/TrkB signaling and GABAergic interneuron integrity affecting spatial memory.

    Evidence AAV overexpression/silencing, CB1R pharmacology in HT22, Western blots, behavior

    PMID:40441519

    Open questions at the time
    • Direct LINGO-1/CB1R binding not biochemically confirmed
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LINGO-1's intracellular localization, cis-dimer/tetramer assembly, and competition with NgR for p75NTR are reconciled into a single coherent signaling topology remains unresolved.
  • No structure of the full NgR1/p75/LINGO-1 complex
  • Native subcellular site of signaling disputed across studies
  • Relationship between RhoA, WNK kinases, and BK-channel roles not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0005198 structural molecule activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
EGFRERBB2KCNMA1NGFRNTRK2RTN4RWNK1WNK3
Complex memberships
BK channel complexNgR1/p75/LINGO-1 receptor complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 LINGO-1 is a component of the NgR1/p75 signaling complex: it binds both NgR1 and p75, and coexpression of NgR1, p75, and LINGO-1 in non-neuronal cells confers responsiveness to oligodendrocyte myelin glycoprotein (OMgp) as measured by RhoA activation. A dominant-negative LINGO-1 construct attenuated myelin inhibition in primary neuronal cultures. Co-immunoprecipitation/binding assays, RhoA activation assay in reconstituted non-neuronal cells, dominant-negative construct in primary neuronal cultures Nature neuroscience High 14966521
2005 LINGO-1 is expressed in oligodendrocytes and negatively regulates oligodendrocyte differentiation and myelination. Attenuation of LINGO-1 (dominant-negative, RNAi, or LINGO-1-Fc) leads to downregulation of RhoA activity and promotes differentiation and myelination; conversely, overexpression activates RhoA and inhibits differentiation. LINGO-1 knockout mice show increased myelination in vivo. Dominant-negative construct, RNAi knockdown, soluble LINGO-1-Fc fusion protein, RhoA activity assay, oligodendrocyte–neuron coculture myelination assay, LINGO-1 knockout mice Nature neuroscience High 15895088
2006 The crystal structure of the LINGO-1 ectodomain reveals a bimodular, kinked LRR–Ig fold. In crystals and in solution, LINGO-1 forms a stable ring-shaped tetramer in which each LRR domain fills an open cleft in an adjacent protomer, burying ~9,200 Ų of surface area; this self-assembly may scaffold simultaneous binding of NgR complex components. X-ray crystallography, biophysical solution analysis The Journal of biological chemistry High 17005555
2006 LINGO-1-Fc (soluble antagonist that blocks LINGO-1 binding to NgR1) administered after spinal cord hemisection in rats significantly decreased RhoA activation, increased neuronal and oligodendrocyte survival, promoted axonal sprouting, and improved functional recovery. In vivo spinal cord injury model in rats, RhoA activation assay, immunohistochemistry, behavioral assessment Molecular and cellular neurosciences Medium 17011208
2007 Axonal LINGO-1 expression, regulated by NGF/TrkA signaling in a dose-dependent manner, inhibits oligodendrocyte differentiation and myelination with equal potency to oligodendrocyte-expressed LINGO-1. Disruption of LINGO-1 on either cell type is sufficient to promote myelination independent of axon diameter; transgenic mice overexpressing LINGO-1 under the neuronal synapsin promoter show greatly inhibited myelination. Neuronal-promoter transgenic mice (synapsin-LINGO-1), co-culture myelination assays, NGF/TrkA dose-response experiments The Journal of neuroscience High 17202489
2007 LINGO-1 inhibition protects dopaminergic (DA) neurons in Parkinson's disease models: LINGO-1 KO mice show increased DA neuron survival and reduced behavioral abnormalities after 6-OHDA or MPTP treatment, accompanied by increased Akt phosphorylation. LINGO-1 antagonists (LINGO-1-Fc, dominant-negative, anti-LINGO-1 antibody) protect DA neurons in vitro partly through direct inhibition of LINGO-1 binding to EGFR, activating the EGFR/Akt signaling pathway. LINGO-1 KO mice, MPTP/6-OHDA PD models, LINGO-1-Fc/DN/antibody antagonism, Western blot for p-Akt, EGFR binding inhibition assay Proceedings of the National Academy of Sciences of the United States of America High 17726113
