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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.
AuthorsNadia Stefanova, Kathrin Schanda, Lars Klimaschewski, Werner Poewe, Gregor K Wenning, Markus Reindl
JournalJournal of neuroscience research (J Neurosci Res) Vol. 73 Issue 3 Pg. 334-40 (Aug 01 2003) ISSN: 0360-4012 [Print] United States
PMID12868067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2003 Wiley-Liss, Inc.
Chemical References
  • Antineoplastic Agents
  • Nerve Tissue Proteins
  • SNCA protein, human
  • Synucleins
  • Tumor Necrosis Factor-alpha
  • alpha-Synuclein
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects, physiology)
  • Brain Neoplasms
  • Cytoskeleton (physiology)
  • Gene Expression
  • Glioblastoma
  • Humans
  • Nerve Tissue Proteins (genetics)
  • Synucleins
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha (pharmacology)
  • alpha-Synuclein

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