title: Tumor necrosis factor-alpha-induced cell death in U373 cells overexpressing alpha-synuclein.
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.
authors.affiliation: Department of Neurology, University of Innsbruck, Innsbruck, Austria.
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schanda
authors.forename: Lars
authors.initials: L
authors.lastname: Klimaschewski
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001932:Brain Neoplasms; D003599:Cytoskeleton / Q000502:physiology; D015870:Gene Expression; D005909:Glioblastoma; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051843:Synucleins; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051844:alpha-Synuclein
chemical_list: D000970:Antineoplastic Agents; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D014409:Tumor Necrosis Factor-alpha; D051844:alpha-Synuclein