26th Meeting of the Hellenic Society for Neuroscience, November 29-December 1, 2013 Jointly with FP7 REGPOT NEUROSIGN TARGETING INFLAMMATORY PATHWAYS TO PROTECT DOPAMINERGIC NEURONS: RELEVANCE TO PARKINSON’S DISEASE X. Chen1,T. N. Martinez2, S. Bandyopadhyay3, A. H. Merrill3, M. G. Tansey1,2, 1
Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322; Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390; 3Sch. of Biol. and the Petit Inst. for Bioengineering and Bioscience., Georgia Inst. of Technol., Atlanta, GA 30332 USA 2
The role of inflammation and immunological processes in the pathogenesis of neurodegenerative diseases is an area of intense investigation. A wealth of new data suggest that neuroinflammatory mechanisms contribute to the pathophysiology of Parkinson’s disease (PD). Our group has previously demonstrated that neutralization of soluble tumor necrosis factor (TNF) by dominant-negative TNF (DN-TNF) inhibitors significantly attenuated the loss of DA neurons both in vitro and in vivo in rat models of nigral cell death and studies are ongoing to extend and confirm these findings in non-human primate models of PD. However, the identity of the signaling pathways downstream of soluble TNF required to mediate neurotoxicity and degeneration remain to be fully elucidated. Using a mouse DA neuron-like cell line (MN9D) and rat primary neuron-glia cultures from ventral mesencephalon (VM), we have identified cellular and signaling mechanisms by which TNF induces DA neuron death. Ceramide is a sphingosine-based lipid signaling molecule downstream of TNF that is involved in the regulation of cellular differentiation, proliferation and apoptosis. Using lipidomics and high-content imaging approaches, we have discovered that soluble TNF-dependent generation of ceramide species and two novel atypical sphingoid bases exert toxic effects on primary DA neurons by triggering ER stress and disrupting mitochondrial respiration leading to their degeneration. Pharmacological inhibitors of sphingomyelinase (SMase), an enzyme that hydrolyzes active ceramide from inactive sphingomyelin pools attenuated solTNF-dependent toxicity in MN9D cells and primary DA neurons from VM. Ongoing studies to understand the links between ceramide metabolism and TNF-dependent death of DA neurons may reveal novel targets for drug discovery and may provide an opportunity to evaluate neuroprotective effects of compounds that prevent formation of toxic ceramide species or aid in their metabolism with the longterm goal of identifying new therapeutic strategies for PD.
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