2007 Loss of LINGO-1 function (gene knockout or anti-LINGO-1 antibody) leads to functional recovery from experimental autoimmune encephalomyelitis, with improved axonal integrity (confirmed by MR diffusion tensor imaging) and newly formed myelin sheaths (confirmed by electron microscopy), demonstrating LINGO-1 as a negative regulator of remyelination in vivo. Lingo1 KO mice, anti-LINGO-1 antibody treatment in EAE model, MR diffusion tensor imaging, electron microscopy Nature medicine High 17906634
2008 Blocking LINGO-1 function with LINGO-1-Fc or anti-LINGO-1 mAb 1A7 promotes retinal ganglion cell (RGC) survival after ocular hypertension and optic nerve transection. The neuroprotective effect is mediated by blocking the RhoA/JNK pathway and promoting Akt phosphorylation (PI3K/Akt pathway); the survival effect is abolished by Akt phosphorylation inhibition. Ocular hypertension rat model, intravitreal injection of LINGO-1-Fc and antibody, Western blot for RhoA/JNK/Akt, specific kinase inhibitors Investigative ophthalmology & visual science High 18326721
2009 LINGO-1 interacts with the serine-threonine kinase WNK1, identified by yeast two-hybrid screen and validated by FRET and co-immunoprecipitation. The interaction is intensified by Nogo66 treatment. WNK1 co-localizes with LINGO-1 in cortical neurons. Suppression of WNK1 (RNAi or dominant-negative fragment) attenuates Nogo66-induced inhibition of neurite extension and inhibits RhoA activation. WNK1 interacts with Rho-GDI1 and this interaction is attenuated by Nogo66, indicating WNK1 regulates RhoA activation downstream of LINGO-1. Yeast two-hybrid, FRET, co-immunoprecipitation, RNAi knockdown, dominant-negative overexpression, RhoA activation assay, neurite outgrowth assay The Journal of biological chemistry High 19363035
2009 LINGO-1 surface expression requires specific N-glycosylation sites located on the concave surface of the LRR domain. Residue-screening by mutagenesis in a mammalian high-throughput system identified key asparagines sufficient to support surface expression. High-throughput mammalian transient expression, PCR-based expression cassette mutagenesis, surface expression assay FEBS letters Medium 19254717
2010 LINGO-1 forms a receptor complex with TrkB and negatively regulates TrkB activation (phosphorylation) in the retina after ocular hypertension injury. LINGO-1 antagonists (antibody 1A7, LINGO-1-Fc) upregulate phospho-TrkB and promote RGC survival; this neuroprotective effect is blocked by anti-BDNF antibody. Co-immunoprecipitation (LINGO-1/TrkB complex), Western blot for p-TrkB, anti-BDNF antibody blockade, ocular hypertension rat model The European journal of neuroscience Medium 20377621
2011 Gangliosides mediate the interaction between NgR1 and LINGO-1 in a cell-free system. Solid-phase binding assays show that sialic acid moieties of gangliosides and the stalk of NgR1 are the principal determinants of NgR1–LINGO-1 molecular interactions. The tripartite complex NgR1/LINGO-1/ganglioside exhibits stronger binding to Nogo-A in the presence of p75. Cell-free solid-phase binding assay, ganglioside depletion/addition experiments Biochemical and biophysical research communications Medium 21872576
2011 Retinoic acid (RA), acting through RAR-β, transcriptionally represses Lingo-1 expression, thereby counteracting myelin-dependent inhibition of neurite outgrowth via the NgR complex. Suppression of Lingo-1 is required for RA-RAR-β to counteract extrinsic inhibition; RA treatment in vivo after dorsal column injury inhibits Lingo-1 expression specifically through RAR-β. RAR-β gain/loss-of-function, Lingo-1 promoter reporter assay, neurite outgrowth assay, in vivo dorsal column injury model The Journal of cell biology Medium 21690307
