2024
Single-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 vulnerability
2017
Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice
Klein ZA, Takahashi H, Ma M, Stagi M, Zhou M, Lam TT, Strittmatter SM. Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron 2017, 95: 281-296.e6. PMID: 28728022, PMCID: PMC5558861, DOI: 10.1016/j.neuron.2017.06.026.Peer-Reviewed Original ResearchConceptsLysosomal protein levelsFrontotemporal lobar degenerationProtein levelsMultiple lysosomal enzymesLysosomal enzymesV0 subunitsTMEM106B geneProteomic analysisProgranulin-deficient miceExtent of neurodegenerationCommon neurodegenerative disorderLysosomal acidificationLysosomal enzyme levelsProtein 1Microglial accumulationRisk modificationFTLD riskBehavioral abnormalitiesRetinal degenerationNeurodegenerative disordersFrontotemporal dementiaGRNTMEM106BFunctional relationshipEnzyme levels
2015
Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation
Henderson MX, Wirak GS, Zhang YQ, Dai F, Ginsberg SD, Dolzhanskaya N, Staropoli JF, Nijssen PC, Lam TT, Roth AF, Davis NG, Dawson G, Velinov M, Chandra SS. Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta Neuropathologica 2015, 131: 621-637. PMID: 26659577, PMCID: PMC4791186, DOI: 10.1007/s00401-015-1512-2.Peer-Reviewed Original ResearchConceptsNeuronal ceroid lipofuscinosesProtein palmitoylationDisease pathwaysPalmitoyl-protein thioesterase 1Forms of NCLEnzyme palmitoyl-protein thioesterase 1Disease-associated proteinsCommon disease pathwaysNCL genesQuantitative proteomicsCSPα mutationsSpecific enzymatic activityCSPαFunctional linkNeuronal ceroid lipofuscinosisGlobal changePPT1Synaptic proteinsEnzymatic activityCeroid lipofuscinosesPalmitoylationGenesCeroid lipofuscinosisNeurodegenerative disordersProtein
2014
Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease
Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, Kanyo J, Zhang Y, Seyb K, Ononenyi C, Foscue E, Anderson GM, Gresack J, Cuny GD, Glicksman MA, Greengard P, Lam TT, Tautz L, Nairn AC, Ellman JA, Lombroso PJ. Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease. PLOS Biology 2014, 12: e1001923. PMID: 25093460, PMCID: PMC4122355, DOI: 10.1371/journal.pbio.1001923.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmino Acid SequenceAnimalsBenzothiepinsCatalytic DomainCell DeathCerebral CortexCognition DisordersCysteineDisease Models, AnimalEnzyme InhibitorsHigh-Throughput Screening AssaysHumansMaleMice, Inbred C57BLMice, KnockoutMolecular Sequence DataNeuronsPhosphorylationPhosphotyrosineProtein Tyrosine Phosphatases, Non-ReceptorSubstrate SpecificityConceptsInhibitors of stepsSpecificity of inhibitorsIsoxazolepropionic acid receptor (AMPAR) traffickingCatalytic cysteinePTP inhibitorsTyrosine phosphataseTyrosine phosphorylationSecondary assaysSTEP KO miceReceptor traffickingFirst large-scale effortN-methyl-D-aspartate receptorsPyk2 activitySTEP inhibitorLarge-scale effortsNovel therapeutic targetSynaptic functionAlzheimer's diseaseNeurodegenerative disordersCortical cellsTherapeutic targetERK1/2Specificity experimentsPhosphataseInhibitorsNonenzymatic domains of Kalirin7 contribute to spine morphogenesis through interactions with phosphoinositides and Abl
Ma XM, Miller MB, Vishwanatha KS, Gross MJ, Wang Y, Abbott T, Lam TT, Mains RE, Eipper BA. Nonenzymatic domains of Kalirin7 contribute to spine morphogenesis through interactions with phosphoinositides and Abl. Molecular Biology Of The Cell 2014, 25: 1458-1471. PMID: 24600045, PMCID: PMC4004595, DOI: 10.1091/mbc.e13-04-0215.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalpainCells, CulturedDendritic SpinesGuanine Nucleotide Exchange FactorsHippocampusMice, KnockoutNeuronsOncogene Proteins v-ablPeptide FragmentsPhosphatidylinositolsPhosphorylationProtein Processing, Post-TranslationalProtein Structure, TertiaryProteolysisRats, Sprague-DawleySynapsesTransferrinConceptsGDP/GTP exchange factorSec14 domainSpectrin repeatsSpine morphogenesisNon-receptor tyrosine kinaseGTP exchange factorSpine formationNatural splice variantSpectrin repeat domainReceptor-mediated endocytosisRho GDP/GTP exchange factorDrosophila orthologueMembrane traffickingPhosphomimetic mutationExchange factorCalpain-mediated degradationRepeat domainTruncation mutantsTyrosine kinaseGenetic studiesCellular membranesSplice variantsRepeatsNonneuronal cellsMorphogenesis
2013
Palmitoylation of Superoxide Dismutase 1 (SOD1) Is Increased for Familial Amyotrophic Lateral Sclerosis-linked SOD1 Mutants*
Antinone SE, Ghadge GD, Lam TT, Wang L, Roos RP, Green WN. Palmitoylation of Superoxide Dismutase 1 (SOD1) Is Increased for Familial Amyotrophic Lateral Sclerosis-linked SOD1 Mutants*. Journal Of Biological Chemistry 2013, 288: 21606-21617. PMID: 23760509, PMCID: PMC3724620, DOI: 10.1074/jbc.m113.487231.Peer-Reviewed Original ResearchMeSH KeywordsAmyotrophic Lateral SclerosisAnimalsBlotting, WesternCell Line, TumorCell MembraneCysteineDisulfidesHEK293 CellsHumansLipoylationLuminescent ProteinsMass SpectrometryMiceMice, TransgenicMutationNeuronsOxidation-ReductionProtein Processing, Post-TranslationalSpinal CordSuperoxide DismutaseSuperoxide Dismutase-1ConceptsWild-type SOD1Familial amyotrophic lateral sclerosisSuperoxide dismutase 1Copper chaperoneCysteine mutagenesisReversible post-translational modificationAcyl-biotin exchangeDisulfide bondingPost-translational modificationsMass spectrometryWild-type superoxide dismutase 1PalmitoylationSOD1 maturationMotor neuron cell lineProtein structureSOD1 mutantsNeuron cell lineAmyotrophic lateral sclerosisZn-superoxide dismutaseHEK cellsResidues 6ChaperonesCell linesMutagenesisDismutase 1
2011
Cyclin-Dependent Kinase 5 Regulates PSD-95 Ubiquitination in Neurons
Bianchetta MJ, Lam TT, Jones SN, Morabito MA. Cyclin-Dependent Kinase 5 Regulates PSD-95 Ubiquitination in Neurons. Journal Of Neuroscience 2011, 31: 12029-12035. PMID: 21849563, PMCID: PMC3190401, DOI: 10.1523/jneurosci.2388-11.2011.Peer-Reviewed Original ResearchConceptsAMPA receptor endocytosisClathrin adaptor protein complex AP-2Receptor endocytosisAP-2Protein complex AP-2PSD-95Cdk5 activityMajor postsynaptic scaffolding proteinCyclin-dependent kinase 5Interaction of MDM2Β-adaptinNonproteolytic functionsUbiquitin E3Scaffolding proteinUbiquitinationMolecular mechanismsActivator p35Kinase 5Postsynaptic scaffolding proteinGenetic reductionPSD-95 protein levelsNMDA receptor stimulationProtein levelsEndocytosisNeurodegenerative diseases