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Tumor necrosis factor-alpha-induced cell death in U373 cells overexpressing alpha-synuclein
Authors:Stefanova Nadia  Schanda Kathrin  Klimaschewski Lars  Poewe Werner  Wenning Gregor K  Reindl Markus
Affiliation:Department of Neurology, University of Innsbruck, Innsbruck, Austria.
Abstract:Intracellular alpha-synuclein inclusion formation in glial cells is frequently seen in Parkinson's disease and multiple system atrophy. Microglial activation in these neurodegenerative disorders suggests that neuroinflammatory responses might interact with alpha-synuclein and contribute to the pathogenesis of these disorders. To study the role of tumor necrosis factor-alpha (TNF-alpha), an important proinflammatory cytokine produced by microglia, on cells overexpressing alpha-synuclein we have used the astrocytoma cell line U373 engineered to express C-terminally truncated alpha-synuclein as a fusion protein with red or green fluorescent proteins. We demonstrate that alpha-synuclein overexpression augmented TNF-alpha-induced apoptotic cell death in U373 cells by induction of caspase activation. Furthermore, TNF-alpha exposure was associated with significant cytoskeletal changes characterized by altered inclusion composition with loss of cytoskeletal proteins and elevation of high-molecular-weight alpha-synuclein species. We conclude that alpha-synuclein overexpression significantly increases the vulnerability of U373 cells to apoptosis through TNF-alpha-mediated pathways.
Keywords:α‐synuclein  apoptosis  glia  TNF‐α  U373
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