2011 The leucine-rich repeat domain and the transmembrane/cytoplasmic domain of LINGO-1 are not required for LINGO-1 self-interaction or interaction with APP; these interactions are mediated by other regions of the ectodomain. Deletional mutagenesis, binding assays Neuroscience letters Low 22133804
2012 LINGO-1 inhibits oligodendrocyte differentiation through intercellular homophilic (trans) self-interactions: soluble LINGO-1 ectodomain binds to full-length LINGO-1 on CHO cells (trans interaction), surface-bound LINGO-1 on astrocytes inhibits OPCs through intercellular signaling, and soluble LINGO-1 ectodomain activates RhoA in OPCs. LINGO-1 acts as both a ligand and a receptor. Recombinant ectodomain binding to LINGO-1-expressing CHO cells, ectopic surface-bound LINGO-1 on astrocytes in coculture, RhoA activation assay in OPCs The Journal of biological chemistry High 22514275
2013 LINGO-1 promotes neuronal apoptosis by binding the serine-threonine kinase WNK3 via the LINGO-1 intracellular domain, reducing WNK3 kinase activity. The LINGO-1/WNK3 co-association is enhanced by Nogo66 treatment. WNK3 suppresses serum-deprivation-induced neuronal apoptosis in a kinase-dependent manner, and inhibiting WNK3 activity mimics the pro-apoptotic effect of LINGO-1 activation. Co-immunoprecipitation (LINGO-1/WNK3), WNK3 kinase activity assay in vitro, shRNA knockdown, dominant-negative WNK3, serum-deprivation apoptosis model in cortical neurons The Journal of biological chemistry High 23482566
2014 LINGO-1 directly binds ErbB2, blocks ErbB2 translocation into lipid rafts, and inhibits ErbB2 phosphorylation/activation, thereby suppressing oligodendrocyte differentiation. In LINGO-1−/− oligodendrocytes, ErbB2 activation does not further enhance differentiation, suggesting LINGO-1 is a gating mechanism for ErbB2-dependent differentiation. Co-immunoprecipitation (LINGO-1/ErbB2), lipid raft fractionation, ErbB2 phosphorylation Western blot, LINGO-1 KO oligodendrocytes, ErbB2 inhibitor/activator pharmacology Molecular and cellular neurosciences High 24583087
2014 Crystal structure of LINGO-1 in complex with the anti-LINGO-1 Li81 Fab reveals that Li81 binds the convex surface of the LRR domain within repeats 4–8. Fab binding blocks oligomerization contact points of LINGO-1 and produces a stable 2:2 LINGO-1/Fab complex by rearranging the quaternary structure, and masks functional epitopes in the Ig domain required for LINGO-1 biological activity in oligodendrocyte differentiation. X-ray crystallography (LINGO-1–Fab co-crystal), biochemical binding studies, oligodendrocyte differentiation functional assay The Journal of pharmacology and experimental therapeutics High 24756303
2014 LINGO-1 forms constitutive cis-dimers (homodimers) at the plasma membrane, demonstrated by co-immunoprecipitation and BRET saturation analysis in HEK293 and SH-SY5Y cells. Cis-dimerization occurs early during biosynthesis. A small molecule (phenoxybenzamine), identified by BRET-based screening as a conformational modulator of LINGO-1 dimers, acts as a positive modulator of LINGO-1 function, increasing LINGO-1-mediated inhibition of EGF receptor signaling and Erk phosphorylation in HEK-293 cells. Co-immunoprecipitation, BRET saturation assay, small-molecule screen, Western blot for EGF receptor signaling/Erk phosphorylation British journal of pharmacology Medium 25257685
2015 LINGO-1 is predominantly localized intracellularly in neurons (cortex and cerebellum). Mutation or truncation of the conserved LINGO-1 C-terminus alters intracellular retention, causing increased plasma membrane expression. p75NTR associates predominantly with natively expressed, intracellular LINGO-1 containing immature N-glycans (pre-trans-Golgi), whereas mutant LINGO-1 with enhanced plasma membrane expression does not associate with p75NTR. Co-immunoprecipitation shows LINGO-1 and NgR compete for binding to p75NTR, contradicting a functional plasma membrane LINGO-1/p75NTR/NgR ternary complex. Subcellular fractionation, immunofluorescence, C-terminus mutagenesis, co-immunoprecipitation, N-glycan analysis The Journal of biological chemistry Medium 25666623
