2024
Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism
Takahashi H, Perez-Canamas A, Lee C, Ye H, Han X, Strittmatter S. Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism. Communications Biology 2024, 7: 1088. PMID: 39237682, PMCID: PMC11377756, DOI: 10.1038/s42003-024-06810-5.Peer-Reviewed Original ResearchConceptsMyelin lipid metabolismCo-immunoprecipitation assaysSulfated derivative sulfatideLipid metabolismAssociated with multiple neurological disordersCo-immunoprecipitationTMEM106BTransmembrane proteinsAmyloid fibrilsTMEM106B deficiencyHypomyelinating leukodystrophyAlzheimer's diseasePhysiological functionsFrontotemporal dementiaMolecular levelNeurodegenerative brainGalactosylceramidaseLipidomic analysisMultiple neurological disordersMetabolismMyelin lipidsDecreased levelsEndolysosomesAmyloidGalactosylceramidase activity
2023
Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions
de Arce K, Ribic A, Chowdhury D, Watters K, Thompson G, Sanganahalli B, Lippard E, Rohlmann A, Strittmatter S, Missler M, Hyder F, Biederer T. Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions. Nature Communications 2023, 14: 459. PMID: 36709330, PMCID: PMC9884278, DOI: 10.1038/s41467-023-36042-w.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Adhesion Molecule-1CognitionMembrane ProteinsMiceMice, KnockoutNerve Tissue ProteinsPrefrontal CortexSynapsesConceptsPrefrontal cortexDKO miceSynCAM 1Aberrant neuronal activityDendritic spine numberPrefrontal cortex synapsesSynapse organizersSynapse numberMature brainNeuronal activityKnockout miceSpine numberSynapse developmentCognitive functionTrans-synaptic complexesImmunoglobulin family membersMiceFamily membersSynapsesLRRTM1Behavioral domainsHippocampusCognitive tasksConcerted roleCortex
2022
Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2
Rodriguez CM, Bechek SC, Jones GL, Nakayama L, Akiyama T, Kim G, Solow-Cordero DE, Strittmatter SM, Gitler AD. Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2. Cell Reports 2022, 41: 111505. PMID: 36288715, PMCID: PMC9664481, DOI: 10.1016/j.celrep.2022.111505.Peer-Reviewed Original ResearchConceptsAmyotrophic lateral sclerosisSpinocerebellar ataxia type 2Nogo receptorAtaxin-2 levelsNovel therapeutic targetNeurodegenerative disease amyotrophic lateral sclerosisGene-based therapeutic strategiesDisease amyotrophic lateral sclerosisNerve injuryAtaxin-2Axonal regenerationAxonal regrowthLateral sclerosisTherapeutic strategiesHuman neuronsKnockout miceTherapeutic targetPotential treatmentType 2Protein levelsPotent modifierProtein ataxin-2Additional strategiesMiceRNA screenAlzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy
Brody AH, Nies SH, Guan F, Smith LM, Mukherjee B, Salazar SA, Lee S, Lam TKT, Strittmatter SM. Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy. Molecular Neurodegeneration 2022, 17: 32. PMID: 35501917, PMCID: PMC9063299, DOI: 10.1186/s13024-022-00526-y.Peer-Reviewed Original ResearchConceptsPS19 miceTau phosphorylationDisease riskPyk2 expressionPyk2 activityHuman neuronal culturesAlzheimer's disease riskNeuro-inflammationSynapse lossTau accumulationTau pathologyMouse survivalC1q depositionT cellsAssociated pathologyMouse modelLittermate controlsMAPK activityHuman neuronsHuman tauNeuronal culturesPyk2 inhibitionVivo modelMouse brainSynaptic function
2021
Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
Nies SH, Takahashi H, Herber CS, Huttner A, Chase A, Strittmatter SM. Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β. Journal Of Biological Chemistry 2021, 297: 101159. PMID: 34480901, PMCID: PMC8477193, DOI: 10.1016/j.jbc.2021.101159.Peer-Reviewed Original ResearchMeSH KeywordsAgingAlzheimer DiseaseAmyloid beta-PeptidesAnimalsCerebral CortexHippocampusMiceMice, KnockoutNeuritesTau ProteinsConceptsTau seedsAlzheimer's diseaseAD model miceWT mouse brainPathological tauSynaptic lossTau accumulationWT miceMouse tauTau pathologyTau burdenModel miceTau inclusionsPharmacological interventionsAD riskCognitive declineMouse brainTau aggregatesPyk2 kinaseKnowledge of factorsKinase inhibitorsMiceFyn kinase inhibitorAβMouse agingB-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF
Bakhuraysah MM, Theotokis P, Lee JY, Alrehaili AA, Aui PM, Figgett WA, Azari MF, Abou-Afech JP, Mackay F, Siatskas C, Alderuccio F, Strittmatter SM, Grigoriadis N, Petratos S. B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF. Scientific Reports 2021, 11: 2890. PMID: 33536561, PMCID: PMC7858582, DOI: 10.1038/s41598-021-82346-6.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisEAE-induced miceB cellsB-cell activating factorMeningeal B cellsLumbosacral spinal cordSecretion of immunoglobulinsG0/G1 phaseImmune cell signalingNeurological progressionAutoimmune encephalomyelitisInflammatory infiltrateAxonal dystrophyCentral nervous system myelinSpinal cordRecombinant BAFFActivating factorNgR1Score 1BAFFBAFF stimulationInfiltratesNgR3System myelinG1 phase
2019
Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma
Sekine Y, Algarate PT, Cafferty WBJ, Strittmatter SM. Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma. Journal Of Neuroscience 2019, 39: 3204-3216. PMID: 30804090, PMCID: PMC6788813, DOI: 10.1523/jneurosci.2996-18.2019.Peer-Reviewed Original ResearchConceptsCNS traumaNeural repairMouse cervical spinal cordSpinal cord traumaCervical spinal cordNon-neuronal cellsInteraction of NogoAxon growth inhibitionAxonal guidance mechanismsNeurological recoveryAxonal sproutingCNS pathwaysCord traumaFunctional recoveryAxon sproutingSpinal cordNgR1 functionUnilateral pyramidotomyAxon regenerationAdult traumaNgR1TraumaAxon growthNogoCytoplasmic mediatorsSystematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance
Smith LM, Kostylev MA, Lee S, Strittmatter SM. Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance. Journal Of Biological Chemistry 2019, 294: 6042-6053. PMID: 30787106, PMCID: PMC6463724, DOI: 10.1074/jbc.ra118.006252.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseAD brainLeukocyte immunoglobulin-like receptorsNogo receptor 1Human AD brainsImmunoglobulin-like receptorsB member 2Brains of individualsReceptor candidatesSoluble AβOsDisease relevanceCell surface expressionHippocampal neuronsMouse modelSynthetic AβAβO bindingMemory impairmentReceptor 1Cellular prion proteinNeuronal synapsesNgR1Molecular pathologyAβAβ speciesMember 2Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss
Lee S, Salazar SV, Cox TO, Strittmatter SM. Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss. Journal Of Neuroscience 2019, 39: 1910-1929. PMID: 30626696, PMCID: PMC6407289, DOI: 10.1523/jneurosci.2983-18.2018.Peer-Reviewed Original ResearchConceptsDendritic spine lossGenetic variationRhoA GTPaseSynapse lossSpine lossBiochemical basisGTPase-activating proteinsFocal adhesion kinasePyk2 functionPyk2 tyrosine kinasePostsynaptic sitesTyrosine kinase Pyk2Disease riskKinase-dependent mechanismOverexpression of Pyk2Dendritic spine densityAdhesion kinaseTransgenic mouse modelBiochemical isolationPyk2 kinaseAlzheimer's disease riskDendritic spine stabilityKinase Pyk2Late-onset Alzheimer's disease (LOAD) riskActin control
2018
Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss
Salazar SV, Cox TO, Lee S, Brody AH, Chyung AS, Haas LT, Strittmatter SM. Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss. Journal Of Neuroscience 2018, 39: 758-772. PMID: 30518596, PMCID: PMC6343652, DOI: 10.1523/jneurosci.1873-18.2018.Peer-Reviewed Original ResearchConceptsTransgenic AD model miceAD model miceAbsence of Pyk2Synaptic dysfunctionModel miceHippocampal slicesSynaptic transmissionAlzheimer's diseaseAmyloid-β plaque pathologyHippocampal Schaffer collateral pathwayDisease riskLearning/memory deficitsDeletion of Pyk2Suppression of LTPBasal synaptic transmissionLate-onset Alzheimer's diseaseImpairment of learningSchaffer collateral pathwayAD-related synaptic dysfunctionAlzheimer's disease riskLate-onset Alzheimer's disease (LOAD) riskOnset Alzheimer's diseaseAge-dependent lossMechanism of actionSynaptic LTDThe nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury
Sekine Y, Siegel CS, Sekine-Konno T, Cafferty WBJ, Strittmatter SM. The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury. Science Signaling 2018, 11 PMID: 29615517, PMCID: PMC6179440, DOI: 10.1126/scisignal.aao4180.Peer-Reviewed Original ResearchConceptsSpinal cord injuryCord injuryAxonal regenerationMid-thoracic spinal cordTraumatic spinal cord injuryPartial neurological recoveryTraumatic CNS injuryDorsal hemisectionNeurological recoveryPeptide nociceptinCNS injuryAxon sproutingORL1 agonistSelective blockadeSpinal cordLocomotor functionNociceptin receptorAxon regenerationNeural repairPrimary neuronsNgR1 proteinAxonal growthNull miceMRNA expressionORL1Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration
Sekine Y, Lin-Moore A, Chenette DM, Wang X, Jiang Z, Cafferty WB, Hammarlund M, Strittmatter SM. Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration. Cell Reports 2018, 23: 415-428. PMID: 29642001, PMCID: PMC5937716, DOI: 10.1016/j.celrep.2018.03.058.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsCaenorhabditis elegansCaenorhabditis elegans ProteinsCentral Nervous SystemFemaleGene Regulatory NetworksGenomeMiceMice, Inbred C57BLMice, KnockoutNerve RegenerationOptic NerveRab GTP-Binding ProteinsRecovery of FunctionRetinal Ganglion CellsRNA InterferenceRNA, Small InterferingSpinal Cord InjuriesSuppressor of Cytokine Signaling ProteinsConceptsAxonal regenerationCentral nervous system axonal regenerationRetinal ganglion cell axon regenerationGreater motor functionOptic nerve crushCerebral cortical neuronsSpinal cord traumaNeurological recoveryCord traumaNerve crushCNS injuryAxonal regrowthCortical neuronsMotor functionAxon regenerationReceptor bindingComprehensive functional screenAdult mammalsInjuryMultiple pathwaysExpression profilesIdentifies pathwaysSignificant overlapPathwayFunction screen
2017
Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease
Salazar SV, Gallardo C, Kaufman AC, Herber CS, Haas LT, Robinson S, Manson JC, Lee MK, Strittmatter SM. Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease. Journal Of Neuroscience 2017, 37: 9207-9221. PMID: 28842420, PMCID: PMC5607466, DOI: 10.1523/jneurosci.0722-17.2017.Peer-Reviewed Original ResearchConceptsDisease onsetAlzheimer's diseaseFamilial Alzheimer's diseaseDisease pathophysiologyCellular prion proteinHippocampal synapse lossSoluble oligomeric amyloidTransgenic Alzheimer's diseaseTime of diagnosisDisease-modifying therapiesAlzheimer's disease pathophysiologyPotential therapeutic targetAD-related phenotypesMonths of ageRole of PrPSymptom onsetSynaptic deficitsPrion proteinSynapse lossCatecholaminergic neuronsPlaque densityBehavioral deficitsOligomeric amyloidMouse modelPresent symptomsLoss 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 levelsProtein Tyrosine Phosphatase δ Mediates the Sema3A-Induced Cortical Basal Dendritic Arborization through the Activation of Fyn Tyrosine Kinase
Nakamura F, Okada T, Shishikura M, Uetani N, Taniguchi M, Yagi T, Iwakura Y, Ohshima T, Goshima Y, Strittmatter SM. Protein Tyrosine Phosphatase δ Mediates the Sema3A-Induced Cortical Basal Dendritic Arborization through the Activation of Fyn Tyrosine Kinase. Journal Of Neuroscience 2017, 37: 7125-7139. PMID: 28637841, PMCID: PMC6705738, DOI: 10.1523/jneurosci.2519-16.2017.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedCerebral CortexDendritesEnzyme ActivationFemaleGene Expression Regulation, EnzymologicMaleMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicNeuronal PlasticityProtein-Tyrosine KinasesProto-Oncogene Proteins c-fynReceptor-Like Protein Tyrosine Phosphatases, Class 2Semaphorin-3AConceptsCortical dendritic growthBasal dendritesCultured dorsal root ganglion neuronsCortical layer V neuronsPrimary cultured dorsal root ganglion (DRG) neuronsDorsal root ganglion neuronsWild-type cortical neuronsBasal dendritic arborizationLayer V neuronsAxon guidanceDouble heterozygous mutantsSpecific guidance cuesProtein tyrosine phosphatase δAxon guidance cuesPoor arborizationV neuronsGuidance cuesGanglion neuronsDendritic arborizationCortical neuronsMutant miceSemaphorin 3ASrc kinaseActivation of FynGrowth cone collapse response
2016
Axonal branching in lateral olfactory tract is promoted by Nogo signaling
