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 stepMitochondria
2022
Neuronal 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 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
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 structureLoss- 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 ResearchConceptsSchwann 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 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
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 phospholipidsParkinsonismVPS35Desipramine
2017
Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially
Luo X, Rosenfeld J, Yamamoto S, Harel T, Zuo Z, Hall M, Wierenga K, Pastore M, Bartholomew D, Delgado M, Rotenberg J, Lewis R, Emrick L, Bacino C, Eldomery M, Coban Akdemir Z, Xia F, Yang Y, Lalani S, Lotze T, Lupski J, Lee B, Bellen H, Wangler M, . Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. PLOS Genetics 2017, 13: e1006905. PMID: 28742085, PMCID: PMC5557584, DOI: 10.1371/journal.pgen.1006905.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAnimals, Genetically ModifiedCalcium ChannelsCerebellar AtaxiaChildChild, PreschoolDrosophila melanogasterFemaleGenome-Wide Association StudyGenome, HumanHumansMaleMicroscopy, Electron, TransmissionMutation, MissenseNeurodegenerative DiseasesNeuroimagingPhenotypePoint MutationConceptsNeurodegenerative phenotypeGenomic rescue constructsS4 transmembrane segmentRescue constructTransmembrane segmentsFunction phenotypesLoss of functionMissense allelesFunction allelesWild typeGlobal developmental delayToxic gainMutant clonesDominant mutationsDevelopmental delayPoint mutationsDrosophilaFunctional impactPhenotypeQ-type voltage-dependent Ca2Early-onset developmental delayNeurological phenotypeAllelesSynaptic functionNovel variants
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