2015 LINGO-1 promotes lysosomal degradation of TrkA, TrkB, and TrkC (Trk neurotrophin receptors) as a negative feedback mechanism: Trk activation promotes Trk association with LINGO-1, and this association drives Trk degradation via a lysosomal pathway, partly within recycling endosomes. A LINGO-1 mutant with deleted extracellular domain enhances TrkA signaling in PC12 cells, likely by acting as an inhibitor of Trk downregulation by full-length LINGO-1. Co-immunoprecipitation (Trk/LINGO-1), lysosomal inhibitor experiments, recycling endosome co-localization, LINGO-1 deletion mutant in PC12 cells Molecular and cellular neurosciences Medium 26546150
2015 LINGO-1 and its paralogs (LINGO-2, LINGO-3) decrease amyloidogenic processing of amyloid precursor protein (APP) by promoting lysosomal degradation of AβPP. Cell-based APP processing assay, lysosomal pathway analysis Pathobiology of aging & age related diseases Low 25758563
2017 LINGO-1 regulates oligodendrocyte differentiation and maturation through the cytoplasmic gelsolin (cGSN) signaling pathway: anti-LINGO-1 antibody-promoted OPC differentiation is accompanied by upregulation of cGSN (an actin-severing protein). cGSN siRNA reduces OPC differentiation; cGSN overexpression promotes differentiation in vitro and remyelination in vivo. Coexpression of cGSN and LINGO-1 blocks the inhibitory effect of LINGO-1, placing cGSN downstream of LINGO-1. Anti-LINGO-1 antibody treatment, cGSN siRNA knockdown, cGSN overexpression in vitro and in vivo, OPC differentiation assay, remyelination in vivo The Journal of neuroscience High 28193690
2017 Lingo1 is the NgR1 co-receptor that mediates Nogo-66 restriction of LTP at hippocampal Schaffer collateral–CA1 synapses. Loss of function for Lingo1 significantly increases LTP. p75NTR is not involved in mediating Nogo-66 effects on LTP. The downstream intracellular mechanism involves the ROCK2-Cofilin pathway to control actin cytoskeleton dynamics. Electrophysiology in acute hippocampal slices (LTP measurement), Lingo1 loss-of-function, p75NTR loss-of-function, ROCK2-Cofilin pathway biochemistry Cerebral cortex High 27166169
2020 LINGO1 is a regulatory subunit of large conductance Ca2+-activated K+ (BK) channels: LINGO1 co-immunoprecipitates with BK channels in human brain; coexpression of LINGO1 and BK channels produces rapidly inactivating BK currents; LINGO1 reduces plasma membrane surface expression of BK channels, causing functional knockdown of BK currents. Co-immunoprecipitation from human brain tissue, electrophysiology (patch clamp) of coexpressed LINGO1/BK channels, surface expression assay Proceedings of the National Academy of Sciences of the United States of America High 31932443
2020 SP1 transcription factor is upregulated in optic nerve crush-injured RGCs, binds the LINGO-1 promoter (confirmed by luciferase assay), and drives increased LINGO-1 expression. Silencing SP1 in vivo reduces LINGO-1 expression and protects RGC structure. Luciferase reporter assay for SP1 binding to LINGO-1 promoter, SP1 overexpression qRT-PCR, SP1 shRNA in vivo, optic nerve crush model CNS neuroscience & therapeutics Medium 32562344
2021 LINGO-1 regulates Wnt5a protein expression (but not mRNA) during neural stem and progenitor cell (NSPC) differentiation by modulating miR-15b-3p levels: LINGO-1 shRNA increases neuronal differentiation, elevates Wnt5a protein, and decreases miR-15b-3p (which suppresses Wnt5a translation). Transplantation of LINGO-1 shRNA-treated NSPCs into SCI mice promotes neural differentiation and motor recovery. LINGO-1 shRNA lentiviral knockdown in NSPCs, miRNA sequencing, Western blot and RT-qPCR for Wnt5a and pathway components, in vivo NSPC transplantation in SCI mice Stem cell research & therapy Medium 34187584
