2025
Myelin–axon interface vulnerability in Alzheimer’s disease revealed by subcellular proteomics and imaging of human and mouse brain
Cai Y, Pinheiro-de-Sousa I, Slobodyanyuk M, Chen F, Huynh T, Kanyo J, Tang P, Fuentes L, Braker A, Welch R, Huttner A, Tong L, Yuan P, Lam T, Petsalaki E, Reimand J, Nairn A, Grutzendler J. Myelin–axon interface vulnerability in Alzheimer’s disease revealed by subcellular proteomics and imaging of human and mouse brain. Nature Neuroscience 2025, 1-18. PMID: 40514588, DOI: 10.1038/s41593-025-01973-8.Peer-Reviewed Original ResearchSubcellular proteomicsAlzheimer's diseaseFemale 5XFAD miceProteomic hitsSubcellular localizationAmyloid-bProtein aggregationLigand-receptor interactionsAD donorsLipid metabolismExpansion microscopyPostmortem human brainProteomicsAxonal outgrowthMouse brainAlzheimerNeuronal plasticityCritical sitesAberrant myelinationMyelin ensheathmentDystrophic axonsMetabolic supportMiceAxonal structureMetabolismA multi-omic approach implicates novel protein dysregulation in post-traumatic stress disorder
Wang J, Liu Y, Li H, Nguyen T, Soto-Vargas J, Wilson R, Wang W, Lam T, Zhang C, Lin C, Lewis D, Glausier J, Holtzheimer P, Friedman M, Williams K, Picciotto M, Nairn A, Krystal J, Duman R, Young K, Zhao H, Girgenti M. A multi-omic approach implicates novel protein dysregulation in post-traumatic stress disorder. Genome Medicine 2025, 17: 43. PMID: 40301990, PMCID: PMC12042318, DOI: 10.1186/s13073-025-01473-1.Peer-Reviewed Original ResearchConceptsPost-traumatic stress disorderDorsolateral prefrontal cortexPsychiatric disordersAutism spectrum disorderPrefrontal cortexDepressive disorderStress disorderGamma-aminobutyric acidGenome-wide association studiesPTSD brainsGenome-wide measurementsStudies of postmortem brainsSubgenual prefrontal cortexDisabling psychiatric disorderMultiple psychiatric disordersPrefrontal cortical areasPTSD casesHuman brain studiesBrain regionsSpectrum disorderGABAergic processesPostmortem brainsMDDProtein co-expression modulesProteomic profilingAuto-sumoylation of the yeast Ubc9 E2 SUMO-conjugating enzyme extends cellular lifespan
Jeong D, Lee D, Kim S, Jeoung S, Zhao D, Knight J, Lam T, Jin J, Lee H, Hochstrasser M, Ryu H. Auto-sumoylation of the yeast Ubc9 E2 SUMO-conjugating enzyme extends cellular lifespan. Nature Communications 2025, 16: 3735. PMID: 40254622, PMCID: PMC12009981, DOI: 10.1038/s41467-025-58925-w.Peer-Reviewed Original ResearchConceptsE2 SUMO-conjugating enzymeSUMO-conjugating enzymeSUMO-specific proteasesPost-translational levelIn vitro evolutionSevere cellular stressCalorie restrictionRegulation of multiple targetsGene expression profilesIncreased mitochondrial activityCellular lifespanLifespan extensionReplicative lifespanCellular stressMitochondrial activityYeastCR-mediated lifespan extensionEnhanced growth rateEnzyme resultsDiverse processesExpression profilesLifespan effectsReplication abilityEnergy metabolismAged cellsSubcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease
Cai Y, Kanyo J, Wilson R, Bathla S, Cardozo P, Tong L, Qin S, Fuentes L, Pinheiro-de-Sousa I, Huynh T, Sun L, Mansuri M, Tian Z, Gan H, Braker A, Trinh H, Huttner A, Lam T, Petsalaki E, Brennand K, Nairn A, Grutzendler J. Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease. Nature Aging 2025, 5: 504-527. PMID: 40065072, PMCID: PMC11922768, DOI: 10.1038/s43587-025-00823-3.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseProximity labeling approachIPSC-derived neuronsSubcellular proteomicsCytoskeleton dynamicsPhosphorylated mTOR levelsDystrophic neuritesLipid transportBiological processesProtein turnoverAD modelHuman induced pluripotent stem cellsAmyloid depositsIPSC modelsProteomicsInduced pluripotent stem cellsPluripotent stem cellsMTOR inhibitionTherapeutic targetAxonal pathologyLabeling approachMTOR levelsMouse brainSpheroid formationAlzheimerUnbiased CSF Proteomics in Patients With Idiopathic Normal Pressure Hydrocephalus to Identify Molecular Signatures and Candidate Biomarkers
