2021
α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss
Trudler D, Sanz-Blasco S, Eisele Y, Ghatak S, Bodhinathan K, Akhtar M, Lynch W, Piña-Crespo J, Talantova M, Kelly J, Lipton S. α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss. Journal Of Neuroscience 2021, 41: 2264-2273. PMID: 33483428, PMCID: PMC8018774, DOI: 10.1523/jneurosci.1871-20.2020.Peer-Reviewed Original ResearchConceptsLewy body dementiaExtrasynaptic NMDA receptorsSynaptic damageParkinson's diseaseNeuronal lossLewy bodiesNMDAR activityDisease progressionΑSyn oligomersPotential disease-modifying interventionsNeurodegenerative diseasesΑ-synucleinExtrasynaptic NMDAR activitySynaptic NMDAR activityDisease-modifying interventionsPatch-clamp recordingsMajor neuropathological characteristicsSynaptic lossAstrocytic glutamateGlutamate releaseSynapse lossSpine lossExtrasynaptic NMDARsFemale miceHippocampal slices
2006
Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons
Yuan H, Gerencser A, Liot G, Lipton S, Ellisman M, Perkins G, Bossy-Wetzel E. Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death & Differentiation 2006, 14: 462-471. PMID: 17053808, DOI: 10.1038/sj.cdd.4402046.Peer-Reviewed Original ResearchConceptsMitochondrial fissionNitric oxideFoci formationCortical neuronsMitochondrial fission machineryBcl-2 familyNitrosative stressAntiapoptotic Bcl-xLNeuronal cell deathFission machineryMitofusin 1Puncta formationBioenergetic crisisBax accumulationMitochondrial inhibitorsNeuronal demiseBcl-xLCell deathMitochondrial dysfunctionMitochondriaNeurodegenerative disordersNO donorNeuronsScission siteFissionHIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection
Kaul M, Ma Q, Medders K, Desai M, Lipton S. HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection. Cell Death & Differentiation 2006, 14: 296-305. PMID: 16841089, DOI: 10.1038/sj.cdd.4402006.Peer-Reviewed Original ResearchConceptsHuman immunodeficiency virus-1Neuronal cell deathStromal cell-derived factor-1HIV-1 envelope glycoprotein gp120Cell-derived factor-1Cell deathHIV-1 coreceptor CCR5Chemokine receptor CCR5Immunodeficiency virus-1Brain-derived cellsEnvelope glycoprotein gp120Intracellular free Ca2Gp120 neurotoxicityCCR5 ligandsHIV coreceptorsP38 mitogen-activated protein kinaseCCR5 agonistsNeuroprotective pathwaysReceptor CCR5Heterologous desensitizationCoreceptor CCR5CXCR4 agonistCCR5Glial culturesGlycoprotein gp120
2001
Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades
Digicaylioglu M, Lipton S. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades. Nature 2001, 412: 641-647. PMID: 11493922, DOI: 10.1038/35088074.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell NucleusCells, CulturedDNAErythropoietinGenes, ReporterJanus Kinase 2NeuronsNeuroprotective AgentsNF-kappa BNitric OxideN-MethylaspartateProtein BindingProtein TransportProtein-Tyrosine KinasesProto-Oncogene ProteinsRatsReceptors, ErythropoietinSignal TransductionSuperoxide DismutaseTumor Necrosis Factor-alphaConceptsHypoxia-inducible factor-1EPO receptorForm of JAK2Transcription factor hypoxia-inducible factor-1NF-κB-dependent transcriptionNF-κB functionActivation of JAK2Subsequent nuclear translocationTranscription factor NF-κBNF-κBFactor NF-κBSignaling cascadesNitric oxideKinase 2NF-κB signaling cascadesHypoxic-ischemic preconditioningNuclear translocationNeuroprotective genesFactor 1JAK2Neuroprotective pathwaysNeuronal apoptosisCerebrocortical neuronsEPO effectsDegenerative damageAssembly with the NR1 Subunit Is Required for Surface Expression of NR3A-Containing NMDA Receptors