2025 The extracellular domain of LINGO1 (but not the transmembrane or intracellular C-terminal tail domain, ITD) is required to inhibit plasmalemmal BK channel expression; this inhibitory effect does not require the 12 LRR repeats. The ITD controls the shift in voltage of half-maximal activation of BK:LINGO currents at different Ca2+ concentrations. The last 8 amino acids of the ITD specifically confer BK current inactivation. Chimeric LINGO1/LINGO2 domain-swap constructs, electrophysiology (patch clamp), surface expression assay The Journal of biological chemistry High 40752573
2025 In hippocampal neurons after surgery/aging, elevated LINGO1 activates the RhoA/ROCK1 signaling pathway through interactions with NgR and p75NTR, promoting myelin loss and abnormal tau phosphorylation, and also inhibits the EGFR/PI3K/Akt pathway, increasing neuronal apoptosis. LINGO1 knockdown reverses these pathological changes and attenuates cognitive decline. LINGO1 AAV knockdown in aged mice after surgery, Western blot for RhoA/ROCK1/NgR/p75NTR and EGFR/PI3K/Akt pathways, behavioral testing International journal of biological sciences Medium 39781463
2025 LINGO-1 negatively regulates CB1R/TrkB signaling in hippocampal neurons: overexpressing LINGO-1 reduces CB1R protein levels and impairs spatial memory in vivo; antagonizing LINGO-1 increases CB1R/TrkB signaling and rescues CCK-GABAergic interneurons. Competitive inhibition between LINGO-1 and CB1R was observed in vitro, and LINGO-1 antagonism reverses CB1R inhibition-induced decreases in DCX, TrkB, and p-TrkB. AAV-mediated LINGO-1 overexpression/silencing in vivo, CB1R agonist/antagonist pharmacology in HT22 neurons, Western blot for CB1R/TrkB/p-TrkB/DCX, spatial memory behavioral testing Experimental neurology Medium 40441519

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nature neuroscience 675 14966521
2005 LINGO-1 negatively regulates myelination by oligodendrocytes. Nature neuroscience 499 15895088
2007 LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nature medicine 402 17906634
2009 Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nature genetics 167 19182806
2007 Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proceedings of the National Academy of Sciences of the United States of America 144 17726113
2013 Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS drugs 141 23681979
2007 NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 138 17202489
2006 LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury. Molecular and cellular neurosciences 125 17011208
2010 LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease. Neurogenetics 104 20369371
2012 LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions. The Journal of biological chemistry 88 22514275
2008 LINGO-1 and its role in CNS repair. The international journal of biochemistry & cell biology 80 18468478
2006 The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. The Journal of biological chemistry 74 17005555
2003 LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with enriched expression in limbic system and neocortex. The European journal of neuroscience 74 14686891
2013 Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau. Acta neuropathologica 71 23543187
2008 LINGO-1 antagonists as therapy for multiple sclerosis: in vitro and in vivo evidence. Expert opinion on biological therapy 71 18774923
2007 TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions. Neuropathology and applied neurobiology 66 17239012
2008 Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection. Investigative ophthalmology & visual science 61 18326721
2012 The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127. Biomaterials 58 23211450
2010 Replication of the LINGO1 gene association with essential tremor in a North American population. European journal of human genetics : EJHG 58 20372186
2009 Combined effect of brain-derived neurotrophic factor and LINGO-1 fusion protein on long-term survival of retinal ganglion cells in chronic glaucoma. Neuroscience 57 19422885
2015 LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice. Scientific reports 55 26383267
