John Elsworth, PhD
Professor Adjunct in PsychiatryCards
Contact Info
About
Titles
Professor Adjunct in Psychiatry
Biography
Dysfunction of brain dopamine neurons is critically involved in the pathology of several neurologic and psychiatric disorders. Dr Elsworth’s research encompasses the “development, dysfunction, and demise” of dopamine neurons. The goal is to understand the mechanisms underlying the particular susceptibility of midbrain dopamine neurons to damage, and devising strategies for protecting, repairing or replacing these cells. As the population of midbrain dopamine neurons exhibits a profound loss during aging, they provide a model system for studying aging mechanisms and repair in other CNS neuronal populations.
Appointments
Departments & Organizations
Education & Training
- PhD
- University of London (1980)
Research
Overview
Midbrain dopamine neurons exhibits an exaggerated loss during aging compared with other neuronal populations and consequently, they provide a model system for studying aging mechanisms and repair strategies that is relevant to other CNS neuronal populations.
Specific dysfunction of dopamine neurons is implicated in several neurological and psychiatric disorders, notably Parkinson’s disease and schizophrenia. During the prenatal period the fetal brain undergoes dramatic changes, as structures and connections form according to strict spatial and temporal criteria. It follows then that during development environmental insults have greater potential to exert profound and permanent changes than at other times during life and may affect the risk of the offspring succumbing to CNS disorders. A major focus of investigations is our finding of varying susceptibility of primate dopamine neurons to damage at different periods of development. Our research has identified prenatal phases when primate dopamine neurons are especially vulnerable to oxidative stress or endocrine disruptors and a postnatal period when they are remarkably resistant to such damage. We are particularly intrigued by neuroprotective factors that are preferentially expressed during the window of resistance to damage (‘juvenile protective factors”) and our recent work has focused on paraoxonase-2, a mitochondrial enzyme which if pharmacologically re-activated later in life could preserve and protect neurons vulnerable to age-dependent deficits.
Another field of research is the regulation of dopamine neurons innervating the prefrontal cortex, as our research has indicated that this input appears to determine alteration of dendrites and synapses on prefrontal pyramidal neurons, which are critical to the executive function of this brain region. Experimental restoration of normal dopamine transmission in the prefrontal cortex would enable treatment of cognitive deficits that are characteristic of Parkinson’s disease and schizophrenia.
Other research is focused on repair or maintenance of the vulnerable neuronal system, using strategies such as implants of modified stem cells and neurotrophic factor gene therapy.
Medical Research Interests
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Jane Rebecca Taylor, PhD
Jennifer Blackburn
Sumit Jamwal, PhD
Benjamin Bunney, MD
E. Leon Kier, MD
Robert Makuch, PhD
Dopamine
Prefrontal Cortex
Parkinson Disease
Oxidative Stress
Mitochondria
Schizophrenia
Publications
2023
Age-associated sex difference in the expression of mitochondria-based redox sensitive proteins and effect of pioglitazone in nonhuman primate brain
Jamwal S, Blackburn J, Elsworth J. Age-associated sex difference in the expression of mitochondria-based redox sensitive proteins and effect of pioglitazone in nonhuman primate brain. Biology Of Sex Differences 2023, 14: 65. PMID: 37770961, PMCID: PMC10540392, DOI: 10.1186/s13293-023-00551-6.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSubstantia nigraSex-dependent expressionPrimate brainAdult male monkeysCerebrospinal fluidMale monkeysPeroxisome proliferator-activated receptor gamma agonistProliferator-activated receptor gamma agonistsEffect of pioglitazoneWeeks of treatmentReceptor gamma agonistsGreater expressionAdult female monkeysNonhuman primate brainNovel neuroprotective treatmentAfrican green monkeysSex-based differencesOral pioglitazoneNeuroprotective treatmentPIO treatmentRisk factorsCNS disordersGamma agonistsPreclinical studiesParkinson's disease
