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
A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels
Dutta D, Kanca O, Byeon S, Marcogliese P, Zuo Z, Shridharan R, Park J, Lin G, Ge M, Heimer G, Kohler J, Wheeler M, Kaipparettu B, Pandey A, Bellen H. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels. Nature Metabolism 2023, 5: 1595-1614. PMID: 37653044, PMCID: PMC11151872, DOI: 10.1038/s42255-023-00873-0.Peer-Reviewed Original ResearchConceptsFatty acid synthesisFe-S cluster biogenesisMitochondrial fatty acid synthesisCeramide levelsMost eukaryotic cellsElevated ceramide levelsIron metabolismCluster biogenesisEukaryotic cellsLoss of functionCellular lipidomeEnoyl coenzymeNeurodegenerative phenotypeIron homeostasisHuman-derived fibroblastsMechanistic linkAcid synthesisCeramideMECRMetabolismNeurodegenerationMtFASBiogenesisLast stepMitochondriaExploring 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 ResearchConceptsPatient-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
Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila
Bosch J, Ugur B, Pichardo-Casas I, Rabasco J, Escobedo F, Zuo Z, Brown B, Celniker S, Sinclair D, Bellen H, Perrimon N. Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila. ELife 2022, 11: e82709. PMID: 36346220, PMCID: PMC9681215, DOI: 10.7554/elife.82709.Peer-Reviewed Original ResearchConceptsSmall open reading framesClasses of genesShares sequence similarityOpen reading frameSequence similarityBicistronic transcriptBiological functionsPhenotypic analysisMitochondrial functionImportant regulatorThousands of peptidesNeuronal functionGenesWealth of informationTranscriptsAnimal lethalityPeptidesRecent studiesParalogsDrosophilaSmORFsMitochondriaRegulatorRegulatesNeuronal peptidesNeuronal activity induces glucosylceramide that is secreted via exosomes for lysosomal degradation in glia
Wang L, Lin G, Zuo Z, Li Y, Byeon S, Pandey A, Bellen H. Neuronal activity induces glucosylceramide that is secreted via exosomes for lysosomal degradation in glia. Science Advances 2022, 8: eabn3326. PMID: 35857503, PMCID: PMC9278864, DOI: 10.1126/sciadv.abn3326.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDrosophilaExosomesGlucosylceramidaseGlucosylceramidesHumansLysosomesNeurogliaNeuronsAn expanded toolkit for Drosophila gene tagging using synthesized homology donor constructs for CRISPR-mediated homologous recombination
Kanca O, Zirin J, Hu Y, Tepe B, Dutta D, Lin W, Ma L, Ge M, Zuo Z, Liu L, Levis R, Perrimon N, Bellen H. An expanded toolkit for Drosophila gene tagging using synthesized homology donor constructs for CRISPR-mediated homologous recombination. ELife 2022, 11: e76077. PMID: 35723254, PMCID: PMC9239680, DOI: 10.7554/elife.76077.Peer-Reviewed Original ResearchLoss 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 ResearchConceptsRetromer functionRetromer localizationVps26 proteinsRetromer subunitsRab7 GTPaseProtein complexesEndolysosomal functionEndolysosomal pathwayLysosomal stressVPS29Endolysosomal dysfunctionSynaptic transmissionSubstrate clearanceRetromerGTPaseProteinVPS35Adult brainBrain homeostasisAlzheimer's diseaseTBC1D5Vps26Ultrastructural evidenceEmbryogenesisMutantsLoss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms
Chung H, Wangler M, Marcogliese P, Jo J, Ravenscroft T, Zuo Z, Duraine L, Sadeghzadeh S, Li-Kroeger D, Schmidt R, Pestronk A, Rosenfeld J, Burrage L, Herndon M, Chen S, Network M, Shillington A, Vawter-Lee M, Hopkin R, Rodriguez-Smith J, Henrickson M, Lee B, Moser A, Jones R, Watkins P, Yoo T, Mar S, Choi M, Bucelli R, Yamamoto S, Lee H, Prada C, Chae J, Vogel T, Bellen H. Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms. Neuron 2020, 106: 589-606.e6. PMID: 32169171, PMCID: PMC7289150, DOI: 10.1016/j.neuron.2020.02.021.Peer-Reviewed Original ResearchMeSH KeywordsAcyl-CoA OxidaseAnimalsAxonsDrosophilaHumansMiceMutationNerve DegenerationNeurogliaRatsConceptsSchwann cellsAxonal lossMurine Schwann cellsPrimary Schwann cellsTreatment of fliesLong-chain fatty acid β-oxidation pathwayNeuronal lossGlial lossSynaptic transmissionRate-limiting enzymeDevelopmental delayACOX1Elevated levelsFatty acid β-oxidation pathwayReactive oxygen speciesDifferent mechanismsPupal deathPatientsDominant variantFunction mutationsGliaOxygen speciesTreatmentDe novoCells