2018 LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice. CNS neuroscience & therapeutics 52 29427384
2020 LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels. Proceedings of the National Academy of Sciences of the United States of America 51 31932443
2014 Increased LINGO1 in the cerebellum of essential tremor patients. Movement disorders : official journal of the Movement Disorder Society 51 24531928
2015 A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders. Neuroscience and biobehavioral reviews 49 26143511
2009 LINGO-1 interacts with WNK1 to regulate nogo-induced inhibition of neurite extension. The Journal of biological chemistry 49 19363035
2010 LINGO1 polymorphisms are associated with essential tremor in Europeans. Movement disorders : official journal of the Movement Disorder Society 43 20310002
2014 Novel implications of Lingo-1 and its signaling partners in schizophrenia. Translational psychiatry 40 24448210
2010 Screening for two SNPs of LINGO1 gene in patients with essential tremor or sporadic Parkinson's disease in Chinese population. Neuroscience letters 33 20600614
2004 Neuronal activity-induced regulation of Lingo-1. Neuroreport 32 15640763
2007 An in vitro study on the involvement of LINGO-1 and Rho GTPases in Nogo-A regulated differentiation of oligodendrocyte precursor cells. Molecular and cellular neurosciences 31 17719796
2019 LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats. Journal of physiology and biochemistry 30 30759305
2017 LINGO-1 Regulates Oligodendrocyte Differentiation through the Cytoplasmic Gelsolin Signaling Pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 28193690
2015 Lingo-1 shRNA and Notch signaling inhibitor DAPT promote differentiation of neural stem/progenitor cells into neurons. Brain research 28 26607252
2010 LINGO-1 negatively regulates TrkB phosphorylation after ocular hypertension. The European journal of neuroscience 28 20377621
2017 Nogo-66 Restricts Synaptic Strengthening via Lingo1 and the ROCK2-Cofilin Pathway to Control Actin Dynamics. Cerebral cortex (New York, N.Y. : 1991) 27 27166169
2010 Lack of association of LINGO1 rs9652490 and rs11856808 SNPs with familial essential tremor. European journal of neurology 27 21219542
2014 LINGO-1 regulates oligodendrocyte differentiation by inhibiting ErbB2 translocation and activation in lipid rafts. Molecular and cellular neurosciences 25 24583087
2012 Neutralization of LINGO-1 during in vitro differentiation of neural stem cells results in proliferation of immature neurons. PloS one 25 22235341
2019 LINGO-1 deficiency promotes nerve regeneration through reduction of cell apoptosis, inflammation, and glial scar after spinal cord injury in mice. Experimental neurology 24 31132364
2014 Structure of the LINGO-1-anti-LINGO-1 Li81 antibody complex provides insights into the biology of LINGO-1 and the mechanism of action of the antibody therapy. The Journal of pharmacology and experimental therapeutics 24 24756303
2011 LINGO1 variants in essential tremor and Parkinson's disease. Acta neurologica Scandinavica 24 21470193
2009 Role of LINGO1 polymorphisms in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 24 19908305
2011 LINGO1 variants in the French-Canadian population. PloS one 22 21264305
2011 RA-RAR-β counteracts myelin-dependent inhibition of neurite outgrowth via Lingo-1 repression. The Journal of cell biology 22 21690307
2005 Expression pattern of LINGO-1 in the developing nervous system of the chick embryo. Gene expression patterns : GEP 22 16024296
2017 Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay. Genetics in medicine : official journal of the American College of Medical Genetics 21 28837161
2017 LINGO-1 and AMIGO3, potential therapeutic targets for neurological and dysmyelinating disorders? Neural regeneration research 21 28966634
2015 LINGO-1 promotes lysosomal degradation of amyloid-β protein precursor. Pathobiology of aging & age related diseases 21 25758563
