2025
diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease
Banerjee P, Wang Y, Carnevale L, Patel P, Raspur C, Tran N, Zhang X, Natarajan R, Roberts A, Baran P, Lipton S. diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease. Antioxidants 2025, 14: 293. PMCID: PMC11939361, DOI: 10.3390/antiox14030293.Peer-Reviewed Original ResearchAlzheimer's diseaseNrf2 transcriptional pathwayTranscriptional pathwaysAmyloid plaque formationMouse model of Alzheimer's diseaseTransgenic mouse model of Alzheimer's diseaseModel of Alzheimer's diseaseAD transgenic miceCorrelated to cognitive declineNeuritic aggregatesTau tanglesAmyloid plaquesPhospho-tauCarnosic acidSynapse lossHuman ADPurified CATransgenic mouse modelPhenolic diterpenesAmyloidMicroglial inflammationPathwayPlaque formationTransgenic miceNrf2S-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
2024
Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer’s and related dementias
Oh C, Nakamura T, Zhang X, Lipton S. Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer’s and related dementias. Neuron 2024, 112: 3823-3850. PMID: 39515322, PMCID: PMC11624102, DOI: 10.1016/j.neuron.2024.10.013.Peer-Reviewed Original ResearchProtein S-nitrosylationS-nitrosylationEndoplasmic reticulumRedox-mediated posttranslational modificationDiseases associated with protein aggregationProtein aggregationSynapse lossModulating protein activityNetwork of proteinsMultiple neurodegenerative disordersUbiquitin-proteasome systemS-nitrosylation reactionPosttranslational modificationsMitochondrial metabolismExcessive nitrosative stressEnzymatic machineryRedox regulationProtein activityProtein networkDysfunction pathwayMicroglial phagocytosisSingle proteinsBioenergetic compromiseReview recent findingsProteinA pro-drug derivative of carnosic acid activates the Nrf2 transcriptional pathway and shows efficacy in Alzheimer’s disease transgenic mice
Banerjee P, Roberts A, Natajarian R, Baran P, Lipton S. A pro-drug derivative of carnosic acid activates the Nrf2 transcriptional pathway and shows efficacy in Alzheimer’s disease transgenic mice. Free Radical Biology And Medicine 2024, 224: s96. DOI: 10.1016/j.freeradbiomed.2024.10.212.Peer-Reviewed Original ResearchUsing in vivo intact structure for system-wide quantitative analysis of changes in proteins
Son A, Kim H, Diedrich J, Bamberger C, McClatchy D, Lipton S, Yates J. Using in vivo intact structure for system-wide quantitative analysis of changes in proteins. Nature Communications 2024, 15: 9310. PMID: 39468068, PMCID: PMC11519357, DOI: 10.1038/s41467-024-53582-x.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseProtein footprinting methodGlobal expression profilingIn vivo conformationStructural alterations of proteinsCo-expressed proteinsMass spectrometry-based methodsAlterations of proteinsProteostasis dysfunctionSpectrometry-based methodsProtein misfoldingConformation of proteinsStructural changesLysine residuesDynamic structural changesBiological functionsProteomics experimentsDimethyl labelingExpression profilesProtein conformationConformational changesProteinIntact proteinDesign of therapeutic interventionsMeasuring dynamic structural changesDetecting Boolean Asymmetric Relationships With a Loop Counting Technique and its Implications for Analyzing Heterogeneity Within Gene Expression Datasets
Zhou H, Lin W, Labra S, Lipton S, Elman J, Schork N, Rangan A. Detecting Boolean Asymmetric Relationships With a Loop Counting Technique and its Implications for Analyzing Heterogeneity Within Gene Expression Datasets. IEEE/ACM Transactions On Computational Biology And Bioinformatics 2024, 22: 27-38. PMID: 39471117, DOI: 10.1109/tcbb.2024.3487434.Peer-Reviewed Original ResearchSubsets of genesGene-gene relationshipsGene expression dataGene-gene interactionsGene expression datasetsRNA-sequencing data setsDetected biclustersExpression datasetsGene pathwaysSubsets of cellsGenesRegulatory effectsBiclusteringCorrelated expressionAsymmetric interactionsSymmetric interactionsInteractionExpressionCellsDysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids
Trudler D, Ghatak S, Bula M, Parker J, Talantova M, Luevanos M, Labra S, Grabauskas T, Noveral S, Teranaka M, Schahrer E, Dolatabadi N, Bakker C, Lopez K, Sultan A, Patel P, Chan A, Choi Y, Kawaguchi R, Stankiewicz P, Garcia-Bassets I, Kozbial P, Rosenfeld M, Nakanishi N, Geschwind D, Chan S, Lin W, Schork N, Ambasudhan R, Lipton S. Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids. Molecular Psychiatry 2024, 30: 1479-1496. PMID: 39349966, PMCID: PMC11919750, DOI: 10.1038/s41380-024-02761-9.Peer-Reviewed Original ResearchMEF2C haploinsufficiency syndromeLoss-of-function mutationsCerebral organoidsHaploinsufficiency syndromeReceptor antagonistHiPSC-neuronsDecreased neurogenesisSevere formCerebrocortical neuronsAnimal studiesExtrasynaptic activationMEF2CAbnormal phenotypesNeurodevelopmentNeuronsDeficitsOrganoidsTranscription factorsMutationsNitroSynapsinGene networksDysregulation of miRNA expressionSingle‐Cell Patch‐Clamp/Proteomics of Human Alzheimer's Disease iPSC‐Derived Excitatory Neurons Versus Isogenic Wild‐Type Controls Suggests Novel Causation and Therapeutic Targets
Ghatak S, Diedrich J, Talantova M, Bhadra N, Scott H, Sharma M, Albertolle M, Schork N, Yates J, Lipton S. Single‐Cell Patch‐Clamp/Proteomics of Human Alzheimer's Disease iPSC‐Derived Excitatory Neurons Versus Isogenic Wild‐Type Controls Suggests Novel Causation and Therapeutic Targets. Advanced Science 2024, 11: e2400545. PMID: 38773714, PMCID: PMC11304297, DOI: 10.1002/advs.202400545.Peer-Reviewed Original ResearchAbundance of individual proteinsIsogenic wild-type controlsSingle-cell (scHuman AD brainsWild-type controlsSingle-cellAlzheimer's diseaseMulticellular organismsSingle-cell physiologyAD brainTherapeutic targetIndividual proteinsProteomic informationGenetic mutationsProteinProteomicsProtein expressionHiPSC-neuronsExcitatory neuronsElectrophysiological statusDisease statesPhysiologyElectrophysiological dataNeuronsNeuronal levelMetabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons
Andreyev A, Yang H, Doulias P, Dolatabadi N, Zhang X, Luevanos M, Blanco M, Baal C, Putra I, Nakamura T, Ischiropoulos H, Tannenbaum S, Lipton S. Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons. Advanced Science 2024, 11: 2306469. PMID: 38235614, PMCID: PMC10966553, DOI: 10.1002/advs.202306469.Peer-Reviewed Original ResearchTricarboxylic acidOxidative phosphorylationAlzheimer's diseaseSynapse lossSynaptic lossPathological correlate of cognitive declineHuman AD brainsTCA cycle inhibitionMetabolic flux experimentsAberrant S-nitrosylationPostmortem human AD brainIsogenic wild-typeAssociated with synaptic lossDysfunctional mitochondrial metabolismMitochondrial bioenergetic functionProtein S-nitrosylationModel of ADMitochondrial energy metabolismCell-permeable derivativeCorrelate of cognitive declineAD brainMitochondrial metabolismEnzyme functionHiPSC-based modelsBioenergetic function“Dark” Pathways of Protein Transnitrosylation Injure Synapses in Alzheimer’s Disease: Mechanism and Potential Treatment
LIPTON S. “Dark” Pathways of Protein Transnitrosylation Injure Synapses in Alzheimer’s Disease: Mechanism and Potential Treatment. 2024, pl. DOI: 10.14869/toxpt.51.1.0_pl.Peer-Reviewed Original ResearchAlzheimer's diseaseDisruption of protein functionUbiquitin-protein hydrolaseS-nitrosylationS-nitrosylation reactionLoss of synapsesCorrelated to cognitive declineGuanosine triphosphataseMitochondrial fragmentationAD brainProtein functionAmyloid-betaAggregated proteinsProtein hydrolaseSynapse lossSynaptic lossBioenergetic compromiseSynaptic damageTransnitrosylation reactionsProteinUCH-L1Environmental factorsEnzymeAlzheimerCascadeEnzymatic and non-enzymatic transnitrosylation: “SCAN”ning the SNO-proteome