Pérez-Otaño I, Schulteis C, Contractor A, Lipton S, Trimmer J, Sucher N, Heinemann S. Assembly with the NR1 Subunit Is Required for Surface Expression of NR3A-Containing NMDA Receptors. Journal Of Neuroscience 2001, 21: 1228-1237. PMID: 11160393, PMCID: PMC6762235, DOI: 10.1523/jneurosci.21-04-01228.2001.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulumNR1-1aPlasma membrane targetingReceptor complexRelative calcium permeabilityNR2 subunitsNR1 subunitSurface expressionMembrane targetingSubunit oligomerizationHeteromultimeric complexesHeteromeric complexesAdditional subunitsNMDA receptor familyPlasma membraneIntracellular traffickingDistinct single-channel propertiesIntracellular clustersFunctional NMDA receptorsSubunitsReceptor familyCell surfaceNMDA receptor subunitsMembrane expressionReticulum
2000
Evidence for coassembly of mutant GABACρ1 with GABAAγ2S, glycine α1 and glycine α2 receptor subunits in vitro
Pan Z, Zhang D, Zhang X, Lipton S. Evidence for coassembly of mutant GABACρ1 with GABAAγ2S, glycine α1 and glycine α2 receptor subunits in vitro. European Journal Of Neuroscience 2000, 12: 3137-3145. PMID: 10998097, DOI: 10.1046/j.1460-9568.2000.00198.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDose-Response Relationship, DrugElectrophysiologyGABA AntagonistsGamma-Aminobutyric AcidGene ExpressionIn Vitro TechniquesMutagenesisNeural InhibitionOocytesPicrotoxinProtein Structure, TertiaryRatsReceptors, GABAReceptors, GABA-AReceptors, GABA-BReceptors, GlycineRetinaXenopus laevisConceptsGlycine alpha1Rho1 subunitAlpha2 subunitHeteromeric receptorsGABA dose-response curveBlockade of GABAVoltage-clamp recordingsGamma-aminobutyric acidXenopus laevis oocyte expression systemTwo-electrode voltage-clamp recordingsDose-response curveResponse propertiesPicrotoxinin sensitivityOocyte expression systemGamma2 subunitGABAReceptor subunitsPharmacological propertiesReceptorsUnique gatingFunctional evidenceGABAAAlpha1Gamma2HomomericRole of p38 Mitogen-Activated Protein Kinase in Axotomy-Induced Apoptosis of Rat Retinal Ganglion Cells
Kikuchi M, Tenneti L, Lipton S. Role of p38 Mitogen-Activated Protein Kinase in Axotomy-Induced Apoptosis of Rat Retinal Ganglion Cells. Journal Of Neuroscience 2000, 20: 5037-5044. PMID: 10864961, PMCID: PMC6772303, DOI: 10.1523/jneurosci.20-13-05037.2000.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisAxonal TransportAxotomyCell NucleusCell SurvivalDizocilpine MaleateEnzyme InhibitorsFluorescent DyesImidazolesKineticsMaleMitogen-Activated Protein KinasesNeuroprotective AgentsOptic NerveP38 Mitogen-Activated Protein KinasesPhosphorylationPyridinesRatsRats, Long-EvansRetinal Ganglion CellsSignal TransductionStilbamidinesTime FactorsConceptsRetinal ganglion cellsProtein kinaseP38 Mitogen-Activated Protein KinaseMitogen-Activated Protein KinaseMAP kinase activationIntracellular signal transductionRole of p38P38 MAP kinase activationApoptotic cell deathDose-dependent mannerP38 MAP kinase inhibitorMAP kinase inhibitorRGC apoptosisOptic nerveGanglion cellsSignal transductionNMDA receptorsAxotomy-induced apoptosisApoptotic signalingKinase activationP38 inhibitorRat retinal ganglion cellsCell deathCell typesOptic nerve traumaNitric oxide (NO·) stabilizes whereas nitrosonium (NO+) enhances filopodial outgrowth by rat retinal ganglion cells in vitro
Cheung S, Bhan I, Lipton S. Nitric oxide (NO·) stabilizes whereas nitrosonium (NO+) enhances filopodial outgrowth by rat retinal ganglion cells in vitro. Brain Research 2000, 868: 1-13. PMID: 10841882, DOI: 10.1016/s0006-8993(00)02161-2.Peer-Reviewed Original ResearchConceptsRat retinal ganglion cellsRetinal ganglion cellsGanglion cellsNitric oxideInhibition of NOSNO synthase substrateGrowth-associated proteinFilopodial outgrowthNOS activityGuanylate cyclaseGrowth cone motilityCyclic nucleotide analogsDistinct actionsSynthase substrateCone motilityNOSS-nitrosylationNucleotide analoguesOutgrowthCytokine-Stimulated, But Not HIV-Infected, Human Monocyte-Derived Macrophages Produce Neurotoxic Levels of l-Cysteine