de Geus M, Wu C, Dodge H, Leslie S, Wang W, Lam T, Kahle K, Chan D, Kivisäkk P, Nairn A, Arnold S, Carlyle B. Unbiased CSF Proteomics in Patients With Idiopathic Normal Pressure Hydrocephalus to Identify Molecular Signatures and Candidate Biomarkers. Neurology 2025, 104: e213375. PMID: 39951680, PMCID: PMC11837848, DOI: 10.1212/wnl.0000000000213375.Peer-Reviewed Original ResearchConceptsNeuronal pentraxin receptorIdiopathic normal pressure hydrocephalusTranscriptome dataAlzheimer's diseaseDifferential expression of proteinsGene ontology analysisDifferential expression analysisGene set enrichment analysisDownregulation of proteinsDifferentially expressed proteinsNormal pressure hydrocephalusBiological process enrichmentExpression of proteinsPotential disease biomarkersOntology analysisProteomic analysis of CSFPathophysiology of idiopathic normal pressure hydrocephalusProteomic analysisProteomic studiesProcess of immune responseEnrichment analysisExpression analysisPressure hydrocephalusDifferential expressionDiagnosis of idiopathic normal pressure hydrocephalusAlterations in newborn metabolite patterns with preterm birth and diabetes in pregnancy
Buck C, McCollum S, Wang W, Lam T, Taylor S, Shabanova V. Alterations in newborn metabolite patterns with preterm birth and diabetes in pregnancy. Pediatric Research 2025, 1-10. PMID: 39824937, DOI: 10.1038/s41390-025-03844-1.Peer-Reviewed Original ResearchPreterm infantsCardiometabolic outcomesMetabolite patternsStudy of termMetabolic changesInfluence of prematuritySkin fold thickness measurementsCohort of infantsUnique metabolic signatureNon-DM groupAdipose developmentExposure to diabetesArm circumference measurementsBody composition assessmentAssociated with adiposityBody fat percentAdverse growthDM exposurePreterm birthTargeted metabolomicsInfant bloodTerm groupDM groupGA groupPretermDysregulation of mTOR signalling is a converging mechanism in lissencephaly
Zhang C, Liang D, Ercan-Sencicek A, Bulut A, Cortes J, Cheng I, Henegariu O, Nishimura S, Wang X, Peksen A, Takeo Y, Caglar C, Lam T, Koroglu M, Narayanan A, Lopez-Giraldez F, Miyagishima D, Mishra-Gorur K, Barak T, Yasuno K, Erson-Omay E, Yalcinkaya C, Wang G, Mane S, Kaymakcalan H, Guzel A, Caglayan A, Tuysuz B, Sestan N, Gunel M, Louvi A, Bilguvar K. Dysregulation of mTOR signalling is a converging mechanism in lissencephaly. Nature 2025, 638: 172-181. PMID: 39743596, PMCID: PMC11798849, DOI: 10.1038/s41586-024-08341-9.Peer-Reviewed Original ResearchP53-induced death domain protein 1Miller-Dieker lissencephaly syndromeMolecular mechanismsDysregulation of protein translationDysregulation of mTOR signalingDomain protein 1Activity of mTOR complexesMTOR pathwayRelevant molecular mechanismsProtein translationHuman lissencephalyClinically relevant molecular mechanismsRecessive mutationsRare mutationsMiller-DiekerGene expressionCerebral cortex developmentMTOR complexesSpectrum disorderMolecular defectsMTOR signalingCongenital brain malformationsProtein 1GeneticsAssociated with epilepsy
2024
Machine Learning Analysis of the Orbitofrontal Cortex Transcriptome of Human Opioid Users Identifies Shisa7 as a Translational Target Relevant for Heroin Seeking Leveraging a Male Rat Model
