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 ResearchMeSH KeywordsAnimalsDrosophilaExosomesGlucosylceramidaseGlucosylceramidesHumansLysosomesNeurogliaNeuronsLow 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 6
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 suppressorRetromer 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 evidenceEmbryogenesisMutants
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 ResearchUbiquilins 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