Yeh M, Kaul M, Zheng J, Nottet H, Thylin M, Gendelman H, Lipton S. Cytokine-Stimulated, But Not HIV-Infected, Human Monocyte-Derived Macrophages Produce Neurotoxic Levels of l-Cysteine. The Journal Of Immunology 2000, 164: 4265-4270. PMID: 10754324, DOI: 10.4049/jimmunol.164.8.4265.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedCerebral CortexCysteineCytokinesDose-Response Relationship, ImmunologicHIV Envelope Protein gp120HIV-1HumansImmune SeraInterleukin 1 Receptor Antagonist ProteinInterleukin-1Macrophage ActivationMacrophagesMonocytesNeuronsRatsRats, Sprague-DawleyReceptors, Interleukin-1Receptors, N-Methyl-D-AspartateSialoglycoproteinsSphingosineTumor Necrosis Factor-alphaConceptsHuman monocyte-derived macrophagesNeuronal injuryTNF-alphaHIV-1N-methyl-D-aspartate (NMDA) subtypeUninfected cellsMacrophages/microgliaCultured rat cerebrocortical neuronsVirus-infected macrophagesRelease of neurotoxinsRat cerebrocortical neuronsEnvelope glycoprotein gp120Monocyte-derived macrophagesDose-dependent mannerNeuropathological symptomsIL-1betaGlutamate receptorsCerebrocortical neuronsHIVGlycoprotein gp120Mononuclear phagocytesNeurotoxic levelsGp120Human monocytesCytokine stimulationInvolvement of Activated Caspase‐3‐Like Proteases in N‐Methyl‐D‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons
Tenneti L, Lipton S. Involvement of Activated Caspase‐3‐Like Proteases in N‐Methyl‐D‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons. Journal Of Neurochemistry 2000, 74: 134-142. PMID: 10617114, DOI: 10.1046/j.1471-4159.2000.0740134.x.Peer-Reviewed Original ResearchConceptsCerebrocortical neuronsNeuronal deathNeuronal apoptosisIncubation of neuronsNMDA receptor activationCaspase-3Time-dependent increaseCentral neuronsNMDA stimulationExcessive activationGlutamate receptorsMild insultReceptor activationCaspase-3-like proteasesDouble labelingNeurodegenerative diseasesNMDANeuronsApoptotic cellsConcordant resultsApoptosisPossible activationActivation of caspasesInsultAffinity labeling technique
1999
Attenuation of NMDA Receptor Activity and Neurotoxicity by Nitroxyl Anion, NO−
Kim W, Choi Y, Rayudu P, Das P, Asaad W, Arnelle D, Stamler J, Lipton S. Attenuation of NMDA Receptor Activity and Neurotoxicity by Nitroxyl Anion, NO−. Neuron 1999, 24: 461-469. PMID: 10571239, DOI: 10.1016/s0896-6273(00)80859-4.Peer-Reviewed Original ResearchChemokines and activated macrophages in HIV gp120-induced neuronal apoptosis
Kaul M, Lipton S. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 8212-8216. PMID: 10393974, PMCID: PMC22214, DOI: 10.1073/pnas.96.14.8212.Peer-Reviewed Original ResearchMeSH KeywordsAIDS Dementia ComplexAnimalsApoptosisCells, CulturedCerebral CortexChemokine CCL4Chemokine CCL5Chemokine CXCL12ChemokinesCytokinesEmbryo, MammalianHIV Envelope Protein gp120HIV-1HumansImmunoglobulin FragmentsMacrophage ActivationMacrophage Inflammatory ProteinsMacrophagesNeurogliaNeuronsOligopeptidesRatsRats, Sprague-DawleyRecombinant ProteinsT-LymphocytesConceptsMacrophages/microgliaNeuronal apoptosisChemokine receptorsSDF-1Brain macrophages/microgliaStromal cell-derived factorRat cerebrocortical culturesBeta-chemokines RANTESCell-derived factorNeurotoxic factorsP38 mitogen-activated protein kinase (MAPK) pathwayProportion of cellsInflammatory proteinP38 mitogen-activated protein kinaseGp120SF2Cerebrocortical culturesReceptor CXCR4MicrogliaHuman neuronsHIV gp120CXCR4 receptorMitogen-activated protein kinase pathwayMitogen-activated protein kinaseNeuronsGp120Neuroprotection by the NMDA receptor-associated open-channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal rat
