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 relevanceAberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer’s disease: Mechanistic insights and potential therapies
Ghatak S, Nakamura T, Lipton S. Aberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer’s disease: Mechanistic insights and potential therapies. Frontiers In Neural Circuits 2023, 17: 1099467. PMID: 36817649, PMCID: PMC9932935, DOI: 10.3389/fncir.2023.1099467.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseSynaptic damageReactive oxygen speciesS-nitrosylation contributesNeuronal hyperactivitySynaptic lossSynapse lossSynaptic degenerationCommon causePotential therapyAD modelCognitive declineHyperexcitabilityDiseaseSingle neuronsActivity contributesMolecular changesProtein S-nitrosylationDeleterious effectsNeural network functionS-nitrosylationOxygen speciesEarly signaturesPatientsTherapy
2022
S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson's Disease and Lewy Body Dementia
Oh C, Dolatabadi N, Cieplak P, Diaz-Meco M, Moscat J, Nolan J, Nakamura T, Lipton S. S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson's Disease and Lewy Body Dementia. Journal Of Neuroscience 2022, 42: 3011-3024. PMID: 35169022, PMCID: PMC8985870, DOI: 10.1523/jneurosci.1508-21.2022.Peer-Reviewed Original ResearchConceptsLewy body dementiaParkinson's diseaseAutophagic fluxInhibits autophagic fluxΑ-synucleinPluripotent stem cell-derived neuronsStem cell-derived neuronsΑ-synuclein secretionS-nitrosylationCell-derived neuronsHuman postmortem brainProtein S-nitrosylationΑ-synuclein aggregationPostmortem brainsConsequent secretionPathologic pathwaysNervous systemAdaptor protein p62Autophagic inhibitionDysfunctional autophagyNeurodegenerative disordersDiseaseIndividual neuronsDementiaSecretion
2021
TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use
Doulias P, Nakamura T, Scott H, McKercher S, Sultan A, Deal A, Albertolle M, Ischiropoulos H, Lipton S. TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use. Journal Of NeuroVirology 2021, 27: 367-378. PMID: 33876414, PMCID: PMC8477648, DOI: 10.1007/s13365-021-00970-4.Peer-Reviewed Original ResearchConceptsNeurocognitive disordersMeth usePathogenesis of HIVHuman postmortem brainAberrant protein S-nitrosylationCNS pathologyControl brainsSynaptic damageS-nitrosylationHIV-1Metabolic compromisePostmortem brainsMethamphetamine useNitric oxideDrug abuseRedox stressNitrosative stressBrainHIVProtein S-nitrosylationDisordersS-nitrosoproteomeSystematic inhibitionTCA cycle enzymesPathogenesisα-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
2019
Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls
Ghatak S, Dolatabadi N, Trudler D, Zhang X, Wu Y, Mohata M, Ambasudhan R, Talantova M, Lipton S. Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls. ELife 2019, 8: e50333. PMID: 31782729, PMCID: PMC6905854, DOI: 10.7554/elife.50333.Peer-Reviewed Original ResearchConceptsDisease brainNeuronal culturesHuman Alzheimer's disease brainCerebral organoidsAD-related mutationsHiPSC-derived neuronsTransgenic AD miceInhibitory synaptic activityMechanisms of hyperexcitabilityAlzheimer's disease brainAberrant electrical activitySodium current densityAD micePathophysiological correlatesSynaptic dysfunctionAD pathophysiologyExcessive excitabilitySynaptic activityObserved hyperexcitabilityCognitive declineBursting activityHyperexcitabilityPresenilin 1Electrical activityNeurite length
2011
Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases
Nakamura T, Lipton S. Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death & Differentiation 2011, 18: 1478-1486. PMID: 21597461, PMCID: PMC3178424, DOI: 10.1038/cdd.2011.65.Peer-Reviewed Original ResearchConceptsS-nitrosylationProtein misfoldingCritical protein thiolsDynamin-related protein 1Protein disulfide isomeraseS-nitrosylation contributesNitrosative stressPosttranslational modificationsMitochondrial dynamicsNeuronal lossSynaptic damageDownstream pathwaysRedox modulationProtein thiolsNormal neuronal signalingMitochondrial dysfunctionN-methyl-D-aspartate (NMDA) receptor activationNeuronal signalingProtein 1Eventual neuronal lossNeuronal cell damageNeuronal cell injuryMisfoldingNeuronal NO synthaseNeurodegenerative diseases
2009
Molecular stages of rapid and uniform neuralization of human embryonic stem cells
Bajpai R, Coppola G, Kaul M, Talantova M, Cimadamore F, Nilbratt M, Geschwind D, Lipton S, Terskikh A. Molecular stages of rapid and uniform neuralization of human embryonic stem cells. Cell Death & Differentiation 2009, 16: 807-825. PMID: 19282867, PMCID: PMC3432273, DOI: 10.1038/cdd.2009.18.Peer-Reviewed Original ResearchConceptsHuman embryonic stem cellsEmbryonic stem cellsNeural precursor cellsDynamic gene expression analysisStem cellsGene expression changesPrecursor cellsGene expression analysisEarly human developmentCoregulated genesPrimitive ectodermExpression analysisExpression changesMouse brainPotent oncogeneMolecular signalingUniform differentiationHuman biologyEfficient differentiationFuture cell-based therapiesFunctional neuronsNeuralizationPosterior markersNeonatal mouse brainNeural proliferation
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 stress
