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 experimentsPhosphataseInhibitors
2013
Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase
Baguley TD, Xu HC, Chatterjee M, Nairn AC, Lombroso PJ, Ellman JA. Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase. Journal Of Medicinal Chemistry 2013, 56: 7636-7650. PMID: 24083656, PMCID: PMC3875168, DOI: 10.1021/jm401037h.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiphenyl CompoundsBlood-Brain BarrierBoronic AcidsCells, CulturedCerebral CortexHumansNeuronsPermeabilityPhosphorous AcidsProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleySmall Molecule LibrariesStereoisomerismStructure-Activity RelationshipSubstrate SpecificityConceptsSubstrate Activity ScreeningProtein tyrosine phosphatase activityProtein tyrosine phosphataseTyrosine phosphatase activityGlutamate receptor internalizationOptimization of fragmentsTyrosine phosphataseDual specificityReceptor internalizationDevelopment of SelectiveSTEP inhibitorPhosphatase activityAlzheimer's diseaseIonotropic glutamate receptorsSubstrate-based approachNonpeptidic inhibitorsPotential targetAD mouse modelDrug discoveryRat cortical neuronsActivity screeningCortical neuronsGlutamate receptorsMouse modelNeuropsychiatric disordersCocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP
Chiodi V, Mallozzi C, Ferrante A, Chen JF, Lombroso PJ, Di Stasi AM, Popoli P, Domenici MR. Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP. Neuropsychopharmacology 2013, 39: 569-578. PMID: 23989619, PMCID: PMC3895235, DOI: 10.1038/npp.2013.229.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCerebral CortexCocaineCorpus StriatumDopamine Uptake InhibitorsEnzyme InhibitorsGene Expression RegulationHumansIn Vitro TechniquesInhibitory Postsynaptic PotentialsMaleMiceMice, Inbred C57BLMice, KnockoutNeural PathwaysNeuronsProtein Tyrosine Phosphatases, Non-ReceptorReceptor, Adenosine A2ASynaptic TransmissionSynaptosomesVanadatesConceptsEffects of cocaineSynaptic transmissionAdenosine A2A receptorsStriatal-enriched protein tyrosine phosphatasePharmacological actionsA2A receptorsWhole-cell voltage-clamp recordingsA2AR antagonist ZM241385Excitatory post-synaptic currentsCocaine-induced reductionMedium spiny neuronsCocaine-induced changesVoltage-clamp recordingsPost-synaptic currentsA2AR knockout miceCorticostriatal slicesStriatal slicesPsychomotor effectsSpiny neuronsSynaptic mechanismsAntagonist ZM241385Synaptic depressionClamp recordingsBrain areasStriatum
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 plasticity
2011
Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders
Goebel-Goody SM, Baum M, Paspalas CD, Fernandez SM, Carty NC, Kurup P, Lombroso PJ. Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders. Pharmacological Reviews 2011, 64: 65-87. PMID: 22090472, PMCID: PMC3250079, DOI: 10.1124/pr.110.003053.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseProtein tyrosine phosphataseTyrosine phosphataseStress-activated protein kinase p38Extracellular regulated kinases 1Brain-specific phosphataseSrc family tyrosine kinase FynProtein kinase p38Tyrosine kinase FynN-methyl-D-aspartate receptorsFragile X syndromeDephosphorylation of ERK1/2Stroke/ischemiaSurface NMDARsKinase FynAlcohol-induced memory lossDiverse neuropsychiatric disordersLocal translationKinase 1Kinase p38STEP expressionX syndromeNeuronal functionDephosphorylationFunction contributes
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 modelsAβ-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
2009
Conceptualizing Autism: The Role for Emergence
Lombroso P, Ogren M, Anderson G. Conceptualizing Autism: The Role for Emergence. Journal Of The American Academy Of Child & Adolescent Psychiatry 2009, 48: 688-691. PMID: 19542823, DOI: 10.1097/chi.0b013e3181a5e3d5.Peer-Reviewed Original ResearchAdolescentAptitudeAutistic DisorderBrainChildComorbidityDiseases in TwinsEpistasis, GeneticGenetic Predisposition to DiseaseGenotypeHumansIntellectual DisabilityMultifactorial InheritancePhenotypeReceptor, Serotonin, 5-HT2AReflex, AbnormalSeizuresSelf-Injurious BehaviorSerotoninStereotyped BehaviorSystems TheoryYoung AdultHeterogeneity and Homogeneity Across the Autism Spectrum: The Role of Development
Lombroso P, Ogren M, Jones W, Klin A. Heterogeneity and Homogeneity Across the Autism Spectrum: The Role of Development. Journal Of The American Academy Of Child & Adolescent Psychiatry 2009, 48: 471-473. PMID: 19395902, DOI: 10.1097/chi.0b013e31819f6c0d.Peer-Reviewed Original Research
2006
Synaptic plasticity: one STEP at a time
Braithwaite SP, Paul S, Nairn AC, Lombroso PJ. Synaptic plasticity: one STEP at a time. Trends In Neurosciences 2006, 29: 452-458. PMID: 16806510, PMCID: PMC1630769, DOI: 10.1016/j.tins.2006.06.007.Peer-Reviewed Original Research
2003
Receptor and nonreceptor protein tyrosine phosphatases in the nervous system
