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
2012
Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model
Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA. Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model. Human Molecular Genetics 2012, 21: 3739-3752. PMID: 22523092, PMCID: PMC3412376, DOI: 10.1093/hmg/dds154.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalpainCoculture TechniquesDisease Models, AnimalEnzyme ActivationEnzyme InhibitorsHuntington DiseaseIon Channel GatingMiceModels, BiologicalNeostriatumNeuronsPhosphorylationPhosphotyrosineProtein TransportProtein Tyrosine Phosphatases, Non-ReceptorReceptors, N-Methyl-D-AspartateSynapsesConceptsYAC128 striatumProtein tyrosine phosphatase activationNMDAR localizationCalpain cleavageProtein tyrosine phosphataseTyrosine phosphatase activationEarly synaptic defectsWhole-cell NMDAR currentsDisease mouse modelGluN2B expressionNMDA receptor traffickingMutant huntingtin proteinCalpain inhibitionTyrosine phosphataseHuntington's diseaseFull-length mhttPlasma membranePhosphatase activationC-terminusReceptor traffickingNMDAR traffickingPolyglutamine repeatsMouse modelHuntingtin proteinNMDA receptor localizationGenetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model
Goebel‐Goody S, Wilson‐Wallis E, Royston S, Tagliatela S, Naegele J, Lombroso P. Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model. Genes Brain & Behavior 2012, 11: 586-600. PMID: 22405502, PMCID: PMC3922131, DOI: 10.1111/j.1601-183x.2012.00781.x.Peer-Reviewed Original ResearchConceptsFragile X syndromeFragile X syndrome mouse modelProtein tyrosine phosphataseMental retardation proteinMRNAs downstreamControl translationTyrosine phosphataseGenetic manipulationGenetic basisFMR1 geneLoss of stepsX syndromeSyndrome mouse modelFMRPReceptor activationGlutamate receptor activationExcess levelsSynaptic strengthSynaptic strengtheningBasal levelsC-Fos activationActivationTranscriptionFynMouse model
2011
Striatal-Enriched Protein Tyrosine Phosphatase Expression and Activity in Huntington's Disease: A STEP in the Resistance to Excitotoxicity
Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas JJ, Lombroso PJ, Alberch J, Pérez-Navarro E. Striatal-Enriched Protein Tyrosine Phosphatase Expression and Activity in Huntington's Disease: A STEP in the Resistance to Excitotoxicity. Journal Of Neuroscience 2011, 31: 8150-8162. PMID: 21632937, PMCID: PMC3472648, DOI: 10.1523/jneurosci.3446-10.2011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCalcineurinCell DeathDisease Models, AnimalGene Expression RegulationGene Products, tatHuntingtin ProteinHuntington DiseaseMiceMice, Neurologic MutantsMice, TransgenicMicroinjectionsNerve Tissue ProteinsNuclear ProteinsPhosphorylationProtein Tyrosine Phosphatases, Non-ReceptorQuinolinic AcidSignal TransductionConceptsStriatal-enriched protein tyrosine phosphataseCell deathSTEP expressionPhosphorylation levelsProtein Tyrosine Phosphatase ExpressionProtein tyrosine phosphataseSTEP phosphorylationTyrosine phosphataseProtein kinasePhosphorylated ERK2Phosphatase expressionHuntington's diseaseSTEP proteinMutant huntingtinCalcineurin activityPhosphorylationExon 1STEP protein levelsDisease mouse modelProtein levelsMouse modelMouse striatumTAT-STEPHuntington's disease mouse modelExpression
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 models
2005
Regulation of NMDA receptor trafficking by amyloid-β
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neuroscience 2005, 8: 1051-1058. PMID: 16025111, DOI: 10.1038/nn1503.Peer-Reviewed Original ResearchMeSH KeywordsAlpha7 Nicotinic Acetylcholine ReceptorAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsCalcineurinCell MembraneCerebral CortexCREB-Binding ProteinDisease Models, AnimalElectric ConductivityEndocytosisEnzyme ActivationMiceNeuronsN-MethylaspartateNuclear ProteinsPeptide FragmentsProtein TransportProtein Tyrosine PhosphatasesProtein Tyrosine Phosphatases, Non-ReceptorReceptors, NicotinicReceptors, N-Methyl-D-AspartateSignal TransductionSynapsesTrans-ActivatorsConceptsNMDA receptorsCortical neuronsAlzheimer's diseaseBrains of patientsAlzheimer's disease pathologyNMDA receptor traffickingGenetic mouse modelsΓ-secretase inhibitorApplication of amyloidSurface NMDA receptorsGlutamatergic transmissionSynaptic dysfunctionPersistent depressionTyrosine phosphatase STEPNicotinic receptorsMouse modelDisease processSynaptic plasticityDisease pathologyNeuronsReceptorsAmyloidSurface expressionUnderlying mechanismReceptor trafficking
2002
Genetics of Childhood Disorders: XXXV. Autoimmune Disorders, Part 8: Animal Models for Noninflammatory Autoimmune Disorders of the Brain
HALLETT J, KIESSLING L, Lombroso P. Genetics of Childhood Disorders: XXXV. Autoimmune Disorders, Part 8: Animal Models for Noninflammatory Autoimmune Disorders of the Brain. Journal Of The American Academy Of Child & Adolescent Psychiatry 2002, 41: 223-225. PMID: 11837413, DOI: 10.1097/00004583-200202000-00017.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoimmune Diseases of the Nervous SystemBrainDisease Models, AnimalHypersensitivityImmunizationRatsTourette Syndrome