2014 Lingo-1 inhibited by RNA interference promotes functional recovery of experimental autoimmune encephalomyelitis. Anatomical record (Hoboken, N.J. : 2007) 21 25045138
2013 LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity. The Journal of biological chemistry 21 23482566
2011 LINGO1 gene analysis in Parkinson's disease phenotypes. Movement disorders : official journal of the Movement Disorder Society 19 21506150
2010 Analysis of LINGO1 (rs9652490) polymorphism in sporadic Parkinson's disease in a Polish population, and a meta-analysis. Neuroscience letters 19 20117178
2010 Passive immunization with LINGO-1 polyclonal antiserum afforded neuroprotection and promoted functional recovery in a rat model of spinal cord injury. Neuroimmunomodulation 19 20203533
2015 Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling. Molecular and cellular neurosciences 18 26546150
2012 LINGO-1 and Neurodegeneration: Pathophysiologic Clues for Essential Tremor. Tremor and other hyperkinetic movements (New York, N.Y.) 18 23439882
2010 LINGO1 is not associated with Parkinson's disease in German patients. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 18 20468067
2008 Inactivation of glycogen synthase kinase-3beta and up-regulation of LINGO-1 are involved in LINGO-1 antagonist regulated survival of cerebellar granular neurons. Cellular and molecular neurobiology 18 18183482
2023 Nogo-A and LINGO-1: Two Important Targets for Remyelination and Regeneration. International journal of molecular sciences 17 36901909
2020 MiR-615 Regulates NSC Differentiation In Vitro and Contributes to Spinal Cord Injury Repair by Targeting LINGO-1. Molecular neurobiology 17 32462552
2015 Analysis and meta-analysis of five polymorphisms of the LINGO1 and LINGO2 genes in Parkinson's disease and multiple system atrophy in a Chinese population. Journal of neurology 17 26254004
2015 LINGO-1 protein interacts with the p75 neurotrophin receptor in intracellular membrane compartments. The Journal of biological chemistry 16 25666623
2012 Lentiviral vectors encoding short hairpin RNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in central nervous system neurones. The journal of gene medicine 16 22499506
2021 LINGO-1 regulates Wnt5a signaling during neural stem and progenitor cell differentiation by modulating miR-15b-3p levels. Stem cell research & therapy 13 34187584
2018 Alterations of Hippocampal Myelin Sheath and Axon Sprouting by Status Convulsion and Regulating Lingo-1 Expression with RNA Interference in Immature and Adult Rats. Neurochemical research 13 29383653
2014 Targeting the cis-dimerization of LINGO-1 with low MW compounds affects its downstream signalling. British journal of pharmacology 13 25257685
2011 Association study between the LINGO1 gene and Parkinson's disease in the Italian population. Parkinsonism & related disorders 13 21752692
2011 Ganglioside mediate the interaction between Nogo receptor 1 and LINGO-1. Biochemical and biophysical research communications 13 21872576
2010 LINGO1 rs9652490 variant in Parkinson disease patients. Neuroscience letters 12 20951767
2015 The potential of LINGO-1 as a therapeutic target for essential tremor. Expert opinion on therapeutic targets 11 25862159
2010 Genetic analysis of "leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing, Nogo receptor-interacting protein-1 (LINGO1)" in two independent Chinese parkinson's disease populations. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 11 20957646
2020 SP1-mediated upregulation of LINGO-1 promotes degeneration of retinal ganglion cells in optic nerve injury. CNS neuroscience & therapeutics 10 32562344
2019 Copy number variation of LINGO1 in familial dystonic tremor. Neurology. Genetics 10 30842974
2011 The leucine-rich repeats of LINGO-1 are not required for self-interaction or interaction with the amyloid precursor protein. Neuroscience letters 10 22133804
2025 Lingo1 in the hippocampus contributes to cognitive dysfunction after anesthesia and surgery in aged mice. International journal of biological sciences 9 39781463
