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Suppression of glia maturation factor expression prevents 1-methyl-4-phenylpyridinium (MPP(+))-induced loss of mesencephalic dopaminergic neurons.
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Neuroscience 2014 Jul;
Authors: M M Khan, S Zaheer, J Nehman, A Zaheer
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-?B)- mediated production of inflammatory mediators by MPP(+). We examined MPP(+)-induced DA neuronal loss in primary cultures of mouse mesencephalic neuron/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 neuron/glia led to decreased production of ROS and downregulation of NF-?B-mediated production of tumor necrosis factor-alpha (TNF-?) and interleukin-1beta (IL-1?) as compared to Wt neuron/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-?B-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.
PMID: 25016212 [PubMed - as supplied by publisher]