2025
S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity
Zhang X, Vlkolinsky R, Wu C, Dolatabadi N, Scott H, Prikhodko O, Zhang A, Blanco M, Lang N, Piña-Crespo J, Nakamura T, Roberto M, Lipton S. S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2418179122. PMID: 40014571, PMCID: PMC11892585, DOI: 10.1073/pnas.2418179122.Peer-Reviewed Original ResearchConceptsActivity-dependent gene expressionGene expressionAlzheimer's diseaseCREB-dependent gene expressionS-nitrosylationNitric oxide (NO)-related speciesTargets of S-nitrosylationNeuronal activity-dependent gene expressionPathogenesis of ADDecreased neurite lengthIncreased neuronal cell deathNeuronal cell deathSynaptic plasticityTranscriptional pathwaysCell deathCRISPR/Cas9 techniqueTranscription coactivator 1AD modelLong-term memory formationIncreased S-nitrosylationLong-term potentiationTherapeutic targetExpressionNeurite lengthCerebrocortical neurons
2023
S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons
Doulias P, Yang H, Andreyev A, Dolatabadi N, Scott H, K Raspur C, Patel P, Nakamura T, Tannenbaum S, Ischiropoulos H, Lipton S. S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons. Cell Chemical Biology 2023, 30: 965-975.e6. PMID: 37478858, PMCID: PMC10530441, DOI: 10.1016/j.chembiol.2023.06.018.Peer-Reviewed Original ResearchConceptsTCA cycleLewy body dementiaAberrant S-nitrosylationMitochondrial metabolic dysfunctionTricarboxylic acid cyclePluripotent stem cellsMitochondrial energy metabolismParkinson's diseaseHiPSC-derived neuronsTCA enzymesMetabolic flux experimentsS-nitrosylationAcid cycleCell deathNeuronal cell deathΑ-ketoglutaratePostmortem human brainEnergy metabolismStem cellsLBD brainsDendritic lengthBioenergetic failureMetabolic dysfunctionSynaptic integrityPathophysiological relevance
2009
Matrix Metalloproteinases in Cerebral Hypoxia-Ischemia
Gu Z, Cui J, Lipton S. Matrix Metalloproteinases in Cerebral Hypoxia-Ischemia. Contemporary Clinical Neuroscience 2009, 225-238. DOI: 10.1007/978-1-60327-579-8_11.Peer-Reviewed Original ResearchNeuronal nitric oxide synthaseAcute cerebral ischemiaCerebral ischemiaMMP-9Neuronal apoptosisCerebral ischemia/reperfusionTransient focal cerebral ischemiaAcute stroke patientsCerebral hypoxia-ischemiaHypoxic-ischemic insultFocal cerebral ischemiaFuture clinical trialsIschemia/reperfusionNitric oxide synthaseMMP-9 activityMMP-2/9 inhibitorNeuronal cell deathShort-term therapyActivation of MMPsS-nitrosylationSignificant therapeutic potentialHypoxia-ischemiaNeuronal injuryIschemic damageStroke patients
2007
Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases
Nakamura T, Lipton S. Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases. Cellular And Molecular Life Sciences 2007, 64: 1609-1620. PMID: 17453143, PMCID: PMC11136414, DOI: 10.1007/s00018-007-6525-0.Peer-Reviewed Original ResearchConceptsUbiquitin-proteasome systemNormal protein degradationProtein disulfide isomeraseMolecular chaperonesSpecific chaperonesGlucose-regulated protein 78Proper foldingProtein misfoldingAberrant proteinsProtein foldingUPS proteinsProtein degradationMolecular mechanismsShock proteinsConformational changesExcessive reactive oxygenCell deathNeuronal cell deathProteinChaperonesProtein 78Reactive oxygenMisfoldingNitrogen speciesNitrosative stressS-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding
Nakamura T, Lipton S. S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding. Cell Death & Differentiation 2007, 14: 1305-1314. PMID: 17431424, DOI: 10.1038/sj.cdd.4402138.Peer-Reviewed Original ResearchConceptsS-nitrosylationProtein functionProtein misfoldingCell deathNeuronal cell deathProper protein foldingProtein disulfide isomeraseCysteine thiol groupsHeat shock proteinsExcessive NMDA receptor activityGlucose-regulated protein 78Neurodegenerative disordersProtein foldingExcitotoxic damageFree radical nitric oxideConformational changesMisfoldingForm of neurotoxicityRadical nitric oxideN-methyl-D-aspartate receptorsNitric oxideExcessive activityProteinProtein 78Chronic neurodegenerative disorders
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
1999
Shakespeare in love—with NMDA receptors?
