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 stepMitochondriaVery-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation
Chung H, Ye Q, Park Y, Zuo Z, Mok J, Kanca O, Tattikota S, Lu S, Perrimon N, Lee H, Bellen H. Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation. Cell Metabolism 2023, 35: 855-874.e5. PMID: 37084732, PMCID: PMC10160010, DOI: 10.1016/j.cmet.2023.03.022.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisMultiple sclerosisAdministration of fingolimodFunctions of S1PNF-κB activationSphingosine-1-phosphate (S1P) synthesisS1P receptor antagonistsElevated VLCFAAutoimmune encephalomyelitisFatty acidsMacrophage infiltrationReceptor antagonistImmune cellsMouse modelTreatment avenuesVLCFA levelsFly gliaLong-chain fatty acidsGliaS1P pathwayS1PNeuroinflammationFingolimodVLCFAAbundant fatty acidsExploring 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 ResearchAn 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 ResearchLow doses of the organic insecticide spinosad trigger lysosomal defects, elevated ROS, lipid dysregulation, and neurodegeneration in flies
Martelli F, Hernandes N, Zuo Z, Wang J, Wong C, Karagas N, Roessner U, Rupasinghe T, Robin C, Venkatachalam K, Perry T, Batterham P, Bellen H. Low doses of the organic insecticide spinosad trigger lysosomal defects, elevated ROS, lipid dysregulation, and neurodegeneration in flies. ELife 2022, 11: e73812. PMID: 35191376, PMCID: PMC8863376, DOI: 10.7554/elife.73812.Peer-Reviewed Original ResearchConceptsReactive oxygen speciesBeneficial insectsBeneficial insect speciesElevated reactive oxygen speciesInsect speciesInsect pestsMitochondrial stressMitochondrial defectsAdult virgin femalesLysosomal defectsGlobal declineAntioxidant N-acetylcysteine amidePopulation sizeSpinosad toxicityMode of actionLipid storageMetabolic tissuesVirgin femalesInsecticide applicationsLysosomal dysfunctionInsectsSevere neurodegenerationSynthetic insecticidesOxygen speciesAlpha 6Daam2 Regulates Myelin Structure and the Oligodendrocyte Actin Cytoskeleton through Rac1 and Gelsolin
Cristobal C, Wang C, Zuo Z, Smith J, Lindeke-Myers A, Bellen H, Lee H. Daam2 Regulates Myelin Structure and the Oligodendrocyte Actin Cytoskeleton through Rac1 and Gelsolin. Journal Of Neuroscience 2022, 42: 1679-1691. PMID: 35101966, PMCID: PMC8896627, DOI: 10.1523/jneurosci.1517-21.2022.Peer-Reviewed Original ResearchConceptsGelsolin levelsOL differentiationMyelin sheathCNS functionMorphogenesis 2Motor coordination deficitsActin cytoskeletonWhite matter diseaseMyelin structureConditional knockout miceWhite matter developmentMyelin compactionMyelin decompactionNeuronal healthCKO miceCoordination deficitsFunctional myelinCompact myelin sheathKnockout miceWhite matterPostnatal developmentProper myelin formationOligodendrocytesMyelin formationOL culturesLoss 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
TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
Cunningham K, Maulding K, Ruan K, Senturk M, Grima J, Sung H, Zuo Z, Song H, Gao J, Dubey S, Rothstein J, Zhang K, Bellen H, Lloyd T. TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS. ELife 2020, 9: e59419. PMID: 33300868, PMCID: PMC7758070, DOI: 10.7554/elife.59419.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusAmyotrophic Lateral SclerosisAnimalsAutophagyBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsBlotting, WesternC9orf72 ProteinDisease Models, AnimalDrosophila melanogasterFemaleFluorescent Antibody TechniqueFrontotemporal DementiaHeLa CellsHumansLysosomesMaleMicrophthalmia-Associated Transcription FactorMicroscopy, Electron, TransmissionMotor CortexConceptsNucleocytoplasmic transportNuclear importC9-ALS/FTDKey transcriptional regulatorAutophagic cargo degradationNeurodegenerative disease pathogenesisLysosome-like organellesProteostasis defectsGGGGCC hexanucleotide repeat expansionTranscriptional regulatorsCargo degradationKey regulatorUbiquitinated aggregatesCytoplasmic mislocalizationHuman cellsAmyotrophic lateral sclerosisGGGGCC repeatsHexanucleotide repeat expansionRepeat expansionFrontotemporal dementiaTFEBC9-ALSAutophagyRegulatorPotent suppressorThe Daam2–VHL–Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation
Ding X, Jo J, Wang C, Cristobal C, Zuo Z, Ye Q, Wirianto M, Lindeke-Myers A, Choi J, Mohila C, Kawabe H, Jung S, Bellen H, Yoo S, Lee H. The Daam2–VHL–Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation. Genes & Development 2020, 34: 1177-1189. PMID: 32792353, PMCID: PMC7462057, DOI: 10.1101/gad.338046.120.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationGene Expression Regulation, DevelopmentalHumansMiceMice, KnockoutMicrofilament ProteinsMultiple SclerosisMyelin SheathNedd4 Ubiquitin Protein LigasesNerve RegenerationNervous System DiseasesOligodendrogliaProtein StabilityRho GTP-Binding ProteinsUbiquitinationVon Hippel-Lindau Tumor Suppressor ProteinConceptsWhite matter injuryUbiquitin-proteasomal systemGenetic knockout mouse modelsOligodendrocyte differentiationWhite matter lesionsKnockout mouse modelDemyelination modelMultiple sclerosisDisease-driving proteinsMatter lesionsOligodendrocyte dysfunctionPathogenic accumulationMouse modelDevelopmental myelinationNeurological disordersGlial biologyOligodendrocyte developmentE3 ligase VHLVHLRepairE3 ubiquitinProteomic analysisRemyelinationSclerosisPatientsNovel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue
Li X, Yang L, Mao Z, Pan X, Zhao Y, Gu X, Eckel‐Mahan K, Zuo Z, Tong Q, Hartig S, Cheng X, Du G, Moore D, Bellen H, Sesaki H, Sun K. Novel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue. The FASEB Journal 2020, 34: 8265-8282. PMID: 32294302, PMCID: PMC7336545, DOI: 10.1096/fj.201903100rr.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulumFlx/Function of Drp1Multicellular organismsPeroxisomal fissionDrp1 ablationER retentionLD dynamicsAutophagy functionER functionNovel roleDrp1LD morphologyKnockout modelsProtein 1Unilocular morphologyAdipose tissueLipid metabolismDynaminOrganellesCold exposureTissueOrganismsLarge sizeMultilocular structureRetromer 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
Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction
Wang J, Rousseau J, Kim E, Ehresmann S, Cheng Y, Duraine L, Zuo Z, Park Y, Li-Kroeger D, Bi W, Wong L, Rosenfeld J, Gleeson J, Faqeih E, Alkuraya F, Wierenga K, Chen J, Afenjar A, Nava C, Doummar D, Keren B, Juusola J, Grompe M, Bellen H, Campeau P. Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. American Journal Of Human Genetics 2019, 105: 1237-1253. PMID: 31785787, PMCID: PMC6904826, DOI: 10.1016/j.ajhg.2019.11.002.Peer-Reviewed Original ResearchAn 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 Researchcindr, 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 PhosphatesR-SNARE ProteinsRab GTP-Binding ProteinsRab7 GTP-Binding ProteinsVesicular Transport Proteins