2024
“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 factorsEnzymeAlzheimerCascade
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 relevancePivotal 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-nitrosoproteomePatientsPathogenesisHidden networks of aberrant protein transnitrosylation contribute to synapse loss in Alzheimer's disease
Lipton S. Hidden networks of aberrant protein transnitrosylation contribute to synapse loss in Alzheimer's disease. Free Radical Biology And Medicine 2022, 193: 171-176. PMID: 36243209, PMCID: PMC9875813, DOI: 10.1016/j.freeradbiomed.2022.10.272.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseParkinson's diseaseNitric oxideSoluble guanylate cyclaseFormation of peroxynitriteSynapse lossNeurocognitive disordersNeurological disordersDiseaseGuanylate cyclaseNeurodevelopmental disordersDisordersProtein S-nitrosylationSuperoxide anionTyrosine nitrationS-nitrosylationHIVS-nitrosationPathogenesisDementiaTargeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Oh C, Nakamura T, Beutler N, Zhang X, Piña-Crespo J, Talantova M, Ghatak S, Trudler D, Carnevale L, McKercher S, Bakowski M, Diedrich J, Roberts A, Woods A, Chi V, Gupta A, Rosenfeld M, Kearns F, Casalino L, Shaabani N, Liu H, Wilson I, Amaro R, Burton D, Yates J, Becker C, Rogers T, Chatterjee A, Lipton S. Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection. Nature Chemical Biology 2022, 19: 275-283. PMID: 36175661, PMCID: PMC10127945, DOI: 10.1038/s41589-022-01149-6.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionViral entrySevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Coronavirus disease 2019 (COVID-19) pandemicSyndrome coronavirus 2Prevention of infectionSARS-CoV-2 spike proteinDisease 2019 pandemicSpread of infectionCoronavirus 2Channel blockadeS-nitrosylationEnzyme 2Binding of ACE2InfectionSpike proteinACE2Envelope proteinProtein S-nitrosylationIon channelsNon-toxic compoundsNovel avenuesAngiotensinTowards development of disease-modifying therapy for Alzheimer's disease using redox chemical biology pathways
Lipton S. Towards development of disease-modifying therapy for Alzheimer's disease using redox chemical biology pathways. Current Opinion In Pharmacology 2022, 66: 102267. PMID: 35870288, PMCID: PMC9509422, DOI: 10.1016/j.coph.2022.102267.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseDisease-modifying therapiesPotential therapeutic efficacySevere side effectsPotential therapeutic targetCerebral organoid modelTranscription factor Nrf2Absence of diseaseNMDA typeGlutamate receptorsDisease processSide effectsTherapeutic targetTransgenic miceTherapeutic efficacyNeurodegenerative disordersNormal tissuesDiseaseFactor Nrf2Organoid modelsProtein S-nitrosylationS-nitrosylationProtein Keap1TherapyNrf2Inhibition of autophagic flux by S-nitrosylation of SQSTM1/p62 promotes neuronal secretion and cell-to-cell transmission of SNCA/α-synuclein in Parkinson disease and Lewy body dementia
Oh C, Nakamura T, Lipton S. Inhibition of autophagic flux by S-nitrosylation of SQSTM1/p62 promotes neuronal secretion and cell-to-cell transmission of SNCA/α-synuclein in Parkinson disease and Lewy body dementia. Autophagy Reports 2022, 1: 223-225. PMID: 38098743, PMCID: PMC10721282, DOI: 10.1080/27694127.2022.2076770.Peer-Reviewed Original ResearchLewy body dementiaParkinson's diseaseSNCA/α-synucleinAutophagic fluxNitric oxideΑ-synucleinHuman postmortem brainS-nitrosylationNeuronal damageAberrant protein S-nitrosylationSynaptic damageΑ-synucleinopathiesPostmortem brainsPathogenic eventsDiseased brainExcessive reactive oxygenSQSTM1/p62Neurodegenerative disordersInhibits autophagic fluxNeuronal secretionCell-based modelCell transmissionProtein S-nitrosylationDementiaDiseaseS-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders
Kim K, Cho E, Eom J, Oh S, Nakamura T, Oh C, Lipton S, Kim Y. S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders. Cell Death & Differentiation 2022, 29: 2137-2150. PMID: 35462559, PMCID: PMC9613756, DOI: 10.1038/s41418-022-01004-0.Peer-Reviewed Original ResearchConceptsS-nitrosylationProtein aggregatesAutophagic fluxProtein S-nitrosylationBlocks autophagic fluxCathepsin BCaspase-dependent neuronal apoptosisPosttranslational modificationsProtease cathepsin BEnzymatic functionLysosomal protease cathepsin BCTSB activityChemical inhibitorsCA-074MeHuman AD brainsEnzymatic activityCysteineNeurodegenerative disordersPostmortem human AD brainTransgenic miceNeuronal apoptosisCTSBAccumulationAD pathogenesisAlzheimer's diseaseS-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
Protein S-Nitrosylation in Neuronal Development