Ellis R, Ferland J, Rahman T, Landry J, Callens J, Pandey G, Lam T, Kanyo J, Nairn A, Dracheva S, Hurd Y. Machine Learning Analysis of the Orbitofrontal Cortex Transcriptome of Human Opioid Users Identifies Shisa7 as a Translational Target Relevant for Heroin Seeking Leveraging a Male Rat Model. Biological Psychiatry 2024, 98: 23-33. PMID: 39725299, DOI: 10.1016/j.biopsych.2024.12.007.Peer-Reviewed Original ResearchRat orbitofrontal cortexOrbitofrontal cortexOpioid use disorderHeroin seekingBehavioral updatingHeroin usersHeroin-seeking behaviorDrug-seeking behaviorGoal-directed behaviorNeurobiological targetsOperant contingenciesUse disorderControl participantsTranslational rat modelGABAergic receptor subunitsHeroin useNeuroimmune processesShisa7AMPA receptorsMale rat modelReceptor subunitsSeekingGene expression signaturesOpioid usersHeroinMachine learning on unbiased proteomics of cerebrospinal fluid uncovers differential molecular signatures of Alzheimer’s disease and Normal Pressure Hydrocephalus
de Geus M, Wu C, Dodge H, Leslie S, Wang W, Lam T, Nairn A, Kivisäkk P, Arnold S, Carlyle B. Machine learning on unbiased proteomics of cerebrospinal fluid uncovers differential molecular signatures of Alzheimer’s disease and Normal Pressure Hydrocephalus. Alzheimer's & Dementia 2024, 20: e091783. PMCID: PMC11714358, DOI: 10.1002/alz.091783.Peer-Reviewed Original ResearchGene set enrichment analysisAlzheimer's diseaseSignatures of Alzheimer's diseasePathology of ADMolecular signaturesPathways related to glycolysisNormal pressure hydrocephalusImmune response pathwaysGene setsResponse pathwaysData-independent acquisition mass spectrometryMolecular-level investigationsEnrichment analysisProteomic investigationsCerebrospinal fluidMetabolic processesProteome quantificationProteinSingle-cell transcriptomic and proteomic analysis of Parkinson’s disease brains
Zhu B, Park J, Coffey S, Russo A, Hsu I, Wang J, Su C, Chang R, Lam T, Gopal P, Ginsberg S, Zhao H, Hafler D, Chandra S, Zhang L. Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains. Science Translational Medicine 2024, 16: eabo1997. PMID: 39475571, DOI: 10.1126/scitranslmed.abo1997.Peer-Reviewed Original ResearchConceptsProteomic analysisAlzheimer's diseasePrefrontal cortexBrain cell typesGenetics of PDParkinson's diseaseCell-cell interactionsChaperone expressionSingle-nucleus transcriptomesExpressed genesTranscriptional changesPostmortem human brainPostmortem brain tissueDiseased brainSynaptic proteinsSingle-cellDown-regulationBrain cell populationsBrain regionsCell typesNeurodegenerative disordersLate-stage PDParkinson's disease brainsDisease etiologyNeuronal vulnerabilityA fluorescence-based assay for measuring polyamine biosynthesis aminopropyl transferase–mediated catalysis
Singh P, Choi J, Wang W, Lam T, Lechner P, Vanderwal C, Pou S, Nilsen A, Mamoun C. A fluorescence-based assay for measuring polyamine biosynthesis aminopropyl transferase–mediated catalysis. Journal Of Biological Chemistry 2024, 300: 107832. PMID: 39342998, PMCID: PMC11541840, DOI: 10.1016/j.jbc.2024.107832.Peer-Reviewed Original ResearchAminopropyl transferaseFluorescence-based assayLack of high-throughput assaysHigh-throughput screeningCarbon chain lengthChemical librariesMass spectrometryChain lengthHigh-throughput assayDrug discoveryMass spectrometry analysisSaccharomyces cerevisiaeThin-layer chromatographyFluorescence intensityCellular functionsSpectrometry analysisPolycationic moleculesFluorescent conjugatesIsoindoleAPT activityCatalysisAssayBenzeneAdductsEnzymeProteomic Profile of Circulating Extracellular Vesicles in the Brain after Δ9-Tetrahydrocannabinol Inhalation