Lipton S, Nakanishi N. Shakespeare in love—with NMDA receptors? Nature Medicine 1999, 5: 270-271. PMID: 10086378, DOI: 10.1038/6481.Peer-Reviewed Original Research
1998
ICAM-1 dependent pathway is not involved in the development of neuronal apoptosis after transient focal cerebral ischemia
Soriano S, Wang Y, Lipton S, Dikkes P, Gutierrez-Ramos J, Hickey P. ICAM-1 dependent pathway is not involved in the development of neuronal apoptosis after transient focal cerebral ischemia. Brain Research 1998, 780: 337-341. PMID: 9507184, DOI: 10.1016/s0006-8993(97)01298-5.Peer-Reviewed Original ResearchConceptsFocal cerebral ischemiaCerebral ischemiaTerminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) stainingICAM-1-dependent pathwayTransient focal cerebral ischemiaICAM-1-deficient miceDUTP-biotin nick end labeling stainingNick end labeling stainingICAM-1 deficiencyNeuronal cell deathEnd labeling stainingPresence of apoptosisIschemic hemisphereNontransgenic littermatesDeficient miceTemporary MCAONeuronal apoptosisBrain sectionsDependent pathwayApoptotic cellsIschemiaNecrosisCell deathMiceApoptosis
1997
Enhanced neuronal death from focal ischemia in AMPA-receptor transgenic mice
Le D, Das S, Wang Y, Yoshizawa T, Sasaki Y, Takasu M, Nemes A, Mendelsohn M, Dikkes P, Lipton S, Nakanishi N. Enhanced neuronal death from focal ischemia in AMPA-receptor transgenic mice. Brain Research 1997, 52: 235-241. PMID: 9495544, DOI: 10.1016/s0169-328x(97)00261-1.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsBrainCell DeathCerebral CortexCrosses, GeneticDisease SusceptibilityFemaleGenetic VariationHeterozygoteIschemic Attack, TransientMaleMiceMice, Inbred C57BLMice, Inbred CBAMice, TransgenicNeocortexNeuronsPolymerase Chain ReactionReceptors, AMPATranscription, GeneticConceptsNeuronal cell deathMiddle cerebral arteryWild-type neuronsTransgenic miceAMPA receptorsCerebral ischemiaFocal ischemiaGluR2 flipExcitatory amino acid receptorsCell deathAcute cerebral ischemiaGlobal cerebral ischemiaAmino acid receptorsAMPAR-mediated currentsGlutamate receptor antagonistsPermanent focal ischemiaGenetic mouse modelsWild-type controlsExcitotoxic damageEAA receptorsLarge infarctionCerebral arteryFocal strokeGlutamate excitotoxicityNeuronal deathJanus faces of NF-κB: Neurodestruction versus neuroprotection
Lipton S. Janus faces of NF-κB: Neurodestruction versus neuroprotection. Nature Medicine 1997, 3: 20-22. PMID: 8986730, DOI: 10.1038/nm0197-20.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CDAnti-Inflammatory Agents, Non-SteroidalApoptosisAspirinCell DeathCerebrovascular DisordersCyclooxygenase InhibitorsDose-Response Relationship, DrugHumansNeuronsNF-kappa BReactive Oxygen SpeciesReceptors, Tumor Necrosis FactorReceptors, Tumor Necrosis Factor, Type ISignal TransductionTumor Necrosis Factor-alphaConceptsNF-κBNeuronal cell deathNeuroprotective roleCell deathNeuroprotectionAspirinNeurodestruction
1996
Similarity of Neuronal Cell Injury and Death in AIDS Dementia and Focal Cerebral Ischemia: Potential Treatment with NMDA Open‐Channel Blockers and Nitric Oxide‐Related Species
Lipton S. Similarity of Neuronal Cell Injury and Death in AIDS Dementia and Focal Cerebral Ischemia: Potential Treatment with NMDA Open‐Channel Blockers and Nitric Oxide‐Related Species. Brain Pathology 1996, 6: 507-517. PMID: 8944320, DOI: 10.1111/j.1750-3639.1996.tb00879.x.Peer-Reviewed Original ResearchConceptsFocal cerebral ischemiaNeuronal cell deathAIDS dementiaNeuronal injuryCerebral ischemiaNeuronal damageCell injuryHIV-1-associated cognitive/motor complexN-methyl-D-aspartate (NMDA) receptor-operated channelsCognitive/motor complexNMDA open-channel blockersHIV-1 envelope protein gp120Cell deathHIV-1 resultsExistence of HIVNeuronal cell injuryReceptor-operated channelsFuture pharmacological interventionsFinal common pathwayEnvelope protein gp120Platelet-activating factorFree radicalsOpen channel blockerAIDS brainsIschemic core
