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Volume 17, Number 6, Issue of March 15, 1997 pp. 1911-1918
Copyright ©1997 Society for Neuroscience

Nedd2 Is Required for Apoptosis after Trophic Factor Withdrawal, But Not Superoxide Dismutase (SOD1) Downregulation, in Sympathetic Neurons and PC12 Cells

Received Oct. 30, 1996; revised Dec. 19, 1996; accepted Dec. 30, 1996.

Carol M. Troy¹, Leonidas Stefanis^{1, 2}, Lloyd A. Greene¹, and Michael L. Shelanski¹

Departments of ¹ Pathology and ² Neurology, Taub Center for Alzheimer's Disease Research and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Activation of cysteine aspartases (caspases) seems to be a required element of apoptotic death in many paradigms. We have shown previously that general inhibitors of cysteine aspartases block apoptosis of PC12 cells and sympathetic neurons evoked by either trophic factor (nerve growth factor and/or serum) deprivation or superoxide dismutase (SOD1) downregulation. Moreover, activation of a caspase family member similar or equivalent to the interleukin-1-converting enzyme (ICE) was implicated for death caused by SOD1 downregulation, but not withdrawal of trophic support. The experiments presented here demonstrate that diminished expression of the cysteine aspartase Nedd2 in PC12 cells and sympathetic neurons induced by an appropriate vector peptide-linked antisense oligonucleotide rescues them from death caused by trophic factor deprivation without inhibiting apoptosis in the same cell types evoked by SOD1 downregulation. Neither the level (as revealed by Western immunoblotting) nor the cellular distribution (as revealed immunohistochemically) of Nedd2 was altered demonstrably by trophic factor deprivation. However, evidence for proteolytic processing of Nedd2 (consistent with commencement of activation) was observed in PC12 cells after withdrawal of trophic support. These findings indicate that neuronal death triggered by different initial causes may be mediated by distinct members of the cysteine aspartase family.

Key words: Nedd2; cysteine aspartases; apoptosis; neuronal cell death; oxidative stress; trophic factor deprivation

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