Paul S, Lombroso P. Receptor and nonreceptor protein tyrosine phosphatases in the nervous system. Cellular And Molecular Life Sciences 2003, 60: 2465-2482. PMID: 14625689, PMCID: PMC11138652, DOI: 10.1007/s00018-003-3123-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainHumansIntracellular Signaling Peptides and ProteinsMitogen-Activated Protein KinasesNerve Tissue ProteinsProtein Tyrosine Phosphatase, Non-Receptor Type 11Protein Tyrosine Phosphatase, Non-Receptor Type 6Protein Tyrosine PhosphatasesProtein Tyrosine Phosphatases, Non-ReceptorReceptor-Like Protein Tyrosine Phosphatases, Class 2Receptor-Like Protein Tyrosine Phosphatases, Class 5Receptors, Cell SurfaceSignal TransductionConceptsProtein tyrosineNonreceptor protein tyrosineDual-specific phosphataseCellular signaling pathwaysNervous systemSignaling pathwaysCellular localizationPhysiological functionsFunctional rolePTPCentral nervous systemIntracellular mechanismsTyrosineImportant rolePhosphatasePathwayRoleLocalizationFunctionReceptors
2002
Genetics of Childhood Disorders: XLIV. Autism, Part 3: Psychopharmacology of Autism
MCDOUGLE C, POSEY D, Lombroso P. Genetics of Childhood Disorders: XLIV. Autism, Part 3: Psychopharmacology of Autism. Journal Of The American Academy Of Child & Adolescent Psychiatry 2002, 41: 1380-1383. PMID: 12410082, DOI: 10.1097/00004583-200211000-00021.Peer-Reviewed Original ResearchGenetics of Childhood Disorders: XLIII. Autism, Part 2: Neural Foundations
SCHULTZ R, KLIN A, Lombroso P. Genetics of Childhood Disorders: XLIII. Autism, Part 2: Neural Foundations. Journal Of The American Academy Of Child & Adolescent Psychiatry 2002, 41: 1259-1262. PMID: 12364850, DOI: 10.1097/00004583-200210000-00018.Peer-Reviewed Original ResearchGenetics of Childhood Disorders: XLI. Stem Cell Research, Part 5: Ethical Questions
OUTKA G, Lombroso P. Genetics of Childhood Disorders: XLI. Stem Cell Research, Part 5: Ethical Questions. Journal Of The American Academy Of Child & Adolescent Psychiatry 2002, 41: 1017-1019. PMID: 12162620, DOI: 10.1097/00004583-200208000-00023.Peer-Reviewed Original Research
2001
Genetics of Childhood Disorders: XXXII. Autoimmune Disorders, Part 5: Streptococcal Infection and Autoimmunity, an Epidemiological Perspective
BESSEN D, Lombroso P. Genetics of Childhood Disorders: XXXII. Autoimmune Disorders, Part 5: Streptococcal Infection and Autoimmunity, an Epidemiological Perspective. Journal Of The American Academy Of Child & Adolescent Psychiatry 2001, 40: 1346-1348. PMID: 11699810, DOI: 10.1097/00004583-200111000-00016.Peer-Reviewed Original ResearchGenetics of Childhood Disorders: XXXI. Autoimmune Disorders, Part 4: Is Sydenham Chorea an Autoimmune Disorder?
LOISELLE C, SINGER H, Lombroso P. Genetics of Childhood Disorders: XXXI. Autoimmune Disorders, Part 4: Is Sydenham Chorea an Autoimmune Disorder? Journal Of The American Academy Of Child & Adolescent Psychiatry 2001, 40: 1234-1236. PMID: 11589538, DOI: 10.1097/00004583-200110000-00019.Peer-Reviewed Original ResearchAntibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette’s syndrome, Sydenham’s chorea, and autoimmune disorders
Morshed S, Parveen S, Leckman J, Mercadante M, Kiss M, Miguel E, Arman A, Yazgan Y, Fujii T, Paul S, Peterson B, Zhang H, King R, Scahill L, Lombroso P. Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette’s syndrome, Sydenham’s chorea, and autoimmune disorders. Biological Psychiatry 2001, 50: 566-577. PMID: 11690591, DOI: 10.1016/s0006-3223(01)01096-4.Peer-Reviewed Original ResearchConceptsTotal antinuclear antibodiesAntinuclear antibodiesAutoimmune disordersTourette syndromeAnticytoskeletal antibodiesAntineural antibodiesStreptococcal infectionT patientsTS patientsBeta-hemolytic streptococcal infectionPrior streptococcal infectionHemolytic streptococcal infectionAntistreptolysin O titerIndirect immunofluorescent assayLevels of immunoreactivityWestern blot techniqueMean rankClinical characteristicsSydenham's choreaO titerPatient groupSC patientsIgG antibodiesIgG classNormal controlsGenetics of Childhood Disorders: XXX. Autoimmune Disorders, Part 3: Myasthenia Gravis and Rasmussen's Encephalitis
LOMBROSO P, MERCADANTE M, Lombroso P. Genetics of Childhood Disorders: XXX. Autoimmune Disorders, Part 3: Myasthenia Gravis and Rasmussen's Encephalitis. Journal Of The American Academy Of Child & Adolescent Psychiatry 2001, 40: 1115-1117. PMID: 11556637, DOI: 10.1097/00004583-200109000-00022.Peer-Reviewed Original ResearchGenetics of Childhood Disorders: XXVIII. Autoimmunity, Part I
MORSHED S, MERCADANTE M, LOMBROSO P, Lombroso P. Genetics of Childhood Disorders: XXVIII. Autoimmunity, Part I. Journal Of The American Academy Of Child & Adolescent Psychiatry 2001, 40: 855-858. PMID: 11437025, DOI: 10.1097/00004583-200107000-00021.Peer-Reviewed Original ResearchGenetics of Childhood Disorders: XXVII. Genes and Cognition in Williams Syndrome
OSBORNE L, POBER B, Lombroso P. Genetics of Childhood Disorders: XXVII. Genes and Cognition in Williams Syndrome. Journal Of The American Academy Of Child & Adolescent Psychiatry 2001, 40: 732-735. PMID: 11392353, DOI: 10.1097/00004583-200106000-00021.Peer-Reviewed Original Research