2019
An efficient CRISPR-based strategy to insert small and large fragments of DNA using short homology arms
Kanca O, Zirin J, Garcia-Marques J, Knight S, Yang-Zhou D, Amador G, Chung H, Zuo Z, Ma L, He Y, Lin W, Fang Y, Ge M, Yamamoto S, Schulze K, Hu Y, Spradling A, Mohr S, Perrimon N, Bellen H. An efficient CRISPR-based strategy to insert small and large fragments of DNA using short homology arms. ELife 2019, 8: e51539. PMID: 31674908, PMCID: PMC6855806, DOI: 10.7554/elife.51539.Peer-Reviewed Original ResearchVAMP 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
An expanded toolkit for gene tagging based on MiMIC and scarless CRISPR tagging in Drosophila
Li-Kroeger D, Kanca O, Lee P, Cowan S, Lee M, Jaiswal M, Salazar J, He Y, Zuo Z, Bellen H. An expanded toolkit for gene tagging based on MiMIC and scarless CRISPR tagging in Drosophila. ELife 2018, 7: e38709. PMID: 30091705, PMCID: PMC6095692, DOI: 10.7554/elife.38709.Peer-Reviewed Original ResearchConceptsNew genetic toolsDouble headerTagged alleleGene taggingPrecise gene manipulationEndogenous genesGenetic toolsProtein functionProtein localizationMultiple downstream applicationsArtificial exonCassette exchangeProtein trappingEmbryo injectionNull allelesExpression patternsGene manipulationGene expressionDNA fragmentsDominant markersGenesCRISPRIntegration efficiencyDownstream applicationsAllelesPhospholipase 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 phospholipidsParkinsonismVPS35Desipramine
2017
A cell cycle-independent, conditional gene inactivation strategy for differentially tagging wild-type and mutant cells
Nagarkar-Jaiswal S, Manivannan S, Zuo Z, Bellen H. A cell cycle-independent, conditional gene inactivation strategy for differentially tagging wild-type and mutant cells. ELife 2017, 6: e26420. PMID: 28561736, PMCID: PMC5493436, DOI: 10.7554/elife.26420.Peer-Reviewed Original Research
2016
Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease
Chouhan A, Guo C, Hsieh Y, Ye H, Senturk M, Zuo Z, Li Y, Chatterjee S, Botas J, Jackson G, Bellen H, Shulman J. Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease. Acta Neuropathologica Communications 2016, 4: 62. PMID: 27338814, PMCID: PMC4918017, DOI: 10.1186/s40478-016-0333-4.Peer-Reviewed Original ResearchMeSH KeywordsAgingAlpha-SynucleinAmyloid beta-PeptidesAnimalsAnimals, Genetically ModifiedCell DeathDisease Models, AnimalDrosophilaElectroretinographyFemaleHumansMembrane PotentialsMicroelectrodesMicroscopy, Electron, TransmissionNeurodegenerative DiseasesNeuronsPeptide FragmentsRetinaTau ProteinsVision, OcularConceptsAdult Drosophila retinaToxic protein speciesDisease-relevant proteinsMicrotubule-associated protein tauMedium-throughput assaysProgressive photoreceptor cell deathCodon-optimized transgeneCommon neurodegenerative proteinopathiesAdult nervous systemDrosophila retinaNeuronal deathProtein speciesGlial cell typesDrosophila modelParkinson's diseaseNervous systemAlzheimer's diseaseAge-dependent neuronal lossPhotoreceptor cell deathCell deathCell typesProtein tauDrosophilaExpression of tauPotential degenerative changes
2015
A genetic toolkit for tagging intronic MiMIC containing genes
Nagarkar-Jaiswal S, DeLuca S, Lee P, Lin W, Pan H, Zuo Z, Lv J, Spradling A, Bellen H. A genetic toolkit for tagging intronic MiMIC containing genes. ELife 2015, 4: e08469. PMID: 26102525, PMCID: PMC4499919, DOI: 10.7554/elife.08469.Peer-Reviewed Original ResearchConceptsProtein interaction partnersGenes/proteinsProtein expression patternsUncharacterized genesGenetic toolkitIntegration cassetteMiMIC insertionsPhiC31 recombinaseProtein tagsFRT sequencesNew exonsGenetic strategiesInteraction partnersExpression patternsGenesExonsPlasmid DNAProteinMass specTagsIntronsLarge collectionGFPImmunoprecipitationMimics