Nakamura T, Lipton S. Enzymatic and non-enzymatic transnitrosylation: “SCAN”ning the SNO-proteome. Molecular Cell 2024, 84: 191-193. PMID: 38242098, DOI: 10.1016/j.molcel.2023.12.018.Peer-Reviewed Original Research
2023
“Dark Matter” Pathways of Protein Transnitrosylation Injure Synapses in Alzheimer’s Disease
Lipton S. “Dark Matter” Pathways of Protein Transnitrosylation Injure Synapses in Alzheimer’s Disease. Free Radical Biology And Medicine 2023, 208: s7. DOI: 10.1016/j.freeradbiomed.2023.10.390.Peer-Reviewed Original ResearchReply to: Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Oh C, Piña-Crespo J, Talantova M, Carnevale L, Stoneham C, Lewinski M, Guatelli J, Lipton S. Reply to: Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection. Nature Chemical Biology 2023, 19: 1306-1308. PMID: 37798355, DOI: 10.1038/s41589-023-01425-z.Peer-Reviewed Original ResearchRestorative effect of NitroSynapsin on synaptic plasticity in an animal model of depression
Tse W, Pochwat B, Szewczyk B, Misztak P, Bobula B, Tokarski K, Worch R, Czarnota-Bojarska M, Lipton S, Zaręba-Kozioł M, Bijata M, Wlodarczyk J. Restorative effect of NitroSynapsin on synaptic plasticity in an animal model of depression. Neuropharmacology 2023, 241: 109729. PMID: 37797736, DOI: 10.1016/j.neuropharm.2023.109729.Peer-Reviewed Original ResearchConceptsMedial prefrontal cortexLong-term potentiationChronic restraint stress mouse modelSynaptic plasticityN-methyl-D-aspartate receptor antagonistRestraint stress mouse modelMale C57BL/6J miceAntidepressant-like activityTail suspension testStress mouse modelFunctional synaptic plasticityMajor depressive disorderAntidepressant potentialPharmacological treatmentPsychotomimetic effectsReceptor antagonistC57BL/6J miceDepressive behaviorSucrose preferenceDepressive disorderNitroSynapsinMouse modelSuspension testBehavioral disturbancesCerebrocortical neuronsS-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 relevanceApoptotic cell death in disease—Current understanding of the NCCD 2023
Vitale I, Pietrocola F, Guilbaud E, Aaronson S, Abrams J, Adam D, Agostini M, Agostinis P, Alnemri E, Altucci L, Amelio I, Andrews D, Aqeilan R, Arama E, Baehrecke E, Balachandran S, Bano D, Barlev N, Bartek J, Bazan N, Becker C, Bernassola F, Bertrand M, Bianchi M, Blagosklonny M, Blander J, Blandino G, Blomgren K, Borner C, Bortner C, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard R, Calin G, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan F, Chen G, Chen Q, Chen Y, Cheng E, Chipuk J, Cidlowski J, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz J, Czabotar P, D’Angiolella V, Daugaard M, Dawson T, Dawson V, De Maria R, De Strooper B, Debatin K, Deberardinis R, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon S, Dynlacht B, El-Deiry W, Elrod J, Engeland K, Fimia G, Galassi C, Ganini C, Garcia-Saez A, Garg A, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green D, Greene L, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick J, Haupt Y, He S, Heery D, Hengartner M, Hetz C, Hildeman D, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost P, Kanneganti T, Karin M, Kashkar H, Kaufmann T, Kelly G, Kepp O, Kimchi A, Kitsis R, Klionsky D, Kluck R, Krysko D, Kulms D, Kumar S, Lavandero S, Lavrik I, Lemasters J, Liccardi G, Linkermann A, Lipton S, Lockshin R, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine J, Martin S, Martinou J, Mastroberardino P, Medema J, Mehlen P, Meier P, Melino G, Melino S, Miao E, Moll U, Muñoz-Pinedo C, Murphy D, Niklison-Chirou M, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman J, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger J, Pentimalli F, Pereira D, Pervaiz S, Peter M, Pinton P, Porta G, Prehn J, Puthalakath H, Rabinovich G, Rajalingam K, Ravichandran K, Rehm M, Ricci J, Rizzuto R, Robinson N, Rodrigues C, Rotblat B, Rothlin C, Rubinsztein D, Rudel T, Rufini A, Ryan K, Sarosiek K, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica G, Silke J, Simon H, Sistigu A, Stephanou