2021
Expression of PON2 isoforms varies among brain regions in male and female African green monkeys
Jamwal S, Blackburn JK, Elsworth JD. Expression of PON2 isoforms varies among brain regions in male and female African green monkeys. Free Radical Biology And Medicine 2021, 178: 215-218. PMID: 34890766, PMCID: PMC8760629, DOI: 10.1016/j.freeradbiomed.2021.12.005.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsAfrican green monkeysParkinson's diseaseBrain regionsParaoxonase 2Different brain regionsFemale monkeysGreen monkeysPON2 expressionOxidative stress-related neurodegenerative disordersFemale African green monkeysNeurodegenerative disordersMale African green monkeysOxidative stressPON2 protein expressionAnti-inflammatory propertiesExpression levelsSignificant differencesBrain tissue samplesDorsolateral prefrontal cortexNeuroprotective strategiesWestern blotting techniquesDopaminergic neuronsPON2 proteinPrimate brainProtective rolePioglitazone transiently stimulates paraoxonase-2 expression in male nonhuman primate brain: Implications for sex-specific therapeutics in neurodegenerative disorders
Blackburn JK, Jamwal S, Wang W, Elsworth JD. Pioglitazone transiently stimulates paraoxonase-2 expression in male nonhuman primate brain: Implications for sex-specific therapeutics in neurodegenerative disorders. Neurochemistry International 2021, 152: 105222. PMID: 34767873, PMCID: PMC8712400, DOI: 10.1016/j.neuint.2021.105222.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsPON2 expressionParkinson's diseaseParaoxonase 2Male African green monkeysShort-term animal modelsOxidative stressPeroxisome proliferator-activated receptor gammaEffect of pioglitazoneWeeks of treatmentProliferator-activated receptor gammaNonhuman primate brainParaoxonase-2 expressionRegion-dependent expressionSex-specific therapeuticsAnti-diabetic drug pioglitazoneAfrican green monkeysDorsolateral prefrontal cortexOral pioglitazonePreclinical evidenceSubstantia nigraClinical trialsPON2 mRNAAnimal modelsPioglitazonePrimate brainSex-based disparity in paraoxonase-2 expression in the brains of African green monkeys
Jamwal S, Blackburn JK, Elsworth JD. Sex-based disparity in paraoxonase-2 expression in the brains of African green monkeys. Free Radical Biology And Medicine 2021, 167: 201-204. PMID: 33722626, PMCID: PMC8096713, DOI: 10.1016/j.freeradbiomed.2021.03.003.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsAfrican green monkeysParaoxonase 2Parkinson's diseaseBrain regionsGreen monkeysOxidative stressReactive oxygen speciesAnti-inflammatory propertiesSex-based disparitiesParaoxonase-2 expressionDifferent brain regionsNigrostriatal systemPON2 expressionDevelopment of therapeuticsNeurodegenerative disordersDiseaseProtein levelsROS levelsLower ROS levelsMitochondrial performanceSex-based variationDisordersMonkeysOxygen speciesMales
2020
PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders
Jamwal S, Blackburn J, Elsworth JD. PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders. Pharmacology & Therapeutics 2020, 219: 107705. PMID: 33039420, PMCID: PMC7887032, DOI: 10.1016/j.pharmthera.2020.107705.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsNeurodegenerative disordersParkinson's diseaseAlzheimer's diseaseParaoxonase 2Mitochondrial biogenesisNeurodegenerative diseasesHuntington's diseasePeroxisome proliferator-activated receptorProliferator-activated receptorPotential therapeutic targetDevastating neurological disorderFunction of neuronsPeroxisome proliferator-activated receptor gamma co-activator-1 alphaPharmacological-based therapiesSymptomatic treatmentCurrent therapiesClinical trialsLigand-inducible transcription factorsTherapeutic targetNeurological disordersDiseasePPARγ modulatorsProgressive lossMitochondrial dysfunctionPromising targetGeneration of Pluripotent Stem Cells Using Somatic Cell Nuclear Transfer and Induced Pluripotent Somatic Cells from African Green Monkeys
