2023
Roles for diacylglycerol in synaptic vesicle priming and release revealed by complete reconstitution of core protein machinery
Sundaram R, Chatterjee A, Bera M, Grushin K, Panda A, Li F, Coleman J, Lee S, Ramakrishnan S, Ernst A, Gupta K, Rothman J, Krishnakumar S. Roles for diacylglycerol in synaptic vesicle priming and release revealed by complete reconstitution of core protein machinery. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2309516120. PMID: 37590407, PMCID: PMC10450444, DOI: 10.1073/pnas.2309516120.Peer-Reviewed Original ResearchConceptsCore protein machineryRelease-ready vesiclesSynaptic vesicle primingVesicle primingProtein machinerySingle-molecule imagingSNAREpin assemblyFunctional intermediatesFunctional reconstitutionMunc13DiacylglycerolCoordinated actionMunc18VesiclesMachineryComplete reconstitutionNew roleSelective effectDetailed characterizationChaperonesRate of caReconstitutionVAMP2ComplexinMutations
2019
Mechanisms of Neurological Dysfunction in GOSR2 Progressive Myoclonus Epilepsy, a Golgi SNAREopathy
Jepson JEC, Praschberger R, Krishnakumar SS. Mechanisms of Neurological Dysfunction in GOSR2 Progressive Myoclonus Epilepsy, a Golgi SNAREopathy. Neuroscience 2019, 420: 41-49. PMID: 30954670, DOI: 10.1016/j.neuroscience.2019.03.057.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulumSNARE proteinsProgressive myoclonus epilepsySecretory trafficking pathwaysCis-Golgi membranesMis-sense mutationsTransport vesiclesGolgi transportTrafficking pathwaysVesicles budSecretory pathwaySuccessive fusion eventsTarget membraneFusion eventsEssential functionsDevelopmental defectsMolecular mechanismsMyoclonus epilepsyProteinFusion stepSevere neurological disordersMutationsMembranePathwayInitial stepMutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
Salpietro V, Malintan NT, Llano-Rivas I, Spaeth CG, Efthymiou S, Striano P, Vandrovcova J, Cutrupi MC, Chimenz R, David E, Di Rosa G, Marce-Grau A, Raspall-Chaure M, Martin-Hernandez E, Zara F, Minetti C, Study D, Group S, Salpietro V, Efthymiou S, Kriouile Y, Khorassani M, Aguennouz M, Karashova B, Avdjieva D, Kathom H, Tincheva R, Van Maldergem L, Nachbauer W, Boesch S, Arning L, Timmann D, Cormand B, Pérez-Dueñas B, Di Rosa G, Pironti E, Goraya J, Sultan T, Kirmani S, Ibrahim S, Jan F, Mine J, Banu S, Veggiotti P, Ferrari M, Verrotti A, Marseglia G, Savasta S, Garavaglia B, Scuderi C, Borgione E, Dipasquale V, Cutrupi M, Portaro S, Sanchez B, Pineda-Marfa’ M, Munell F, Macaya A, Boles R, Heimer G, Papacostas S, Manole A, Malintan N, Zanetti M, Hanna M, Rothman J, Kullmann D, Houlden H, Bello O, De Zorzi R, Fortuna S, Dauber A, Alkhawaja M, Sultan T, Mankad K, Vitobello A, Thomas Q, Mau-Them F, Faivre L, Martinez-Azorin F, Prada C, Macaya A, Kullmann D, Rothman J, Krishnakumar S, Houlden H. Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment. American Journal Of Human Genetics 2019, 104: 721-730. PMID: 30929742, PMCID: PMC6451933, DOI: 10.1016/j.ajhg.2019.02.016.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAutistic DisorderBrainChildChild, PreschoolEpilepsyExocytosisFemaleHeterozygoteHumansIntellectual DisabilityLipidsMagnetic Resonance ImagingMaleMembrane FusionMovement DisordersMuscle HypotoniaMutationNeurodevelopmental DisordersNeuronsNeurotransmitter AgentsPhenotypeProtein DomainsR-SNARE ProteinsSynapsesVesicle-Associated Membrane Protein 2ConceptsNon-synonymous variantsDe novo mutationsSNARE protein VAMP2Synaptic membrane fusionC-terminal regionNovo mutationsSNARE motifSynaptosomal-associated protein 25C-terminusMembrane fusionVAMP2Vesicle fusionHuman brain developmentAcid deletionSynaptic vesiclesVesicular exocytosisHeterozygous de novo mutationsProtein 25Hyperkinetic movement disordersAdditional neurological featuresHuman neurodevelopmentCentral visual impairmentDisease mechanismsUnrelated individualsMutations
