2022
Towards 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 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 concentrationsS-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
2013
Combating Oxidative/Nitrosative Stress with Electrophilic Counterattack Strategies
Satoh T, Akhtar M, Lipton S. Combating Oxidative/Nitrosative Stress with Electrophilic Counterattack Strategies. 2013, 277-307. DOI: 10.1007/978-94-007-5787-5_10.Peer-Reviewed Original ResearchPro-electrophilic drugsKeap1/Nrf2 pathwayTranscription-dependent pathwayCysteine thiol oxidationNitrosative stressOxidative stressStress-induced oxidationHeat shock proteinsRedox regulationSpecific cysteineProlonged oxidative stressNrf2 pathwayPhase 2 enzymesKeap1/Nrf2Redox stressThiol oxidationElectrophilic compoundsDefense systemHerb rosemaryPathwayNormal cellsCarnosic acidNeurodegenerative disordersCounterattack strategiesDeplete glutathione
2009
Excitotoxicity in Neurodegenerative Disease
Haeberlein S, Lipton S. Excitotoxicity in Neurodegenerative Disease. 2009, 77-86. DOI: 10.1016/b978-008045046-9.00498-8.Peer-Reviewed Original ResearchHuman immunodeficiency virus-associated dementiaExcessive glutamate stimulationSpinal cord traumaMajor excitatory neurotransmitterAmyotrophic lateral sclerosisCord traumaExcitatory neurotransmitterGlutamate stimulationLateral sclerosisParkinson's diseaseTherapeutic interventionsAlzheimer's diseaseNeurodegenerative disordersDiseaseNeurodegenerative diseasesDownstream mechanismsHuntington's diseaseExcitotoxicityBrainSclerosisGlaucomaEpilepsyDementiaStrokeNeurotransmitters
2007
S-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 siteFissionActivation 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