1995
Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function
Ankarcrona M, Dypbukt J, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton S, Nicotera P. Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995, 15: 961-973. PMID: 7576644, DOI: 10.1016/0896-6273(95)90186-8.Peer-Reviewed Original ResearchConceptsIschemic brain injurySubpopulation of neuronsNeuronal cell deathPostsynaptic glutamate receptorsMitochondrial functionEarly necrotic phaseCerebellar granule cellsNeuronal deathBrain injuryGlutamate receptorsGranule cellsIntracellular Ca2Glutamate accumulationEarly necrosisNecrosisMitochondrial membrane potentialApoptotic nucleiIncubation mediumIntracellular debrisCell deathLow molecular weight fragmentsNecrotic phaseNeuronsApoptosisDeath
1993
Delayed administration of memantine prevents N‐methyl‐D‐aspartate receptor‐mediated neurotoxicity
Pellegrini J, Lipton S. Delayed administration of memantine prevents N‐methyl‐D‐aspartate receptor‐mediated neurotoxicity. Annals Of Neurology 1993, 33: 403-407. PMID: 8098195, DOI: 10.1002/ana.410330414.Peer-Reviewed Original ResearchConceptsExcitatory amino acidsN-methyl-D-aspartate receptor-mediated neurotoxicityPotent N-methyl-D-aspartate antagonistNeonatal rat retinal ganglion cellsN-methyl-D-aspartate (NMDA) subtypeN-methyl-D-aspartate antagonistsRat retinal ganglion cellsImmunodeficiency syndrome (AIDS) dementiaAcute neurological conditionsHypoxia/ischemiaChronic neurodegenerative diseasesRetinal ganglion cellsNeuronal cell deathMicroM memantineAntiparkinsonian drugsCentral neuronsGanglion cellsExcessive activationGlutamate receptorsNeurological conditionsNeurodegenerative diseasesHuntington's diseaseNeurotoxicityPrimary culturesDisease
1991
HIV‐Related Neurotoxicity
Lipton S. HIV‐Related Neurotoxicity. Brain Pathology 1991, 1: 193-199. PMID: 1669708, DOI: 10.1111/j.1750-3639.1991.tb00659.x.Peer-Reviewed Original ResearchConceptsNeuronal injuryCentral nervous system manifestationsL-type voltage-dependent calcium channelsVoltage-dependent calcium channelsNervous system manifestationsHIV-1 infectionToxic factorsWhite matter lesionsNeuronal cell deathIntracellular calcium concentrationNeuronal cell typesNeuronal lossSystem manifestationsMatter lesionsEndogenous glutamateImmune cellsGlutamate receptorsGp 120Human neuronsCalcium channelsGp120 fragmentRodent neuronsHIVGp120Potential neurotoxins
1990
Comparison of delayed administration of competitive and uncompetitive antagonists in preventing NMDA receptor-mediated neuronal death.
Levy D, Lipton S. Comparison of delayed administration of competitive and uncompetitive antagonists in preventing NMDA receptor-mediated neuronal death. Neurology 1990, 40: 852-5. PMID: 1970428, DOI: 10.1212/wnl.40.5.852.Peer-Reviewed Original ResearchConceptsMK-801Uncompetitive antagonistCompetitive antagonistNMDA receptor-mediated neuronal deathN-methyl-D-aspartate receptorsRetinal ganglion cell neuronsStudies of excitotoxicityGanglion cell neuronsGlutamate-induced injuryNeuronal cell deathUncompetitive NMDA antagonistsHypoxia-ischemiaNeurologic injuryProtective dosesNeuronal deathCentral neuronsInitial insultNMDA antagonistsProtective effectCell neuronsAntagonistMinutes of exposureToxic damageInjuryCell death
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