Stieg P, Sathi S, Warach S, Le D, Lipton S. Neuroprotection by the NMDA receptor-associated open-channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal rat. European Journal Of Pharmacology 1999, 375: 115-120. PMID: 10443569, DOI: 10.1016/s0014-2999(99)00214-9.Peer-Reviewed Original ResearchConceptsMagnetic resonance imagingSide effectsInfarct sizeNeonatal ratsChannel blockersNMDA receptorsFocal cerebral ischemia modelNeurobehavioral side effectsIschemic brain injuryEffects of memantineExcitatory amino acidsInduction of strokeRodent stroke modelsAdult animal modelsCerebral ischemia modelSubstantial side effectsCerebral focal ischemiaNumerous side effectsNeuronal cell culturesNeonatal neuronsPhotochemical thrombosisPhotothrombotic modelNeuronal injuryCerebral ischemiaFocal ischemiaRatio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures
D'Emilia D, Lipton S. Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures. Neuroscience Letters 1999, 265: 103-106. PMID: 10327179, DOI: 10.1016/s0304-3940(99)00210-4.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate agonistRat cerebrocortical culturesS-nitrosocysteineS-nitrosohomocysteineNeuronal degenerationCerebrocortical culturesS-nitrosothiolsSubsequent neurotoxicityAcute exposureDetermine outcomeNitric oxideForm peroxynitriteNeurotoxicityS-nitrosylationEndogenous O2S-nitrosoproteinsAgonists
1998
Role of Caspases in N‐Methyl‐d‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons
Tenneti L, D'Emilia D, Troy C, Lipton S. Role of Caspases in N‐Methyl‐d‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons. Journal Of Neurochemistry 1998, 71: 946-959. PMID: 9721720, DOI: 10.1046/j.1471-4159.1998.71030946.x.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid Chloromethyl KetonesAnimalsApoptosisCalciumCaspase 1Cells, CulturedCerebral CortexCysteine EndopeptidasesCysteine Proteinase InhibitorsIntracellular MembranesLipid PeroxidesMembrane PotentialsMitochondriaN-MethylaspartateNeuronsRatsRats, Sprague-DawleyReactive Oxygen SpeciesSignal TransductionConceptsInterleukin-1beta-converting enzymeMitochondrial membrane potentialReactive oxygen speciesRole of caspasesZ-VAD-FMKROS formationMembrane potentialReceptor activationCaspase activationDownstream eventsPseudosubstrate peptideNeuronal apoptosisMitochondrial depolarizationCysteine proteasesLipid peroxidationCaspasesCerebrocortical neuronsSubstrate cleavageIntracellular processesForm of deathN-methyl-D-aspartate (NMDA) receptor activationCortical neuronal apoptosisApoptosisCatalytic siteNMDA receptor activationNeuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation
Chen H, Wang Y, Rayudu P, Edgecomb P, Neill J, Segal M, Lipton S, Jensen F. Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience 1998, 86: 1121-1132. PMID: 9697119, DOI: 10.1016/s0306-4522(98)00163-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBody TemperatureBrain IschemiaCytoplasmExcitatory Amino Acid AntagonistsExcitatory Postsynaptic PotentialsIn Vitro TechniquesLong-Term PotentiationMaleMaze LearningMemantineMicroscopy, ElectronNeuronsNeuroprotective AgentsRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateVacuolesConceptsN-methyl-D-aspartate antagonistsLong-term potentiationAspartate antagonistDizocilpine maleateSide effectsUncompetitive N-methyl-D-aspartate antagonistsN-methyl-D-aspartate blockersMorris water maze performancePost-ischemic administrationHypoxia/ischemiaExcitatory postsynaptic currentsN-methyl-D-aspartate (NMDA) channelsAdverse side effectsWater maze performanceHuman CNS disordersExcitotoxic disordersNeuroprotective concentrationsClinical tolerabilityNeuroprotective dosesClinical efficacyInfarct sizePostsynaptic currentsHippocampal slicesCNS disordersAdult ratsCloning and characterization of mouse GABAC receptor subunits
