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Journal of Neuroscience, Vol 16, 253-261, Copyright © 1996 by Society for Neuroscience
Downregulation of Cu/Zn superoxide dismutase leads to cell death via the nitric oxide-peroxynitrite pathway
CM Troy, D Derossi, A Prochiantz, LA Greene and ML Shelanski
Department of Pathology, Taub Center for Alzheimer's Disease Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
We previously showed that the downregulation of Cu/Zn superoxide dismutase
(SOD1) activity in PC12 cells by exposure to an appropriate antisense
oligonucleotide causes their apoptotic death. In this report, we used this
model to examine the pathways by which SOD1 downregulation leads to death
and to compare these pathways with those responsible for death caused by
withdrawal of trophic support. To improve delivery of the SOD1 antisense
oligonucleotide, we coupled it to a carrier "vector" peptide homologous to
the third helix of the Drosophila Antennapedia homeodomain. This caused not
only efficient cellular uptake even in the presence of serum, but also
inhibition of SOD1 activity and promotion of apoptosis at 100-fold lower
concentrations of oligonucleotide. Death induced by SOD1 downregulation
appeared to require the reaction of superoxide with nitric oxide (NO) to
form peroxynitrite. In support of this, inhibitors of NO synthase, the
enzyme responsible for NO synthesis, blocked death in our experiments,
whereas NO generators and donors accelerated cell death. N-Acetylcysteine
and chlorophenylthiol cAMP, which rescue PC12 cells and neurons from the
withdrawal of nerve growth factor and other forms of trophic support, did
not protect PC12 cells from SOD1 downregulation. In contrast,
overexpression of bcl-2, which also rescues these cells form loss of
trophic support, was equally effective in saving the cells in the SOD1
downregulation paradigm. Taken together with past findings, such
observations suggest that SOD1 downregulation and withdrawal of trophic
support trigger apoptosis via distinct initial mechanisms but may utilize a
common final pathway to bring about death. Our findings may be relevant to
the causes and potential amelioration of neuronal degenerative disorders
caused by impaired regulation of cellular levels of NO and superoxide.
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