A, Stockwell B, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait S, Tang D, Tavernarakis N, Troy C, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden M, Vanderluit J, Verkhratsky A, Villunger A, von Karstedt S, Voss A, Vousden K, Vucic D, Vuri D, Wagner E, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang H, Zakeri Z, Zawacka-Pankau J, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease—Current understanding of the NCCD 2023. Cell Death & Differentiation 2023, 30: 1097-1154. PMID: 37100955, PMCID: PMC10130819, DOI: 10.1038/s41418-023-01153-w.Peer-Reviewed Original ResearchConceptsRegulated cell deathCell deathAdult tissue homeostasisMultiple human disordersApoptotic cell deathOrganismal developmentOrganismal homeostasisMolecular machineryContext of diseaseApoptotic apparatusMammalian systemsCaspase familyTissue homeostasisGenetic strategiesHuman disordersNomenclature CommitteeApoptosisHomeostasisMachineryOncogenesisProteaseCell lossActivationFamilyDeathPivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis
Okuda K, Nakahara K, Ito A, Iijima Y, Nomura R, Kumar A, Fujikawa K, Adachi K, Shimada Y, Fujio S, Yamamoto R, Takasugi N, Onuma K, Osaki M, Okada F, Ukegawa T, Takeuchi Y, Yasui N, Yamashita A, Marusawa H, Matsushita Y, Katagiri T, Shibata T, Uchida K, Niu S, Lang N, Nakamura T, Zhang K, Lipton S, Uehara T. Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis. Nature Communications 2023, 14: 621. PMID: 36739439, PMCID: PMC9899281, DOI: 10.1038/s41467-023-36232-6.Peer-Reviewed Original ResearchConceptsS-nitrosylationDNA methyltransferasesEnzymatic activityGene expressionDe novo DNA methylationNovo DNA methylationAberrant S-nitrosylationProtein S-nitrosylationDNA methyltransferase 3BDNMT enzymatic activityStructure-based virtual screeningEpigenetic regulationDNA methylationCysteine residuesMethyltransferase 3BVivo cancer modelsS-adenosylAberrant upregulationNeoplastic cell proliferationHuman colonic adenomasMethylationCyclin D2Cell proliferationTumor formationDNMT3BAberrant 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
Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3
Yang H, Oh C, Amal H, Wishnok J, Lewis S, Schahrer E, Trudler D, Nakamura T, Tannenbaum S, Lipton S. Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3. Science Advances 2022, 8: eade0764. PMID: 36516243, PMCID: PMC9750152, DOI: 10.1126/sciadv.ade0764.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseAD brainPostmortem Alzheimer's diseaseComplement component 3Sex-dependent mannerConsequent cognitive declineSynaptic phagocytosisΒ-estradiol levelsFemale predominanceAberrant protein S-nitrosylationSynaptic damageAD pathogenesisSNO proteinsCognitive declineProtein SDiseaseRobust alterationsBrainComponent 3Protein S-nitrosylationHuman brainS-nitrosylationS-nitrosoproteomePatientsPathogenesisUnfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging
Cabral‐Miranda F, Tamburini G, Martinez G, Ardiles A, Medinas D, Gerakis Y, Hung M, Vidal R, Fuentealba M, Miedema T, Duran‐Aniotz C, Diaz J, Ibaceta‐Gonzalez C, Sabusap C, Bermedo‐Garcia F, Mujica P, Adamson S, Vitangcol K, Huerta H, Zhang X, Nakamura T, Sardi S, Lipton S, Kennedy B, Henriquez J, Cárdenas J, Plate L, Palacios A, Hetz C. Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging. The EMBO Journal 2022, 41: embj2022111952. PMID: 36314651, PMCID: PMC9670206, DOI: 10.15252/embj.2022111952.Peer-Reviewed Original ResearchConceptsUnfolded protein responseER stress sensor IRE1Stress sensor IRE1IRE1/XBP1 signalingTranscription factor XBP1Mammalian brain agingNeurodegenerative diseasesProteostasis networkEndoplasmic reticulum stressProteomic profilingProtein responseCell senescenceGenetic disruptionBrain agingXBP1 expressionReticulum stressMammalian brainMajor risk factorActive formHealthy brain agingSynaptic functionXBP1Age-related cognitive declinePathwayHippocampal tissue
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