2024
Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila
Liao J, Chung H, Shih C, Wong K, Dutta D, Nil Z, Burns C, Kanca O, Park Y, Zuo Z, Marcogliese P, Sew K, Bellen H, Verheyen E. Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila. Nature Communications 2024, 15: 3326. PMID: 38637532, PMCID: PMC11026413, DOI: 10.1038/s41467-024-47623-8.Peer-Reviewed Original ResearchConceptsMitochondrial fissionRNA polymerase IINon-nuclear functionsDrp1-mediated fissionPhosphorylation of Drp1Elevated levels of ROSMitochondrial kinaseBang sensitivityLevels of PINK1Polymerase IIFly lifespanPhosphorylated Drp1PINK1 deficiencyDrp1 phosphorylationTranscriptional controlElongated mitochondriaLevels of ROSOverexpression of CDK8CDK8Drp1Mitochondrial dysmorphologyBehavioral defectsPINK1DrosophilaCytoplasm
2023
Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)
Lin G, Tepe B, McGrane G, Tipon R, Croft G, Panwala L, Hope A, Liang A, Zuo Z, Byeon S, Wang L, Pandey A, Bellen H. Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14). ELife 2023, 12: e82555. PMID: 36645408, PMCID: PMC9889087, DOI: 10.7554/elife.82555.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCeramidesDrosophilaDrosophila ProteinsEye ProteinsGroup VI Phospholipases A2MiceNeuroaxonal DystrophiesNeuronsParkinsonian DisordersConceptsPatient-derived neural progenitor cellsNeural progenitor cellsPatient-derived neuronsPediatric neurodegenerative disorderRetromer functionMitochondrial morphologyEndolysosomal pathwayMitochondrial defectsProlong lifespanNeurodegenerative phenotypeProgenitor cellsMouse modelRecessive variantsNeurodegenerative disordersGene therapy approachesPathwayInfantile neuroaxonal dystrophyHomologCellsTherapeutic strategiesAzoramidePurkinje cellsFliesPhenotypeMetabolism
2022
Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling
Marcogliese P, Dutta D, Ray S, Dang N, Zuo Z, Wang Y, Lu D, Fazal F, Ravenscroft T, Chung H, Kanca O, Wan J, Douine E, Network U, Pena L, Yamamoto S, Nelson S, Might M, Meyer K, Yeo N, Bellen H. Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling. Science Advances 2022, 8: eabl5613. PMID: 35044823, PMCID: PMC8769555, DOI: 10.1126/sciadv.abl5613.Peer-Reviewed Original ResearchConceptsAxonal lossPatient-derived astrocytesChildhood-onset neurodegenerative disordersNeuronal depletionNeural dysfunctionNeuronal expressionNeurological defectsPharmacological inhibitionNeurodegenerative disordersNeuronal maintenanceNeurological phenotypeWnt antagonistsDownstream signalingIRF2BPLBinding proteinInhibitionWntSignalingWnt transcriptionAstrocytesDysfunctionAntagonistBrain
2020
Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain
Ye H, Ojelade S, Li-Kroeger D, Zuo Z, Wang L, Li Y, Gu J, Tepass U, Rodal A, Bellen H, Shulman J. Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain. ELife 2020, 9: e51977. PMID: 32286230, PMCID: PMC7182434, DOI: 10.7554/elife.51977.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsBrainDrosophilaDrosophila ProteinsEndosomesLysosomesSynaptic TransmissionVesicular Transport ProteinsConceptsRetromer functionRetromer localizationVps26 proteinsRetromer subunitsRab7 GTPaseProtein complexesEndolysosomal functionEndolysosomal pathwayLysosomal stressVPS29Endolysosomal dysfunctionSynaptic transmissionSubstrate clearanceRetromerGTPaseProteinVPS35Adult brainBrain homeostasisAlzheimer's diseaseTBC1D5Vps26Ultrastructural evidenceEmbryogenesisMutants
2019
cindr, the Drosophila Homolog of the CD2AP Alzheimer’s Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis
Ojelade S, Lee T, Giagtzoglou N, Yu L, Ugur B, Li Y, Duraine L, Zuo Z, Petyuk V, De Jager P, Bennett D, Arenkiel B, Bellen H, Shulman J. cindr, the Drosophila Homolog of the CD2AP Alzheimer’s Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis. Cell Reports 2019, 28: 1799-1813.e5. PMID: 31412248, PMCID: PMC6703184, DOI: 10.1016/j.celrep.2019.07.041.Peer-Reviewed Original ResearchConceptsPlasma membrane calcium ATPaseDisease risk genesDisease susceptibility genesSynaptic vesicle recyclingUbiquitin-proteasome systemMembrane calcium ATPaseAlzheimer’s disease risk genesDrosophila homologConserved roleAlzheimer's disease susceptibility genesSynaptic proteostasisAdaptor proteinNeuronal requirementsVesicle recyclingProteostasisCindrRisk genesSusceptibility genesSynapse maturationHuman postmortem brainHuman tauProtein levelsNeurofibrillary tangle pathologyNull miceAD susceptibilityUbiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification
Şentürk M, Lin G, Zuo Z, Mao D, Watson E, Mikos A, Bellen H. Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification. Nature Cell Biology 2019, 21: 384-396. PMID: 30804504, PMCID: PMC6534127, DOI: 10.1038/s41556-019-0281-x.Peer-Reviewed Original ResearchMeSH KeywordsAmyotrophic Lateral SclerosisAnimalsAnimals, Genetically ModifiedAutophagyCarrier ProteinsCell Cycle ProteinsDrosophila melanogasterDrosophila ProteinsGene Expression Regulation, DevelopmentalHEK293 CellsHumansHydrogen-Ion ConcentrationLysosomesMutationNervous SystemSignal TransductionTOR Serine-Threonine KinasesConceptsAutophagic fluxDefective autophagic fluxEndoplasmic reticulum stressReticulum stressRegulator of autophagyConserved roleAmyotrophic lateral sclerosisMammalian cellsProteasomal degradationImpaired proteostasisDemise of neuronsUbiquilinLysosome acidificationFamilial amyotrophic lateral sclerosisLysosomal acidificationATPase activityMTORMutantsAutophagyDrosophilaProteostasisAcidificationCommon featureGenesLateral sclerosisVAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway
Mao D, Lin G, Tepe B, Zuo Z, Tan K, Senturk M, Zhang S, Arenkiel B, Sardiello M, Bellen H. VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway. Autophagy 2019, 15: 1214-1233. PMID: 30741620, PMCID: PMC6613884, DOI: 10.1080/15548627.2019.1580103.Peer-Reviewed Original ResearchAnimalsAutophagosomesAutophagyCarrier ProteinsDrosophilaDrosophila ProteinseIF-2 KinaseEndoplasmic ReticulumEndosomesGolgi ApparatusHEK293 CellsHeLa CellsHumansLysosomal-Associated Membrane Protein 2LysosomesMembrane ProteinsMiceMice, Inbred C57BLMutationPhosphatidylinositol Phosphatesrab GTP-Binding Proteinsrab7 GTP-Binding ProteinsR-SNARE ProteinsVesicular Transport Proteins
2018
Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain
Lin G, Lee P, Chen K, Mao D, Tan K, Zuo Z, Lin W, Wang L, Bellen H. Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain. Cell Metabolism 2018, 28: 605-618.e6. PMID: 29909971, DOI: 10.1016/j.cmet.2018.05.019.Peer-Reviewed Original ResearchMeSH Keywordsalpha-SynucleinAnimalsBrainCell Line, TumorCeramidesDrosophilaDrosophila ProteinsFeedback, PhysiologicalFemaleGroup VI Phospholipases A2Group X Phospholipases A2HeLa CellsHumansLysosomesMaleMembrane FluidityMutationNeuronsNuclear ProteinsParkinson DiseaseRNA-Binding ProteinsSphingolipidsVesicular Transport ProteinsConceptsIPLA2-VIAImpairs synaptic transmissionEarly-onset parkinsonismSynaptic transmissionNeuroaxonal dystrophyParkinson's diseaseNeuronal functionBrain tissueNeurodegenerative disordersΑ-synucleinPLA2G6Ceramide levelsProgressive increaseNeurodegenerationLysosomal stressPositive feedback loopRetromer functionPhospholipid compositionCeramideGlycerol phospholipidsParkinsonismVPS35DesipramineA gene-specific T2A-GAL4 library for Drosophila
Lee P, Zirin J, Kanca O, Lin W, Schulze K, Li-Kroeger D, Tao R, Devereaux C, Hu Y, Chung V, Fang Y, He Y, Pan H, Ge M, Zuo Z, Housden B, Mohr S, Yamamoto S, Levis R, Spradling A, Perrimon N, Bellen H. A gene-specific T2A-GAL4 library for Drosophila. ELife 2018, 7: e35574. PMID: 29565247, PMCID: PMC5898912, DOI: 10.7554/elife.35574.Peer-Reviewed Original ResearchConceptsFunction phenotypesIntrons of genesExpression of hundredsCell-type specificityLethal insertionsEssential genesGene functionEndogenous promoterLethal mutationsCDNA constructsGene expressionInserted cassettesGenesPowerful resourceExpressionPhenotypeSignal 3DrosophilaGAL4Severe lossIntronsChromosomesTranscriptionCRISPRPromoter