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 gp120Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers
Satoh T, Okamoto S, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton S. Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 768-773. PMID: 16407140, PMCID: PMC1334635, DOI: 10.1073/pnas.0505723102.Peer-Reviewed Original ResearchConceptsNeurite outgrowth-promoting prostaglandinsHemeoxygenase-1Cerebral ischemia/reperfusion injuryKeap1/Nrf2/HOIschemia/reperfusion injuryGlutamate-related excitotoxicityKeap1/Nrf2 pathwayNrf2/HOHO-1 expressionCultured neuronal cellsInactivation of Nrf2Phase II enzymesThiol-dependent mannerTranscription factor Nrf2HO-1 promoterNeuroprotective actionReperfusion injuryNeuroprotective compoundsNrf2 pathwayTherapeutic approachesNrf2 translocationAntioxidant responsive elementNeurodegenerative disordersNeuronal cellsFactor Nrf2
2005
HIV leucoencephalopathy and TNFα expression in neurones
Rostasy K, Monti L, Lipton S, Hedreen J, Gonzalez R, Navia B. HIV leucoencephalopathy and TNFα expression in neurones. Journal Of Neurology Neurosurgery & Psychiatry 2005, 76: 960. PMID: 15965202, PMCID: PMC1739718, DOI: 10.1136/jnnp.2004.036889.Peer-Reviewed Original ResearchMeSH KeywordsAdultAIDS Dementia ComplexAnti-Retroviral AgentsBasal GangliaBiopsyBrainDiffusion Magnetic Resonance ImagingDisease ProgressionFollow-Up StudiesFrontal LobeHIV Envelope Protein gp41HumansMacrophagesMaleMicrogliaMiddle AgedNeurologic ExaminationNeuronsNeuropsychological TestsSaquinavirStavudineTreatment OutcomeTumor Necrosis Factor-alphaZidovudineConceptsAIDS dementia complexPathogenesis of ADCImaging studiesMicroglia/macrophage activationProgressive formDeep white matter changesMicroglia/macrophagesExpression of TNFalphaWhite matter changesNecrosis factor alphaMeans of immunohistochemistryViral protein expressionNeuroradiological featuresAntiretroviral treatmentHIV infectionThird patientBrain biopsyProgressive dementiaDementia complexTreatment regimensBasal gangliaClinical historyFactor alphaTNFα expressionFrontal cortexHIV-1 infection and AIDS: consequences for the central nervous system
Kaul M, Zheng J, Okamoto S, Gendelman H, Lipton S. HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death & Differentiation 2005, 12: 878-892. PMID: 15832177, DOI: 10.1038/sj.cdd.4401623.Peer-Reviewed Original ResearchMeSH KeywordsAcquired Immunodeficiency SyndromeAIDS Dementia ComplexAnimalsAntiretroviral Therapy, Highly ActiveApoptosisApoptosis Regulatory ProteinsBrainChemokinesForecastingHIV Envelope Protein gp120HIV-1HumansMembrane GlycoproteinsMicrogliaNerve DegenerationNeuronsReceptors, ChemokineSignal TransductionStem CellsTNF-Related Apoptosis-Inducing LigandTumor Necrosis Factor-alphaConceptsHuman immunodeficiency virus-1Glutamate receptor-mediated excitotoxicityReceptor-mediated excitotoxicityHIV-1 infectionImmune competent cellsExtracellular matrix-degrading enzymesImmunodeficiency virus-1Central nervous systemFuture therapeutic interventionsMatrix-degrading enzymesFrank dementiaInflammatory mediatorsNeuronal damageMotor dysfunctionChemokine receptorsGlial functionDegenerative mechanismsNeurological problemsParticular macrophagesBehavioral abnormalitiesNervous systemTherapeutic interventionsNeuropathological responsesVirus 1Infection
2004
Signaling pathways to neuronal damage and apoptosis in human immunodeficiency virus type 1-associated dementia: Chemokine receptors, excitotoxicity, and beyond
Kaul M, Lipton S. Signaling pathways to neuronal damage and apoptosis in human immunodeficiency virus type 1-associated dementia: Chemokine receptors, excitotoxicity, and beyond. Journal Of NeuroVirology 2004, 10: 97-101. PMID: 14982746, DOI: 10.1080/753312759.Peer-Reviewed Original ResearchConceptsNeuronal damageChemokine receptorsN-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicityHuman immunodeficiency virus-1 (HIV-1) infectionHuman immunodeficiency virus type 1Immunodeficiency virus type 1Applicable therapeutic interventionReceptor-mediated excitotoxicityVirus-1 infectionVirus type 1HIV infectionInflammatory factorsHIV-1Therapeutic interventionsType 1Downstream mechanismsExcitotoxicityDementiaInfectionReceptorsNeuropathologyPathwayDamage
2001
Nitric oxide and respiration
Lipton S. Nitric oxide and respiration. Nature 2001, 413: 119-121. PMID: 11557961, DOI: 10.1038/35093186.Peer-Reviewed Original ResearchErythropoietin-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 damagePathways to neuronal injury and apoptosis in HIV-associated dementia
Kaul M, Garden G, Lipton S. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 2001, 410: 988-994. PMID: 11309629, DOI: 10.1038/35073667.Peer-Reviewed Original ResearchConceptsHuman immunodeficiency virus-1Neuronal injuryRelease of macrophageImmunodeficiency virus-1Direct injuryTherapeutic interventionsAlarming occurrenceNeurodegenerative diseasesInjuryVirus 1NeuronsDementiaViral proteinsMacrophagesFree radicalsApoptosisToxinPathwayExcitotoxicityMicrogliaHIVDiseaseBrainIs tissue plasminogen activator a threat to neurons?
Traynelis S, Lipton S. Is tissue plasminogen activator a threat to neurons? Nature Medicine 2001, 7: 17-18. PMID: 11135603, DOI: 10.1038/83289.Peer-Reviewed Original Research
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