title: Suppression of glia maturation factor expression prevents 1-methyl-4-phenylpyridinium (MPP⁺)-induced loss of mesencephalic dopaminergic neurons.
abstract: Inflammation mediated by glial activation appears to play a critical role in the pathogenesis of Parkinson disease (PD). Glia maturation factor (GMF), a proinflammatory protein predominantly localized in the central nervous system was isolated, sequenced and cloned in our laboratory. We have previously demonstrated immunomodulatory and proinflammatory functions of GMF, but its involvement in 1-methyl-4-phenylpyridinium (MPP(+)), active metabolite of classical parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), inducing loss of dopaminergic (DA) neurons has not been studied. Here we show that altered expression of GMF has direct consequences on the production of reactive oxygen species (ROS) and nuclear factor-kappa B (NF-κB)- mediated production of inflammatory mediators by MPP(+). We examined MPP(+)-induced DA neuronal loss in primary cultures of mouse mesencephalic neurons/glia obtained from GMF-deficient (GMF knockout (GMF-KO)) and GMF-containing wild-type (Wt) mice. We demonstrate that deficiency of GMF in GMF-KO neurons/glia led to decreased production of ROS and downregulation of NF-κB-mediated production of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) as compared to Wt neurons/glia. Additionally, overexpression of GMF induced DA neurodegeneration, whereas GMF downregulation by GMF-specific shRNA protected DA neurons from MPP-induced toxicity. Subsequently, GMF deficiency ameliorates antioxidant balance, as evidenced by the decreased level of lipid peroxidation, less ROS production along with increased level of glutathione; and attenuated the DA neuronal loss via the downregulation of NF-κB-mediated inflammatory responses. In conclusion, our overall data indicate that GMF modulates oxidative stress and release of deleterious agents by MPP(+) leading to loss of DA neurons. Our study provides new insights into the potential role of GMF and identifies targets for therapeutic interventions in neurodegenerative diseases.
authors.affiliation: Department of Neurology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Khan
authors.affiliation: Department of Neurology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: S
authors.initials: S
authors.lastname: Zaheer
authors.affiliation: Department of Neurology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nehman
authors.affiliation: Department of Neurology, University of Iowa, Iowa City, IA 52242, USA; VA Health Care System, Iowa City, IA, USA. Electronic address: asgar-zaheer@uiowa.edu.
authors.forename: A
authors.initials: A
authors.lastname: Zaheer
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D020904:Glia Maturation Factor / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008636:Mesencephalon / Q000187:drug effects* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020904:Glia Maturation Factor; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium
keywords: NF-κB; cytokines; glia maturation factor; neurodegeneration; oxidative stress; reactive oxygen species