Nakamura T, Zhang X, Oh C, Lipton S. Protein S-Nitrosylation in Neuronal Development. 2021, 91-105. DOI: 10.1201/9781003204091-10.Peer-Reviewed Original ResearchPost-translational modificationsProtein S-nitrosylationS-nitrosylationReactive nitrogen speciesNeuronal developmentNeuronal differentiationTranscription factor MEF2Protein-protein interactionsIon channel activityProtein traffickingEnzymatic functionCysteine thiolsProtein conformationCellular mechanismsChannel activityNormal brain developmentNitrogen speciesSynaptic functionNitric oxide actsPathological processesBiological actionsProteinNeuronal survivalBiological systemsNeurogenesisProtein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration
Nakamura T, Oh C, Zhang X, Lipton S. Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration. Free Radical Biology And Medicine 2021, 172: 562-577. PMID: 34224817, PMCID: PMC8579830, DOI: 10.1016/j.freeradbiomed.2021.07.002.Peer-Reviewed Original ResearchConceptsProtein misfoldingUbiquitin-proteasome systemCellular protein quality control machineryReactive oxygen speciesS-nitrosylationProtein quality control machineryQuality control machineryPost-translational modificationsNeurodegenerative diseasesProtein S-nitrosylationGenetic mutationsMost neurodegenerative diseasesMolecular chaperonesROS/RNSControl machineryLysosomal pathwayRare genetic mutationsMolecular mechanismsMolecular eventsMisfoldingMitochondrial dysfunctionTyrosine nitrationProteinOxygen speciesNeuronal demiseProtein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders
Nakamura T, Oh C, Zhang X, Tannenbaum S, Lipton S. Protein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders. Antioxidants & Redox Signaling 2021, 35: 531-550. PMID: 33957758, PMCID: PMC8388249, DOI: 10.1089/ars.2021.0081.Peer-Reviewed Original ResearchConceptsRelated reactive nitrogen speciesS-nitrosylationRedox-based posttranslational modificationProtein S-nitrosylationGlyceraldehyde-3-phosphate dehydrogenaseInhibitor of apoptosisThiol-containing proteinsNeurodegenerative diseasesSignaling networksPosttranslational modificationsReactive nitrogen speciesTransnitrosylation reactionsNuclear proteinsUnderstanding of agingCysteine thiolsTransnitrosylationBiochemical pathwaysChemical biologyMechanisms of diseaseProteinCaspase-3Nitrogen speciesUCH-L1Neurodegenerative disordersPhysiological concentrationsTCA 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 enzymesPathogenesisS-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD
Pirie E, Oh C, Zhang X, Han X, Cieplak P, Scott H, Deal A, Ghatak S, Martinez F, Yeo G, Yates J, Nakamura T, Lipton S. S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2021368118. PMID: 33692125, PMCID: PMC7980404, DOI: 10.1073/pnas.2021368118.Peer-Reviewed Original ResearchConceptsProtein misfolding/aggregationCell spreadMisfolding/aggregationRNA-binding activityOligomerization/aggregationHuman-induced pluripotent stem cellsProtein TDP-43Pluripotent stem cellsALS/FTDTDP-43 aggregationTDP-43Cognate proteinProtein aggregationS-nitrosylationRare genetic mutationsCell-based modelFTD disordersAmyotrophic lateral sclerosisAbsence of mutationsTriggers aggregationStem cellsGenetic mutationsDisulfide linkagesNitrosative stressNeurodegenerative disorders
2017
Chapter 27 Aberrant Nitric Oxide Signaling Contributes to Protein Misfolding in Neurodegenerative Diseases via S-Nitrosylation and Tyrosine Nitration
Nakamura T, Lipton S. Chapter 27 Aberrant Nitric Oxide Signaling Contributes to Protein Misfolding in Neurodegenerative Diseases via S-Nitrosylation and Tyrosine Nitration. 2017, 373-384. DOI: 10.1016/b978-0-12-804273-1.00027-2.Peer-Reviewed Original ResearchReactive oxygen speciesS-nitrosylationProtein misfoldingProtein quality control machineryQuality control machineryAberrant S-nitrosylationUbiquitin-proteasome systemCysteine thiol groupsNeurodegenerative diseasesMolecular chaperonesMisfolded proteinsControl machineryMolecular mechanismsMitochondrial impairmentTyrosine nitrationPathological productionProteinMisfoldingSignaling contributesKey pathological featureOxygen speciesNeuronal demiseNitrogen speciesNitrosative stressGenetic risk factors
2012
Redox control of protein misfolding and mitochondrial fragmentation via s-nitrosylation: Implications for synaptic damage in neurodegenerative diseases
Lipton⁎ S. Redox control of protein misfolding and mitochondrial fragmentation via s-nitrosylation: Implications for synaptic damage in neurodegenerative diseases. Free Radical Biology And Medicine 2012, 53: s29. DOI: 10.1016/j.freeradbiomed.2012.08.133.Peer-Reviewed Original Research
2011
Redox Regulation of Protein Misfolding, Synaptic Damage, and Neuronal Loss in Neurodegenerative Diseases
Nakamura T, Lipton S. Redox Regulation of Protein Misfolding, Synaptic Damage, and Neuronal Loss in Neurodegenerative Diseases. 2011, 65-99. DOI: 10.1002/9781118063903.ch2.Peer-Reviewed Original ResearchRedox 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