2017
The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission
Ugur B, Bao H, Stawarski M, Duraine LR, Zuo Z, Lin YQ, Neely GG, Macleod GT, Chapman ER, Bellen HJ. The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission. Cell Reports 2017, 21: 3794-3806. PMID: 29281828, PMCID: PMC5747319, DOI: 10.1016/j.celrep.2017.12.005.Peer-Reviewed Original ResearchConceptsSynaptic vesiclesKrebs cycle enzymeRole of metabolitesC2 domainPlasma membraneMitochondrial metabolismSynaptic transmissionMetabolic regulationCycle enzymesSynaptic roleAlpha-ketoglutarateSyt1ΑKGNeurodegenerative disordersDependent processesRegulationMetabolitesIDH3ASynaptotagmin1Multiple levelsFliesRoleFusionVesiclesATP
2016
WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes
David-Morrison G, Xu Z, Rui Y, Charng W, Jaiswal M, Yamamoto S, Xiong B, Zhang K, Sandoval H, Duraine L, Zuo Z, Zhang S, Bellen H. WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes. Developmental Cell 2016, 36: 139-151. PMID: 26812014, PMCID: PMC4730548, DOI: 10.1016/j.devcel.2015.12.019.Peer-Reviewed Original ResearchConceptsPontin/Reptin complexMTOR activityRapamycin complex 1Energy statusRegulation of metabolismEnergy-dependent activationDrosophila screenEnergy-dependent mannerTTT complexRAG interactionsMTORC1 activityMechanistic targetReptinPhysical interactionRegulatorDimerizationNeuronal dysfunctionComplexesPontinHomologActivationComplexes 1AdaptorAutophagyMTORRab8 directs furrow ingression and membrane addition during epithelial formation in Drosophila melanogaster
Mavor L, Miao H, Zuo Z, Holly R, Xie Y, Loerke D, Blankenship J. Rab8 directs furrow ingression and membrane addition during epithelial formation in Drosophila melanogaster. Development 2016, 143: 892-903. PMID: 26839362, PMCID: PMC4813336, DOI: 10.1242/dev.128876.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsAnimals, Genetically ModifiedCell MembraneCRISPR-Cas SystemsCrosses, GeneticCytoplasmDrosophila melanogasterDrosophila ProteinsEmbryo, NonmammalianEpitheliumExocytosisFemaleGene Expression Regulation, DevelopmentalGolgi ApparatusGTP PhosphohydrolasesGuanosine TriphosphateMaleMembrane ProteinsMicroscopy, ConfocalProtein Structure, Tertiaryrab GTP-Binding ProteinsConceptsFurrow ingressionMembrane additionPlasma membranePlasma membrane furrowsLarge cytoplasmic aggregatesCRISPR/Cas9 technologyIntracellular trafficking pathwaysMembrane furrowsRab8 functionDrosophila embryosDrosophila melanogasterTrafficking pathwaysMembrane compartmentsEndogenous localizationProtein Rab11Early embryosCytoplasmic aggregatesCas9 technologyRab8Membrane storesCell surfaceEpithelial sheetsRab11Cell morphologyCompartmental behavior
2015
A rapid, membrane-dependent pathway directs furrow formation through RalA in the early Drosophila embryo
Holly R, Mavor L, Zuo Z, Blankenship J. A rapid, membrane-dependent pathway directs furrow formation through RalA in the early Drosophila embryo. Development 2015, 142: 2316-2328. PMID: 26092850, PMCID: PMC4510590, DOI: 10.1242/dev.120998.Peer-Reviewed Original ResearchConceptsEarly Drosophila embryoDrosophila embryosFurrow formationPlasma membraneRalA functionMembrane trafficking pathwaysEarly syncytial Drosophila embryoExocyst complex subunitsEarly fly embryoSyncytial Drosophila embryosWild-type embryosMyosin II functionF-actin recruitmentExocyst complexExocytic vesiclesMembrane traffickingFly embryoTrafficking pathwaysComplex subunitsFurrow ingressionChromosomal segregationCytoskeletal remodelingCell divisionCytokinetic furrowRalA