Iketani M, Yokoyama T, Kurihara Y, Strittmatter SM, Goshima Y, Kawahara N, Takei K. Axonal branching in lateral olfactory tract is promoted by Nogo signaling. Scientific Reports 2016, 6: 39586. PMID: 28000762, PMCID: PMC5175167, DOI: 10.1038/srep39586.Peer-Reviewed Original ResearchConceptsLateral olfactory tractCultured OB neuronsOB neuronsCollateral branchesAxonal branchingOlfactory bulbOlfactory tractAxonal bundlesMajor projection neuronsReceptor 1 antagonistKnockdown of NogoCollateral formationProjection neuronsPrimary axonsNogo signalingMitral cellsMiceNeuronsExpression levelsAbnormal increaseTractNogoAntagonistAxons
2015
Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease
Haas LT, Salazar SV, Kostylev MA, Um JW, Kaufman AC, Strittmatter SM. Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease. Brain 2015, 139: 526-546. PMID: 26667279, PMCID: PMC4840505, DOI: 10.1093/brain/awv356.Peer-Reviewed Original ResearchConceptsCellular prion proteinDisease-related phenotypesPrion proteinMetabotropic glutamate receptor 5Glutamate receptor 5Protein tyrosine kinase 2 betaCalmodulin-dependent protein kinase IICalcium/calmodulin-dependent protein kinase IIProtein kinase IIReceptor 5Protein associatesGenetic interactionsObligate complexesGenetic couplingDisease pathogenesisDisease pathologyKinase IIIntracellular proteinsAlzheimer's disease-related phenotypesSingle heterozygotesProteinBiochemical evidenceProtein mediatorsDisease-modifying interventionsTransgenic model miceGene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury
Zou Y, Stagi M, Wang X, Yigitkanli K, Siegel CS, Nakatsu F, Cafferty WB, Strittmatter SM. Gene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury. Journal Of Neuroscience 2015, 35: 10429-10439. PMID: 26203138, PMCID: PMC4510284, DOI: 10.1523/jneurosci.1718-15.2015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsDisease Models, AnimalGene Knockdown TechniquesImmunohistochemistryInositol Polyphosphate 5-PhosphatasesMiceMice, Inbred C57BLMice, KnockoutNerve RegenerationPhosphoric Monoester HydrolasesRecovery of FunctionReverse Transcriptase Polymerase Chain ReactionSpinal Cord InjuriesConceptsSpinal cord injuryCord injuryEndogenous suppressorAxon regenerationNonoverlapping substrate specificityGenome-wide scaleHigh-throughput functional screensFunctional recoveryAxonal regenerationCNS axon repairSpinal cord injury researchDorsal hemisection injuryMammalian genesPI3K/AKT/mTOR pathwayCNS axon growthAKT/mTOR pathwayLipid phosphataseCorticospinal tract axonsCNS axon regenerationAdult mammalian CNSFunctional screenSubstrate specificityNovel suppressorShRNA resultsINPP5FSac2/INPP5F is an inositol 4-phosphatase that functions in the endocytic pathway
Nakatsu F, Messa M, Nández R, Czapla H, Zou Y, Strittmatter SM, De Camilli P. Sac2/INPP5F is an inositol 4-phosphatase that functions in the endocytic pathway. Journal Of Cell Biology 2015, 209: 85-95. PMID: 25869668, PMCID: PMC4395491, DOI: 10.1083/jcb.201409064.Peer-Reviewed Original ResearchConceptsEndocytic membranesPosition of inositolRecruitment of inositolSAC domainEndocytic pathwayPlasma membraneINPP5FSequential dephosphorylationOCRLDephosphorylationEndocytosisSynaptojaninRab5EndosomesYeastInositolMembranePhosphataseMacropinosomesClathrinCoimmunoprecipitationPtdInsPhosphoinositideVesiclesPathway
2014
Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice
Hafler BP, Klein ZA, Zhou Z, Strittmatter SM. Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice. Brain Research 2014, 1588: 168-174. PMID: 25234724, PMCID: PMC4254024, DOI: 10.1016/j.brainres.2014.09.023.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedElectroretinographyGranulinsImmunohistochemistryIntercellular Signaling Peptides and ProteinsMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalNeuronal Ceroid-LipofuscinosesOptical ImagingPhotoreceptor Cells, VertebrateProgranulinsRetinal DegenerationRetinal Ganglion CellsConceptsProgranulin-deficient miceNeuronal ceroid lipofuscinosisAdult-onset neuronal ceroid lipofuscinosisDeficient miceRetinal degenerationCeroid lipofuscinosisRetinal ganglion cellsCentral nervous systemAutofluorescent storage materialMotor dysfunctionNeuropathological analysisGanglion cellsVision lossOptic atrophyEarly deathAutofluorescent lipopigmentsClinical observationsNervous systemDegenerative pathologyMiceDegenerationHomozygous mutationAutofluorescent materialPatientsNeurons