John Elsworth, PhD
Research & Publications
Biography
News
Research Summary
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.
Specialized Terms: Dopamine neurons; Aging; Oxidative stress; Mitochondrial dysfunction; Uncoupling proteins; Neurotrophic factors; Development; Parkinson’s disease; Striatum; Prefrontal cortex; Schizophrenia.
Extensive Research Description
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.
Coauthors
Research Interests
Age Factors; Dopamine; Mitochondria; Parkinson Disease; Schizophrenia; Prefrontal Cortex; Oxidative Stress; Stem Cell Transplantation
Selected Publications
- 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 & Medicine 2022, 178: 215-218. PMID: 34890766, PMCID: PMC8760629, DOI: 10.1016/j.freeradbiomed.2021.12.005.
- Pioglitazone 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 2022, 152: 105222. PMID: 34767873, PMCID: PMC8712400, DOI: 10.1016/j.neuint.2021.105222.
- Sex-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 & Medicine 2021, 167: 201-204. PMID: 33722626, PMCID: PMC8096713, DOI: 10.1016/j.freeradbiomed.2021.03.003.
- 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 2021, 219: 107705. PMID: 33039420, PMCID: PMC7887032, DOI: 10.1016/j.pharmthera.2020.107705.
- Gene 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.
- Parkinson's disease treatment: past, present, and future.Elsworth JD. Parkinson's disease treatment: past, present, and future. Journal Of Neural Transmission (Vienna, Austria : 1996) 2020, 127: 785-791. PMID: 32172471, PMCID: PMC8330829, DOI: 10.1007/s00702-020-02167-1.
- Pioglitazone 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.