Lallai V, Lam T, Garcia-Milian R, Chen Y, Fowler J, Manca L, Piomelli D, Williams K, Nairn A, Fowler C. Proteomic Profile of Circulating Extracellular Vesicles in the Brain after Δ9-Tetrahydrocannabinol Inhalation. Biomolecules 2024, 14: 1143. PMID: 39334909, PMCID: PMC11430348, DOI: 10.3390/biom14091143.Peer-Reviewed Original ResearchConceptsImmediate early gene c-fosChronic THC exposureEarly gene c-fosCannabinoid 1 receptorGene c-fosSex-specific mannerTHC exposurePsychoactive componentExtracellular vesiclesCentral signaling mechanismDrug effectsTHCChoroid plexus epithelial cellsFemale ratsC-fosPlexus epithelial cellsBrainCannabisRelease of EVsRegulate intercellular communicationCerebrospinal fluidEpithelial cellsIntercellular signaling mediatorsEV signalingIntercellular communicationCellular stiffness sensing through talin 1 in tissue mechanical homeostasis
Chanduri M, Kumar A, Weiss D, Emuna N, Barsukov I, Shi M, Tanaka K, Wang X, Datye A, Kanyo J, Collin F, Lam T, Schwarz U, Bai S, Nottoli T, Goult B, Humphrey J, Schwartz M. Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis. Science Advances 2024, 10: eadi6286. PMID: 39167642, PMCID: PMC11338229, DOI: 10.1126/sciadv.adi6286.Peer-Reviewed Original ResearchConceptsTissue mechanical homeostasisStiffness sensingExtracellular matrixTalin-1Mechanical homeostasisExtracellular matrix mechanicsIncreased cell spreadingCell spreadingTalinMutationsCellular sensingFibrillar collagenReduced axial stiffnessTissue mechanical propertiesMechanical propertiesAxial stiffnessCompliant substratesHomeostasisRupture pressureArp2/3ARPC5LStiffnessHomeostasis hypothesisResident cellsTissue stiffnessA complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell–cell contacts
Johnson B, Iuliano M, Lam T, Biederer T, De Camilli P. A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell–cell contacts. Journal Of Cell Biology 2024, 223: e202311137. PMID: 39158698, PMCID: PMC11334333, DOI: 10.1083/jcb.202311137.Peer-Reviewed Original ResearchConceptsPlasma membraneNon-vesicular lipid transferSites of cell contactC-terminus motifsCell contact-dependent signalsContact-dependent signalingCell-cell contactER/PM junctionsTMEM24ER proteinsPM proteinsSynCAM 1Cell adhesion moleculesCellular functionsLipid transferC2CD2Phospholipid transportLipid transportCell contactProteinAdhesion moleculesCalcium homeostasisCellsFamily membersParalogsCell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone
Norton E, Whaley L, Jones V, Brooks M, Russo M, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann Y, Lam T, Chaichana K, Anastasiadis P, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. Science Advances 2024, 10: eadn1607. PMID: 39110807, PMCID: PMC11305394, DOI: 10.1126/sciadv.adn1607.Peer-Reviewed Original ResearchConceptsBrain tumor-initiating cellsLateral ventricleNeuronal maturationMalignancy-associated phenotypesSubventricular zone contactIncreased expression of cathepsin BMalignant primary brain tumorTumor-initiating cellsAggressive malignant primary brain tumorPrimary brain tumorTumor microenvironment researchExpression of cathepsin BNeural stem/progenitor cellsCathepsin BInduction of senescenceStem/progenitor cellsCell-intrinsicSubventricular zoneCross-talkTherapeutic strategiesBrain tumorsIncreased expressionGBM biologyLentiviral knockdownGlioblastomaPhosphorylation of the nuclear poly(A) binding protein (PABPN1) during mitosis protects mRNA from hyperadenylation and maintains transcriptome dynamics
Gordon J, Phizicky D, Schärfen L, Brown C, Escayola D, Kanyo J, Lam T, Simon M, Neugebauer K. Phosphorylation of the nuclear poly(A) binding protein (PABPN1) during mitosis protects mRNA from hyperadenylation and maintains transcriptome dynamics. Nucleic Acids Research 2024, 52: 9886-9903. PMID: 38943343, PMCID: PMC11381358, DOI: 10.1093/nar/gkae562.Peer-Reviewed Original ResearchPoly(A)-binding proteinTranscriptome dynamicsNuclear poly(A) binding proteinPoly(A) binding proteinMode of gene regulationFunctional consequences of phosphorylationLong-read sequencingIncreased mRNA turnoverNucleo-cytoplasmic exportConsequences of phosphorylationRegulation of poly(ACohort of mRNAsGene expression programsMRNA biogenesisCytoplasmic mixingMRNA turnoverGene regulationShorter poly(ARNA stabilityMitotic kinasesPoly(ACell cycleMRNA synthesisIncreased transcriptionBinding proteinBERNN: Enhancing classification of Liquid Chromatography Mass Spectrometry data with batch effect removal neural networks
