 |
 Previous Article | Next Article 
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.
This article has been cited by other articles:
|
|
|
|
 
P. C. Patel, D. A. Giljohann, D. S. Seferos, and C. A. Mirkin
Nanomaterials in Medicine Special Feature Sackler Colloquium: Peptide antisense nanoparticles
PNAS,
November 11, 2008;
105(45):
17222 - 17226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-C. Zhang, L.-M. Mao, X.-Y. Liu, N. K. Parelkar, A. Arora, L. Yang, M. Hains, E. E. Fibuch, and J. Q. Wang
In Vivo Regulation of Homer1a Expression in the Striatum by Cocaine
Mol. Pharmacol.,
April 1, 2007;
71(4):
1148 - 1158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Aquilano, P. Vigilanza, G. Rotilio, and M. R. Ciriolo
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuroblastoma cells: a rationale for the redundancy of SOD1
FASEB J,
August 1, 2006;
20(10):
1683 - 1685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Turner, A. A. Arzumanov, and M. J. Gait
Synthesis, cellular uptake and HIV-1 Tat-dependent trans-activation inhibition activity of oligonucleotide analogues disulphide-conjugated to cell-penetrating peptides
Nucleic Acids Res.,
January 7, 2005;
33(1):
27 - 42.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Davidson, S. Harel, V. A. Arboleda, G. F. Prunell, M. L. Shelanski, L. A. Greene, and C. M. Troy
Highly Efficient Small Interfering RNA Delivery to Primary Mammalian Neurons Induces MicroRNA-Like Effects before mRNA Degradation
J. Neurosci.,
November 10, 2004;
24(45):
10040 - 10046.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Maruyama, T. Ohuchi, K. Yoshida, Y. Shibata, F. Sugawara, and T. Arai
Protective Properties of Neoechinulin A against SIN-1-Induced Neuronal Cell Death
J. Biochem.,
July 1, 2004;
136(1):
81 - 87.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Binder and G. Lindblom
Charge-Dependent Translocation of the Trojan Peptide Penetratin across Lipid Membranes
Biophys. J.,
August 1, 2003;
85(2):
982 - 995.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Moncion, N. T. Truong, A. Garrone, P. Beaune, R. Barouki, and I. de Waziers
Identification of a 16-Nucleotide Sequence That Mediates Post-transcriptional Regulation of Rat CYP2E1 by Insulin
J. Biol. Chem.,
November 22, 2002;
277(48):
45904 - 45910.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Troy, J. E. Friedman, and W. J. Friedman
Mechanisms of p75-mediated Death of Hippocampal Neurons. ROLE OF CASPASES
J. Biol. Chem.,
September 6, 2002;
277(37):
34295 - 34302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. S. Levenson, K. M. Svoboda, K. M. Pease, S. A. Kaiser, B. Chen, L. A. Simons, B. D. Jovanovic, P. A. Dyck, and V. C. Jordan
Gene Expression Profiles with Activation of the Estrogen Receptor {alpha}-Selective Estrogen Receptor Modulator Complex in Breast Cancer Cells Expressing Wild-Type Estrogen Receptor
Cancer Res.,
August 1, 2002;
62(15):
4419 - 4426.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Heigold, C. Sers, W. Bechtel, B. Ivanovas, R. Schafer, and G. Bauer
Nitric oxide mediates apoptosis induction selectively in transformed fibroblasts compared to nontransformed fibroblasts
Carcinogenesis,
June 1, 2002;
23(6):
929 - 941.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Oubrahim, P. B. Chock, and E. R. Stadtman
Manganese(II) Induces Apoptotic Cell Death in NIH3T3 Cells via a Caspase-12-dependent Pathway
J. Biol. Chem.,
May 31, 2002;
277(23):
20135 - 20138.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Delledonne, J. Zeier, A. Marocco, and C. Lamb
Signal interactions between nitric oxide and reactive oxygen intermediates in the plant hypersensitive disease resistance response
PNAS,
October 16, 2001;
(2001)
231178298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Paxinou, Q. Chen, M. Weisse, B. I. Giasson, E. H. Norris, S. M. Rueter, J. Q. Trojanowski, V. M.-Y. Lee, and H. Ischiropoulos
Induction of {alpha}-Synuclein Aggregation by Intracellular Nitrative Insult
J. Neurosci.,
October 15, 2001;
21(20):
8053 - 8061.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Troy, S. A. Rabacchi, J. B. Hohl, J. M. Angelastro, L. A. Greene, and M. L. Shelanski
Death in the Balance: Alternative Participation of the Caspase-2 and -9 Pathways in Neuronal Death Induced by Nerve Growth Factor Deprivation
J. Neurosci.,
July 15, 2001;
21(14):
5007 - 5016.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. K. Combs, J. C. Karlo, S.-C. Kao, and G. E. Landreth
{beta}-Amyloid Stimulation of Microglia and Monocytes Results in TNF{alpha}-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis
J. Neurosci.,
February 15, 2001;
21(4):
1179 - 1188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Milhavet, H. E. M. McMahon, W. Rachidi, N. Nishida, S. Katamine, A. Mangé, M. Arlotto, D. Casanova, J. Riondel, A. Favier, et al.