Chung YG, Seay M, Elsworth J, Redmond D. Generation of Pluripotent Stem Cells Using Somatic Cell Nuclear Transfer and Induced Pluripotent Somatic Cells from African Green Monkeys. Stem Cells And Development 2020, 29: 1294-1307. PMID: 32715987, DOI: 10.1089/scd.2020.0059.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAnimalsBase SequenceCell LineChlorocebus aethiopsChromosome BandingCloning, OrganismCulture MediaCytogenetic AnalysisDNADopaminergic NeuronsEmbryonic DevelopmentEmbryonic Stem CellsFemaleGenotypeHumansInduced Pluripotent Stem CellsMitochondriaNuclear Transfer TechniquesOvaryTyrosine 3-MonooxygenaseConceptsAfrican green monkeysInduced pluripotent stem cellsCell linesGreen monkeysStem cellsEffective cell replacement therapyPromising potential therapyPluripotent stem cellsDopamine depletionReplacement therapyDopamine neuronsCell replacement therapyBrain pathologyDonor monkeyParkinson's diseasePotential therapyMonkey studiesFemale monkeysClinical predictive powerImmune rejectionImmune systemAccidental exposurePossible treatmentIPSC linesRodent experimentsGene therapy and immunotherapy as promising strategies to combat Huntington’s disease-associated neurodegeneration: emphasis on recent updates and future perspectives
Jamwal S, Elsworth JD, Rahi V, Kumar P. Gene therapy and immunotherapy as promising strategies to combat Huntington’s disease-associated neurodegeneration: emphasis on recent updates and future perspectives. Expert Review Of Neurotherapeutics 2020, 20: 1123-1141. PMID: 32720531, DOI: 10.1080/14737175.2020.1801424.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsGene therapyClinical trialsDisease-modifying therapiesMutant huntingtinTreatment of HDAntibody-based therapiesPotential therapeutic interventionsNew therapeutic targetsGene-based therapiesImmune activationClinical dataImmunotherapyTherapeutic targetFunctional restorationTherapeutic interventionsTherapyHD pathogenesisMHTT proteinRecent updatesFuture perspectivesPromising strategyTrialsCurrent statusConsiderable attentionHDParkinson’s disease treatment: past, present, and future
Elsworth JD. Parkinson’s disease treatment: past, present, and future. Journal Of Neural Transmission 2020, 127: 785-791. PMID: 32172471, PMCID: PMC8330829, DOI: 10.1007/s00702-020-02167-1.Peer-Reviewed Original ResearchCitationsAltmetricPioglitazone activates paraoxonase-2 in the brain: A novel neuroprotective mechanism
Blackburn JK, Curry DW, Thomsen AN, Roth RH, Elsworth JD. Pioglitazone activates paraoxonase-2 in the brain: A novel neuroprotective mechanism. Experimental Neurology 2020, 327: 113234. PMID: 32044330, PMCID: PMC7089823, DOI: 10.1016/j.expneurol.2020.113234.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsParaoxonase 2Novel neuroprotective mechanismParaoxonase-2 expressionAnti-diabetic drug pioglitazoneReactive oxygen species productionNeuroprotective strategiesNeuroprotective mechanismsBrain traumaMouse striatumOxygen species productionParkinson's diseaseAlzheimer's diseaseTherapeutic potentialPioglitazoneDiseaseOxidative stressDrug pioglitazoneSpecies productionBrainNeuroprotectionIschemiaStriatumExpressionPathologyTrauma
2018
Human–Monkey Chimeras for Modeling Human Disease: Opportunities and Challenges
De Los Angeles A, Hyun I, Latham S, Elsworth J, Redmond D. Human–Monkey Chimeras for Modeling Human Disease: Opportunities and Challenges. Stem Cells And Development 2018, 27: 1599-1604. PMID: 30319057, PMCID: PMC7366261, DOI: 10.1089/scd.2018.0162.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsImportant ethical considerationsModeling Human DiseaseHuman PS cellsInterspecies chimerasUse of monkeysChimera researchEthical considerationsEthical concernsInvasive researchCell researchPolitical issuesScientific valueBiomedical researchLight of advancesHuman stem cellsJurisdictionsPS cellsHoly grailQuestions
Academic Achievements & Community Involvement
activity Monash University, Melbourne
ResearchDetails01/01/2010 - PresentAustraliaAbstract/SynopsisBioenergetics and dopamine neuron function with Dr Zane Andrews
activity St Kitts Biomedical Research Foundation
ResearchDetails01/01/1985 - PresentSaint Kitts and NevisAbstract/SynopsisAn AAALAC accredited facility for study of non-human primates in a source country.
News
News
- September 27, 2017
Battling belly fat: Specialized immune cells impair metabolism in aging
- May 14, 2015
Yale scientist receives Sanberg Award from American Society of Neural Therapy and Repair
- May 08, 2015
FN 00: John D. Elsworth
- April 15, 2002
Cocaine and the fetus