2024 Resveratrol and 1,25-dihydroxyvitamin D decrease Lingo-1 levels, and improve behavior in harmaline-induced Essential tremor, suggesting potential therapeutic benefits. Scientific reports 9 38684734
2023 Antagonizing LINGO-1 reduces activated microglia and alleviates dendritic spine loss in the hippocampus of APP/PS1 transgenic mice. Neuroscience letters 9 38142924
2022 Effect of expression of PPARG, DNM2L, RRAD, and LINGO1 on broiler chicken breast muscle satellite cell function. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 8 35278723
2013 LINGO1 rs9652490 and rs11856808 polymorphisms are not associated with risk for multiple sclerosis. BMC neurology 8 23574883
2023 Genetic and Epigenetic Regulation in Lingo-1: Effects on Cognitive Function and White Matter Microstructure in a Case-Control Study for Schizophrenia. International journal of molecular sciences 7 37958608
2021 LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3. Human cell 7 33830473
2019 Inhibition of the leucine-rich repeat protein lingo-1 enhances RGC survival in optic nerve injury. Experimental and therapeutic medicine 7 31885701
2015 Effect of retinoic acid on expression of LINGO-1 and neural regeneration after cerebral ischemia. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 7 25673193
2012 Genetic variation in LINGO-1 (rs9652490) and risk of Parkinson's disease: twelve studies and a meta-analysis. Neuroscience letters 7 22710005
2019 LINGO-1 shRNA Loaded by Pluronic F-127 Promotes Functional Recovery After Ventral Root Avulsion. Tissue engineering. Part A 6 30794055
2023 Inhibition of LINGO1 as a therapeutic target to promote axonal regeneration and repair for neurological disorders. 3 Biotech 5 37854938
2009 Swift residue-screening identifies key N-glycosylated asparagines sufficient for surface expression of neuroglycoprotein Lingo-1. FEBS letters 5 19254717
2018 Perinatal administration of phencyclidine alters expression of Lingo-1 signaling pathway proteins in the prefrontal cortex of juvenile and adult rats. Neuronal signaling 4 32714588
2021 Knockdown of Lingo-1 by short hairpin RNA promotes cognitive function recovery in a status convulsion model. 3 Biotech 3 34221810
2025 Therapeutic Potential of Agmatine in Essential Tremor Through Regulation of Lingo-1 and Inflammatory Pathways. Brain and behavior 2 39779480
2025 Resveratrol Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion by Targeting Lingo-1, NgR1, p75, and RhoA/ROCK-2 Pathways. Iranian journal of pharmaceutical research : IJPR 2 40718448
2025 Analyses of Nogo-Family Genes in Mouse and Human Microglia Omics Datasets Identify LINGO1 as a Candidate Drug Target in Alzheimer's Disease. Current neuropharmacology 2 40754867
2017 LINGO-1 is a New Therapy Target and Biomarker for Ewing Sarcoma. Clinics in oncology (Belmont, Calif.) 2 30613826
2025 The role of LINGO-1 in regulating CB1R/TrkB signalling and GABAergic interneurons in Alzheimer's disease pathogenesis. Experimental neurology 1 40441519
2025 Distinct domains of LINGO1 control surface expression and biophysical properties of large conductance Ca2+- and voltage-activated potassium (BK) channels. The Journal of biological chemistry 1 40752573
2026 Transcriptional activation of LINGO1 facilitates proliferation and immune escape in colorectal cancer. Scientific reports 0 41699010
2025 Effects of subanesthetic dose of ketamine on motor and cognitive outcomes of harmaline-induced essential tremor model: a focus on Lingo-1 and inflammatory pathways. BMC neuroscience 0 40751128
2025 Modulation of Lingo-1 and NMDA receptor expression by memantine and vitamin D3 co-therapy attenuates motor and non-motor symptoms in essential tremor. Naunyn-Schmiedeberg's archives of pharmacology 0 41191052
2018 Dynamic expression of p75NTR and Lingo-1 during development of mouse retinofugal pathway. Neuroscience letters 0 30201307
2014 [LINGO-1 expression of brain tissue in experimental autoimmune encephalomyelitis mouse]. Zhonghua yi xue za zhi 0 24924721

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