2017
Two Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal Assembly
Rebane AA, Wang B, Ma L, Qu H, Coleman J, Krishnakumar S, Rothman JE, Zhang Y. Two Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal Assembly. Journal Of Molecular Biology 2017, 430: 479-490. PMID: 29056461, PMCID: PMC5805579, DOI: 10.1016/j.jmb.2017.10.012.Peer-Reviewed Original ResearchConceptsSoluble N-ethylmaleimide-sensitive factor attachment receptorSNARE assemblySynaptic exocytosisMembrane fusionSingle-molecule optical tweezersT-SNARE complexVesicle-associated SNAREsTarget plasma membraneC-terminal assemblyFour-helix bundleC-terminal regionSNARE complexPlasma membraneMolecular mechanismsZipperingMutationsNumerous diseasesAssembly energyNeurotransmitter releaseExocytosisAttachment receptorAssemblyNeurological disordersOptical tweezersComplexesMutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity
Praschberger R, Lowe SA, Malintan NT, Giachello CNG, Patel N, Houlden H, Kullmann DM, Baines RA, Usowicz MM, Krishnakumar SS, Hodge JJL, Rothman JE, Jepson JEC. Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity. Cell Reports 2017, 21: 97-109. PMID: 28978487, PMCID: PMC5640804, DOI: 10.1016/j.celrep.2017.09.004.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDendritesDrosophila melanogasterFemaleFibroblastsGene ExpressionGenetic Association StudiesGolgi ApparatusHumansMaleMembrane FusionMutationMyoclonic Epilepsies, ProgressivePhenotypePrimary Cell CultureQb-SNARE ProteinsRecombinant ProteinsSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSecretory PathwaySynapsesYoung AdultConceptsMembrane fusionGolgi membrane fusionProgressive myoclonus epilepsyGenotype-phenotype relationshipsPresynaptic cytoskeletonEssential proteinsDrosophila modelMembrinMutationsPathogenic mutationsSynaptic functionProteinMyoclonus epilepsyExplanatory basisCytoskeletonGrowthSynaptic integrityPathway deficitsNervous systemMulti-layered strategySnareFusionFragmentationHomozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome
Salpietro V, Lin W, Delle Vedove A, Storbeck M, Liu Y, Efthymiou S, Manole A, Wiethoff S, Ye Q, Saggar A, McElreavey K, Krishnakumar SS, Group S, Pitt M, Bello OD, Rothman JE, Basel‐Vanagaite L, Hubshman MW, Aharoni S, Manzur AY, Wirth B, Houlden H. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Annals Of Neurology 2017, 81: 597-603. PMID: 28253535, PMCID: PMC5413866, DOI: 10.1002/ana.24905.Peer-Reviewed Original ResearchConceptsPresynaptic congenital myasthenic syndromeCongenital myasthenic syndromePresynaptic impairmentMyasthenic syndromeLow compound muscle action potentialsNeuromuscular junctionCompound muscle action potentialPresynaptic neuromuscular junctionHomozygous mutationMuscle action potentialsAnn NeurolNMJ transmissionElectrodiagnostic examinationNeurophysiological featuresAction potentialsLew/Homozygous variantMRNA levelsSyndromeWhole exomeImpairmentVAMP1Kuwaiti familyNonsense mutationMutations