2022
Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain
Dedek A, Xu J, Lorenzo LÉ, Godin AG, Kandegedara CM, Glavina G, Landrigan JA, Lombroso PJ, De Koninck Y, Tsai EC, Hildebrand ME. Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain. Brain 2022, 145: 1124-1138. PMID: 35323848, PMCID: PMC9050559, DOI: 10.1093/brain/awab408.Peer-Reviewed Original ResearchConceptsBrain-derived neurotrophic factorSuperficial dorsal horn neuronsDorsal horn neuronsFemale ratsNeurotrophic factorNeuronal mechanismsCentral neuronal mechanismsSpinal nociceptive circuitsSpinal pain processingSuperficial dorsal hornChronic pain syndromeLamina I neuronsPreclinical pain modelsHuman organ donorsSynaptic NMDAR responsesNMDAR potentiationSpinal hyperexcitabilityInflammatory painNociceptive circuitsPain syndromeTactile allodyniaDorsal hornPain modelPathological painLaminae I
2020
Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity
Xu J, Liu RJ, Fahey S, Frick L, Leckman J, Vaccarino F, Duman RS, Williams K, Swedo S, Pittenger C. Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity. American Journal Of Psychiatry 2020, 178: 48-64. PMID: 32539528, PMCID: PMC8573771, DOI: 10.1176/appi.ajp.2020.19070698.Peer-Reviewed Original ResearchConceptsStriatal cholinergic interneuronsCholinergic interneuronsMouse brain slicesObsessive-compulsive disorderControl subjectsBrain slicesPediatric autoimmune neuropsychiatric disordersIntravenous immunoglobulin treatmentAutoimmune neuropsychiatric disordersAcute mouse brain slicesParvalbumin-expressing GABAergic interneuronsPediatric obsessive-compulsive disorderBrain antigensImmunoglobulin treatmentBaseline serumStreptococcal infectionCritical cellular targetsSymptom improvementGABAergic interneuronsInduced autoimmunityIgG antibodiesMouse slicesIndependent cohortBehavioral pathologyNeuron types
2019
Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing
Dedek A, Xu J, Kandegedara CM, Lorenzo LÉ, Godin AG, De Koninck Y, Lombroso PJ, Tsai EC, Hildebrand ME. Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing. Brain 2019, 142: 1535-1546. PMID: 31135041, PMCID: PMC6536915, DOI: 10.1093/brain/awz105.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate receptorsLaminae INMDAR responsesDorsal horn synapsesSpinal pain processingNerve injury modelSpinal dorsal hornSynaptic NMDAR responsesTyrosine phosphatase STEP61Loss of inhibitionBehavioral hypersensitivityInflammatory painNeuropathic painDorsal hornPain statesPathological painPain targetsChronic painPain processingInjury modelAssociated downregulationRodent modelsReceptor potentiationPainSTEP61 activity
2016
Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing
Hildebrand ME, Xu J, Dedek A, Li Y, Sengar AS, Beggs S, Lombroso PJ, Salter MW. Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing. Cell Reports 2016, 17: 2753-2765. PMID: 27926876, DOI: 10.1016/j.celrep.2016.11.024.Peer-Reviewed Original ResearchConceptsBrain-derived neurotrophic factorN-methyl-D-aspartate receptorsLaminae INeurotrophin brain-derived neurotrophic factorPeripheral nerve injury modelSynaptic N-methyl-D-aspartate receptorsBDNF-TrkB signalingSpinal pain processingNerve injury modelChronic pain statesActivation of TrkBNMDAR dysregulationNMDAR potentiationPain amplificationPain hypersensitivityNeuropathic painPain statesPain processingNeurotrophic factorSpinal neuronsSynaptic excitationSynaptic inhibitionNMDAR currentsInjury modelPotentiationInhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models
Xu J, Hartley BJ, Kurup P, Phillips A, Topol A, Xu M, Ononenyi C, Foscue E, Ho SM, Baguley TD, Carty N, Barros CS, Müller U, Gupta S, Gochman P, Rapoport J, Ellman JA, Pittenger C, Aronow B, Nairn AC, Nestor MW, Lombroso PJ, Brennand KJ. Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Molecular Psychiatry 2016, 23: 271-281. PMID: 27752082, PMCID: PMC5395367, DOI: 10.1038/mp.2016.163.Peer-Reviewed Original ResearchConceptsBrain-specific tyrosine phosphataseDephosphorylation of GluN2BExtracellular signal-regulated kinase 1/2Signal-regulated kinase 1/2Glutamate receptor internalizationPluripotent stem cellsKnockout mouse modelTyrosine phosphataseMouse modelKinase 1/2Receptor internalizationImportant regulatorGenetic reductionLoss of NMDARsStem cellsN-methyl DPharmacological inhibitionProtein levelsSynaptic functionSTEP61Patient cohortForebrain neuronsBehavioral deficitsExcitatory neuronsSchizophrenia model
2015
STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease
Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC. STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 1202-1207. PMID: 25583483, PMCID: PMC4313846, DOI: 10.1073/pnas.1417423112.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCorpus StriatumCyclic AMP Response Element-Binding ProteinDown-RegulationGene Expression Regulation, EnzymologicHEK293 CellsHumansMAP Kinase Signaling SystemMiceMice, KnockoutMitogen-Activated Protein Kinase 3MPTP PoisoningProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyUbiquitinationUbiquitin-Protein LigasesUp-RegulationConceptsE3 ubiquitin ligase ParkinSubstantia nigra pars compactaPathophysiology of PDProtein tyrosine phosphataseUbiquitin ligase ParkinSporadic Parkinson's diseaseE3 ligase ParkinRegulation of ParkinParkinson's diseaseTyrosine phosphataseParkin mutantsE3 ligaseProteasome systemDopaminergic neuronsDownstream targetsAutosomal recessive juvenile parkinsonismNovel substrateSTEP61ParkinCellular modelSTEP61 levelsSNc dopaminergic neuronsProtein levelsFunction contributesERK1/2
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 experimentsPhosphataseInhibitorsAlterations in STriatal‐Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128 Huntington's disease mouse model
Gladding CM, Fan J, Zhang LY, Wang L, Xu J, Li EH, Lombroso PJ, Raymond LA. Alterations in STriatal‐Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128 Huntington's disease mouse model. Journal Of Neurochemistry 2014, 130: 145-159. PMID: 24588402, PMCID: PMC4065618, DOI: 10.1111/jnc.12700.Peer-Reviewed Original ResearchConceptsDisease mouse modelYAC128 Huntington's disease mouse modelHuntington's disease mouse modelYAC128 miceCalpain-mediated cleavageMitogen-activated protein kinaseMouse modelCalpain inhibitionProtein tyrosine Phosphatase 61Wild-type cortical neuronsP38 phosphorylationNMDA receptor traffickingSTEP61 levelsSynaptic dysfunctionNMDAR localizationP38 mitogen-activated protein kinaseStriatal apoptosisCortical neuronsExtracellular signal-regulated proteinApoptotic signalingMutant huntingtin proteinStriatal tissueStriatal neurodegenerationTransgenic miceCalcium homeostasis
2012
The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications
Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ. The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Translational Psychiatry 2012, 2: e137-e137. PMID: 22781170, PMCID: PMC3410627, DOI: 10.1038/tp.2012.63.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate receptorsSTEP61 levelsSurface expressionPostmortem anterior cingulate cortexGluN2B-containing N-methyl-D-aspartate receptorsGluN1/GluN2B receptorsMK-801 treatmentPathophysiology of schizophreniaAnterior cingulate cortexSTEP knockout miceDorsolateral prefrontal cortexChronic administrationChronic treatmentNeuroleptic treatmentAntipsychotic medicationGlutamatergic functionMK-801Glutamate hypothesisMedications resultsTyrosine phosphatase STEPGlutamatergic signalingKnockout miceGluN2B receptorsCingulate cortexSynaptic plasticityStriatal-Enriched Protein Tyrosine Phosphatase in Alzheimer’s Disease
Xu J, Kurup P, Nairn AC, Lombroso PJ. Striatal-Enriched Protein Tyrosine Phosphatase in Alzheimer’s Disease. Advances In Pharmacology 2012, 64: 303-325. PMID: 22840751, PMCID: PMC3740556, DOI: 10.1016/b978-0-12-394816-8.00009-x.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseNeurofibrillary tanglesStriatal-enriched protein tyrosine phosphataseAmyloid plaquesTreatment of ADHyperphosphorylated tau proteinSubstantial economic burdenProgressive diseasePotential clinical applicationsClinical symptomsBeta amyloidGlutamate receptorsEconomic burdenTau proteinCortical accumulationCognitive functionMemory lossBeneficial effectsDiseaseNeuronal membranesCommon formMultiple intracellularMillions of peopleClinical applicationImportant target
2011
Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation
Sergienko E, Xu J, Liu WH, Dahl R, Critton DA, Su Y, Brown BT, Chan X, Yang L, Bobkova EV, Vasile S, Yuan H, Rascon J, Colayco S, Sidique S, Cosford ND, Chung TD, Mustelin T, Page R, Lombroso PJ, Tautz L. Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation. ACS Chemical Biology 2011, 7: 367-377. PMID: 22070201, PMCID: PMC3288537, DOI: 10.1021/cb2004274.Peer-Reviewed Original ResearchConceptsHematopoietic protein tyrosine phosphataseP38 activationMitogen-activated protein kinases ERK1/2Protein tyrosine phosphataseUnique amino acid residuesSmall molecule modulatorsProtein kinases ERK1/2Amino acid residuesRegulation of MAPKNew drug targetsCell cycle arrestTyrosine phosphataseHePTPMutagenesis experimentsKinases ERK1/2Acid residuesCatalytic pocketCell senescenceDrug targetsTransient activationCycle arrestT-cell acute lymphoblastic leukemiaHematopoietic cellsERK1/2Prolonged activation
