Oxygen JNKies: phosphatases overdose on ROS.
ABSTRACT Proinflammatory cytokine TNFalpha triggers cell death by inducing reactive oxygen species (ROS). These then inflict cytotoxicity through downstream activation of the JNK MAPK cascade. Yet the mechanisms by which ROS trigger JNK signaling have remained elusive. In a recent issue of Cell, Kamata et al. now provide one such mechanism.
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ABSTRACT: System requirements: World Wide Web browser and PDF reader. Mode of access: Avaliable through the Internet. Title from document title page. Includes abstract. Document formatted into pages: contains xiii, 116 p. Theses (Ph. D.)--Marshall University, 2006. Bibliography: p. 99-112.
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ABSTRACT: After approximately 3 weeks in vitro, hippocampal neurons present many of the typical hallmarks accompanying neuronal aging in vivo, including accumulation of reactive oxygen species (ROS), lipofuscin granules, heterochromatic foci, and activation of the Jun N-terminal protein kinase (pJNK) and p53/p21 pathways. In addition, hippocampal neurons in vitro undergo a gradual loss of cholesterol, which is important for the activation of the prosurvival tyrosine kinase receptor TrkB. Here, we used the hippocampal in vitro system to investigate the possible cause of age-accompanying cholesterol loss. We report that cholesterol loss during in vitro aging is paralleled by upregulation and translocation to the neuronal surface of cholesterol-24-hydroxylase (Cyp46), the enzyme responsible for cholesterol removal from neurons. Chronic reduction of electrical activity diminished cholesterol loss in aged neurons and precluded the upregulation of cholesterol-24-hydroxylase. In agreement with a cause-effect relationship, stimulation of excitatory neurotransmission in young neurons led to cholesterol loss. Mechanistically, N-methyl-D-aspartate (NMDA)-mediated excitatory neurotransmission leads to cholesterol loss through generation of reactive oxygen species derived from the activation of the stress-responsive enzyme NADPH oxidase. Supporting the relevance of the in vitro data, reduced cholesterol was also detected in synaptic membranes from old mice brains. Furthermore, excitatory neurotransmission via the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase pathway induced cholesterol loss in purified brain synaptosomes. The current studies highlight excitatory neurotransmission as 1 of the mechanisms involved in cholesterol loss during aging.Neurobiology of aging 06/2011; 32(6):1043-53. DOI:10.1016/j.neurobiolaging.2010.06.001 · 4.85 Impact Factor
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ABSTRACT: Zonisamide, originally known as an antiepileptic drug, has been approved in Japan as adjunctive therapy with levodopa for the treatment of Parkinson's disease (PD). Although zonisamide reduces neurotoxicity, the precise mechanism of this action is not known. Here, we show that zonisamide increases cell viability in SH-SY5Y cells via an anti-apoptotic effect and by upregulating levels of manganese superoxide dismutase (MnSOD). These results would give us novel evidences of PD treatment.Neuroscience Letters 09/2010; 481(2):88-91. DOI:10.1016/j.neulet.2010.06.058 · 2.06 Impact Factor