2022
Inhibition of autophagic flux by S-nitrosylation of SQSTM1/p62 promotes neuronal secretion and cell-to-cell transmission of SNCA/α-synuclein in Parkinson disease and Lewy body dementia
Oh C, Nakamura T, Lipton S. Inhibition of autophagic flux by S-nitrosylation of SQSTM1/p62 promotes neuronal secretion and cell-to-cell transmission of SNCA/α-synuclein in Parkinson disease and Lewy body dementia. Autophagy Reports 2022, 1: 223-225. PMID: 38098743, PMCID: PMC10721282, DOI: 10.1080/27694127.2022.2076770.Peer-Reviewed Original ResearchLewy body dementiaParkinson's diseaseSNCA/α-synucleinAutophagic fluxNitric oxideΑ-synucleinHuman postmortem brainS-nitrosylationNeuronal damageAberrant protein S-nitrosylationSynaptic damageΑ-synucleinopathiesPostmortem brainsPathogenic eventsDiseased brainExcessive reactive oxygenSQSTM1/p62Neurodegenerative disordersInhibits autophagic fluxNeuronal secretionCell-based modelCell transmissionProtein S-nitrosylationDementiaDiseaseS-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson's Disease and Lewy Body Dementia
Oh C, Dolatabadi N, Cieplak P, Diaz-Meco M, Moscat J, Nolan J, Nakamura T, Lipton S. S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson's Disease and Lewy Body Dementia. Journal Of Neuroscience 2022, 42: 3011-3024. PMID: 35169022, PMCID: PMC8985870, DOI: 10.1523/jneurosci.1508-21.2022.Peer-Reviewed Original ResearchConceptsLewy body dementiaParkinson's diseaseAutophagic fluxInhibits autophagic fluxΑ-synucleinPluripotent stem cell-derived neuronsStem cell-derived neuronsΑ-synuclein secretionS-nitrosylationCell-derived neuronsHuman postmortem brainProtein S-nitrosylationΑ-synuclein aggregationPostmortem brainsConsequent secretionPathologic pathwaysNervous systemAdaptor protein p62Autophagic inhibitionDysfunctional autophagyNeurodegenerative disordersDiseaseIndividual neuronsDementiaSecretion
2021
Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia
Trudler D, Nazor K, Eisele Y, Grabauskas T, Dolatabadi N, Parker J, Sultan A, Zhong Z, Goodwin M, Levites Y, Golde T, Kelly J, Sierks M, Schork N, Karin M, Ambasudhan R, Lipton S. Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2025847118. PMID: 33833060, PMCID: PMC8054017, DOI: 10.1073/pnas.2025847118.Peer-Reviewed Original ResearchConceptsHuman microgliaLike receptor family pyrinFibrillar αSynA9 dopaminergic neuronsInterleukin-1β secretionCaspase-1 activationMicroglial activationFamily pyrinAntibody therapyNeuronal deathParkinson's diseaseMicrogliaMouse brainΑ-synucleinDual stimulationMitochondrial damageΑSynAntibodiesInflammationNLRP3Cognate antibodiesHuman brainDiseaseNeuronsStem cellsα-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss
Trudler D, Sanz-Blasco S, Eisele Y, Ghatak S, Bodhinathan K, Akhtar M, Lynch W, Piña-Crespo J, Talantova M, Kelly J, Lipton S. α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss. Journal Of Neuroscience 2021, 41: 2264-2273. PMID: 33483428, PMCID: PMC8018774, DOI: 10.1523/jneurosci.1871-20.2020.Peer-Reviewed Original ResearchConceptsLewy body dementiaExtrasynaptic NMDA receptorsSynaptic damageParkinson's diseaseNeuronal lossLewy bodiesNMDAR activityDisease progressionΑSyn oligomersPotential disease-modifying interventionsNeurodegenerative diseasesΑ-synucleinExtrasynaptic NMDAR activitySynaptic NMDAR activityDisease-modifying interventionsPatch-clamp recordingsMajor neuropathological characteristicsSynaptic lossAstrocytic glutamateGlutamate releaseSynapse lossSpine lossExtrasynaptic NMDARsFemale miceHippocampal slices