Pelletier S, Leclercq M, Roux-Dalvai F, de Geus M, Leslie S, Wang W, Lam T, Nairn A, Arnold S, Carlyle B, Precioso F, Droit A. BERNN: Enhancing classification of Liquid Chromatography Mass Spectrometry data with batch effect removal neural networks. Nature Communications 2024, 15: 3777. PMID: 38710683, PMCID: PMC11074280, DOI: 10.1038/s41467-024-48177-5.Peer-Reviewed Original ResearchConceptsLC-MS experimentsLC-MSLiquid chromatography mass spectrometry dataComplex biological samplesMass spectrometry dataLiquid chromatography mass spectrometryChromatography mass spectrometryMass spectrometrySpectrometry dataEffective removalBiological samplesExperimental conditionsBatch effect removalSample processing protocolBatch effectsSpectrometryBatch effect correction methodsCorrecting batch effectsRemoval of batch effectsOptimal conditions for carrying out trypsin digestions on complex proteomes: From bulk samples to single cells
Mansuri M, Bathla S, Lam T, Nairn A, Williams K. Optimal conditions for carrying out trypsin digestions on complex proteomes: From bulk samples to single cells. Journal Of Proteomics 2024, 297: 105109. PMID: 38325732, PMCID: PMC10939724, DOI: 10.1016/j.jprot.2024.105109.Peer-Reviewed Original ResearchComplex proteomesProtein cleavage activityOptimal conditionsTrypsin digestion protocolReversed phase HPLC separationMass spectrometry workflowMS-based proteomicsMass spectrometric analysisC-terminal amino acid residuesTrypsin digestionChromatographic separationDigestion protocolAmino acid residuesHPLC separationMS/MS analysisGlobal proteomic analysisSingle cellsSample matrixSpectrometric analysisCleavage specificityGeneration of peptidesAcid residuesDown proteinsProteomic analysisCleavage activity
2023
Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis
Shi X, DeCiucis M, Grabinska K, Kanyo J, Liu A, Lam T, Shen H. Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. Molecular Cell 2023, 84: 802-810.e6. PMID: 38157846, PMCID: PMC10922821, DOI: 10.1016/j.molcel.2023.12.008.Peer-Reviewed Original ResearchProtein quality controlMitochondrial protein quality controlDual regulationMetabolic compartmentalizationIron homeostasisMitochondrial iron-sulfur clustersIron-sulfur clustersMitochondrial transportersProtein regulationMammalian cellsCRISPR knockoutCysteine residuesTransporter regulationLoop 1SLC25A39Glutathione homeostasisMetabolic sensingGlutathione uptakeMature neuronsProtein levelsHomeostasisRegulationAFG3L2Biochemical featuresMitochondrial glutathione levelsMass spectrometry on cerebrospinal fluid uncovers association of novel glycolysis biomarkers with Alzheimer’s disease in a complex clinical cohort
de Geus M, Leslie S, Wang W, Lam T, Broekman M, Neefjes S, Nairn A, Carlyle B, Arnold S. Mass spectrometry on cerebrospinal fluid uncovers association of novel glycolysis biomarkers with Alzheimer’s disease in a complex clinical cohort. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.078466.Peer-Reviewed Original ResearchAlzheimer's diseaseMild cognitive impairmentHospital neurology serviceNon-AD diagnosesDiagnostic lumbar puncturePrognosis of ADCerebrospinal fluid biomarkersClinic cohortFurther mechanistic studiesNeurology serviceFDG-PETBrain metabolismFluid biomarkersLumbar puncturePatient cohortClinical indicationsDisease progressionATN biomarkersClinical cohortTreatment responseComplex cohortBackground DiagnosisCSF samplesTreatment efficacyLinear regression analysis
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