Greka A, Koolen J, Lipton S, Zhang D. Cloning and characterization of mouse GABAC receptor subunits. Neuroreport 1998, 9: 229-232. PMID: 9507960, DOI: 10.1097/00001756-199801260-00010.Peer-Reviewed Original Research
1997
Molecular basis of glutamate toxicity in retinal ganglion cells
Sucher N, Lipton S, Dreyer E. Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Research 1997, 37: 3483-3493. PMID: 9425525, DOI: 10.1016/s0042-6989(97)00047-3.Peer-Reviewed Original ResearchConceptsRetinal ganglion cellsExcitatory amino acidsNMDA receptor antagonistRetinal ischemiaReceptor antagonistGanglion cellsGlutamate toxicityAnterior ischemic optic neuropathyN-methyl-D-aspartate (NMDA) subtypeNMDA receptor-mediated toxicityNon-NMDA receptor subtypesAcute vascular insultCentral artery occlusionOptic nerve traumaIschemic optic neuropathyGlutamate-induced neurotoxicitySelective NMDA receptor antagonistGlutamate-induced depolarizationVoltage-gated Ca2Amino acid glutamateOptic neuritisNerve traumaArtery occlusionFuture clinical useNeuronal lossAgonist-induced closure of constitutively open γ-aminobutyric acid channels with mutated M2 domains
Pan Z, Zhang D, Zhang X, Lipton S. Agonist-induced closure of constitutively open γ-aminobutyric acid channels with mutated M2 domains. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 6490-6495. PMID: 9177245, PMCID: PMC21077, DOI: 10.1073/pnas.94.12.6490.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCloning, MolecularFemaleGABA AgonistsGABA AntagonistsGamma-Aminobutyric AcidIon Channel GatingIon ChannelsMacromolecular SubstancesMembrane PotentialsMolecular Sequence DataMutagenesis, Site-DirectedOocytesOrganophosphorus CompoundsPoint MutationRatsReceptors, GABAReceptors, GlycineReceptors, NicotinicRecombinant ProteinsSequence AlignmentSequence Homology, Amino AcidVirulence Factors, BordetellaXenopus laevisConceptsLigand-gated ion channelsChannel gatingIon channelsAmino acid residuesAminobutyric acid channelsSingle-point mutantsAbsence of ligandChannel pore regionStructure-function relationshipsPoint mutantsAcid channelImportant new insightsAllosteric transitionSubunit resultsAcid residuesM2 domainConstitutive currentReceptor proteinPore regionAgonist bindingAgonist regulationSubstituting alanineM2 regionSpontaneous channel openingChannel openingNeurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor
Lipton S, Kim W, Choi Y, Kumar S, D’Emilia D, Rayudu P, Arnelle D, Stamler J. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 5923-5928. PMID: 9159176, PMCID: PMC20882, DOI: 10.1073/pnas.94.11.5923.Peer-Reviewed Original ResearchMeSH Keywords2-Amino-5-phosphonovalerate6-Cyano-7-nitroquinoxaline-2,3-dioneAdultAnimalsCells, CulturedCerebral CortexChildDizocilpine MaleateEmbryo, MammalianEvoked PotentialsGlycineHomocysteineHumansKineticsKynurenic AcidNeuronsNeurotoxinsN-MethylaspartateRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateConceptsN-methyl-D-aspartate receptorsGlycine coagonist siteHomocysteine neurotoxicityNeuronal damageHead traumaVascular diseaseTotal homocysteineNeurotoxic concentrationsGlycine levelsCoagonist siteNeuroprotective activityCoagulation systemNervous systemDisease pathogenesisPartial antagonistExcessive Ca2HomocysteineAdverse effectsElevated levelsPathological conditionsDual actionVessel wallReceptorsReactive oxygen generationPathogenesis