2010
Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer’s disease mouse model
Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ. Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer’s disease mouse model. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 19014-19019. PMID: 20956308, PMCID: PMC2973892, DOI: 10.1073/pnas.1013543107.Peer-Reviewed Original ResearchConceptsStriatal-enriched tyrosine phosphataseTyrosine phosphataseDisease mouse modelStriatal-enriched phosphataseAlzheimer's diseaseCellular deficitsGenetic manipulationNMDA receptorsMouse modelTriple transgenic AD mouse modelIncurable neurodegenerative disorderTransgenic AD mouse modelAlzheimer's disease mouse modelPathophysiology of ADSTEP inhibitorGenetic reductionAD mouse modelHuman AD patientsSoluble Aβ oligomersSynaptic functionPhosphataseNeurodegenerative disordersAD patientsDevastating disorderAnimal modelsThe role of STEP in Alzheimer's disease
Kurup P, Zhang Y, Venkitaramani DV, Xu J, Lombroso PJ. The role of STEP in Alzheimer's disease. Channels 2010, 4: 347-350. PMID: 20699650, PMCID: PMC3230511, DOI: 10.4161/chan.4.5.12910.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate (NMDA) type glutamate receptorsAlzheimer's diseaseProtein tyrosine Phosphatase 61AD prefrontal cortexAD mouse modelType glutamate receptorsGlutamate receptor traffickingNeuronal surface membraneNMDAR internalizationAβ treatmentPutative causative agentGlutamate receptorsMouse modelCulture resultsGluN1/Prefrontal cortexDiseaseNeuronal membranesNMDAR endocytosisAdditional studiesAβCausative agentSurface expressionUbiquitin-proteasome systemReceptor complexAβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61
Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ. Aβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61. Journal Of Neuroscience 2010, 30: 5948-5957. PMID: 20427654, PMCID: PMC2868326, DOI: 10.1523/jneurosci.0157-10.2010.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAnimalsCell LineCells, CulturedCerebral CortexEndocytosisHumansIn Vitro TechniquesMiceMice, KnockoutMice, TransgenicMiddle AgedNeuronsProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateUbiquitinated ProteinsUbiquitinationConceptsAlzheimer's diseaseAbeta treatmentNR2B subunitProtein tyrosine Phosphatase 61Cognitive deficitsNMDA receptor internalizationHuman AD brainsMouse cortical culturesNR1/NR2B receptorsNMDA receptor endocytosisIonotropic glutamate receptorsTyrosine phosphatase STEP61AD brainCortical slicesCortical culturesGlutamate receptorsNR2B receptorsPostsynaptic terminalsPrefrontal cortexNeuronal membranesElevated levelsCortexReceptor internalizationUbiquitin-proteasome systemStep activity
2002
Cloning, expression and characterization of a novel human VMP gene*
Cheng C, Xu J, Ye X, Dai J, Wu Q, Zeng L, Wang L, Zhao W, Ji C, Gu S, Xie Y, Mao Y. Cloning, expression and characterization of a novel human VMP gene*. Molecular Biology Reports 2002, 29: 281-286. PMID: 12463420, DOI: 10.1023/a:1020402410522.Peer-Reviewed Original ResearchConceptsMembrane proteinsVesicular membrane proteinsNovel human genePutative molecular weightNeuron-specific membrane proteinMicrotubule-binding domainPutative membraneRT-PCR analysisHuman genesOrganelle transportVmp genesC-terminalAmino acidsCloningGenesProteinHydrophilic tailImportant roleCDNAMolecular weightMicrotubulesDomainKDaExpression
2001
Cloning, expression and characterization of a novel human REPS1 gene1The nucleotide sequence reported in this paper has been submitted to GenBank under accession number AF251052.1
Xu J, Zhou Z, Zeng L, Huang Y, Zhao W, Cheng C, Xu M, Xie Y, Mao Y. Cloning, expression and characterization of a novel human REPS1 gene1The nucleotide sequence reported in this paper has been submitted to GenBank under accession number AF251052.1. Biochimica Et Biophysica Acta 2001, 1522: 118-121. PMID: 11750063, DOI: 10.1016/s0167-4781(01)00310-4.Peer-Reviewed Original ResearchConceptsHuman fetal brain libraryFetal brain libraryAmino acid identitySignal transduction pathwaysDownstream target proteinsNorthern blot analysisProtein familySmall GTPaseBinding partnerAcid identityTransduction pathwaysNucleotide sequenceVariety of tissuesBrain libraryTarget proteinsReps1Blot analysisProteinRalBP1Recent findingsStrong expressionExpressionRalGTPaseImportant role