Stuart Lipton, MD/PhD
Adjunct Professor of NeurologyAbout
Titles
Adjunct Professor of Neurology
Biography
Neurologist/neuroscientist Stuart Lipton, MD, PhD is a renowned expert in dementia. He was trained at Cornell University, the University of Pennsylvania, and Harvard University. In addition to running a basic-science laboratory, he has an active clinical neurology practice focusing on dementia and general neurology. Lipton completed his PhD thesis research with John Dowling at Harvard, followed by clinical residency and a postdoctoral fellowship at Harvard with Torsten Wiesel during the time that Wiesel won the Nobel prize. He was then on the Harvard faculty for over 20 years before moving to La Jolla as founding director of a new neuroscience center in 2000. He is best known for first describing the mechanism of action and contributing to the clinical development of the FDA-approved Alzheimer’s drug, memantine (Namenda®), and for discovering the posttranslational redox modification, protein S-nitrosylation.
Recently, Lipton combined memantine with S-nitrosylation chemistry to produce a new drug called NitroSynapsin, which displays disease-modifying activity in animal models of Alzheimer’s disease, both protecting synapses and improving neurobehavioral deficits. Lipton’s group also characterized HIV-related pathways to neuronal damage, discovered the NR3 (now known at GluN3) family of modulatory NMDA receptor subunits, characterized the molecular pathways for protecting neurons with Erythropoietin, and discovered the transcription factor MEF2C. His group showed that MEF2C activity is regulated by S-nitrosylation and serves as a master switch for neurogenesis from human neural stem cells. Dysregulated MEF2C is involved in the pathogenesis of Parkinson’s disease, Alzheimer’s disease, Autism-Spectrum Disorder, and Vascular dementia. Lipton was awarded the Ernst Jung Prize in Medicine and is an elected fellow of the AAAS. He recently received an Alzheimer’s Disease Association Award, a Michael J. Fox Foundation Grant, and an NIH Director’s Grant Award.
Appointments
Education & Training
- Research Fellow
- Harvard Medical School, Dept. of Neurobiology (1983)
- Board Certification
- American Board of Psychiatry & Neurology, Neurology (1982)
- Resident and Chief Resident in Neurology
- Brigham & Women's Hospital, Beth Israel Deaconess Medical Center, Boston Children's Hospital (1981)
- Intern in Medicine
- Beth Israel Deaconess Medical Center, Harvard Medical School (1978)
- MD/PhD
- University of Pennsylvania, Biochemistry & Biophysics (1977)
- BA
- Cornell University, Neurobiology and Immunology (1971)
Research
Publications
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 PMID: 39515322, 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 ResearchDetecting 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, PP: 1-12. 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 interactionsInteractionExpressionCellsUsing 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 changesDysregulation 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, 1-18. PMID: 39349966, 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 expression“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 factorsEnzymeAlzheimerCascadeSingle‐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 functionEnzymatic 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 Research