Prion infection impairs the cellular response to oxidative stress
PNAS,
November 22, 2000;
(2000)
250289197.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J. F. Torres-Roca, J. W. Tung, D. R. Greenwald, J. M. Brown, L. A. Herzenberg, L. A. Herzenberg, and P. D. Katsikis
An Early Oxygen-Dependent Step Is Required for Dexamethasone-Induced Apoptosis of Immature Mouse Thymocytes
J. Immunol.,
November 1, 2000;
165(9):
4822 - 4830.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Gow, Q. Chen, M. Gole, M. Themistocleous, V. M.-Y. Lee, and H. Ischiropoulos
Two distinct mechanisms of nitric oxide-mediated neuronal cell death show thiol dependency
Am J Physiol Cell Physiol,
June 1, 2000;
278(6):
C1099 - C1107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Ciriolo, A. De Martino, E. Lafavia, L. Rossi, M. T. Carri, and G. Rotilio
Cu,Zn-Superoxide Dismutase-dependent Apoptosis Induced by Nitric Oxide in Neuronal Cells
J. Biol. Chem.,
February 18, 2000;
275(7):
5065 - 5072.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Troy, S. A. Rabacchi, W. J. Friedman, T. F. Frappier, K. Brown, and M. L. Shelanski
Caspase-2 Mediates Neuronal Cell Death Induced by beta -Amyloid
J. Neurosci.,
February 15, 2000;
20(4):
1386 - 1392.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. G. Nicholls and S. L. Budd
Mitochondria and Neuronal Survival
Physiol Rev,
January 1, 2000;
80(1):
315 - 360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-Y. Zhang and S. H. Phan
Inhibition of Myofibroblast Apoptosis by Transforming Growth Factor beta 1
Am. J. Respir. Cell Mol. Biol.,
December 1, 1999;
21(6):
658 - 665.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
C. Raoul, C. E. Henderson, and B. Pettmann
Programmed Cell Death of Embryonic Motoneurons Triggered through the Fas Death Receptor
J. Cell Biol.,
November 29, 1999;
147(5):
1049 - 1062.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Zaman, H. Ryu, D. Hall, K. O'Donovan, K.-I Lin, M. P. Miller, J. C. Marquis, J. M. Baraban, G. L. Semenza, and R. R. Ratan
Protection from Oxidative Stress-Induced Apoptosis in Cortical Neuronal Cultures by Iron Chelators Is Associated with Enhanced DNA Binding of Hypoxia-Inducible Factor-1 and ATF-1/CREB and Increased Expression of Glycolytic Enzymes, p21waf1/cip1, and Erythropoietin
J. Neurosci.,
November 15, 1999;
19(22):
9821 - 9830.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Balabanli, Y. Kamisaki, E. Martin, and F. Murad
Requirements for heme and thiols for the nonenzymatic modification of nitrotyrosine
PNAS,
November 9, 1999;
96(23):
13136 - 13141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Arstall, D. B. Sawyer, R. Fukazawa, and R. A. Kelly
Cytokine-Mediated Apoptosis in Cardiac Myocytes : The Role of Inducible Nitric Oxide Synthase Induction and Peroxynitrite Generation
Circ. Res.,
October 29, 1999;
85(9):
829 - 840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-M. Kim, H.-T. Chung, S.-S. Kim, J.-A Han, Y.-M. Yoo, K.-M. Kim, G.-H. Lee, H.-Y. Yun, A. Green, J. Li, et al.
Nitric Oxide Protects PC12 Cells from Serum Deprivation-Induced Apoptosis by cGMP-Dependent Inhibition of Caspase Signaling
J. Neurosci.,
August 15, 1999;
19(16):
6740 - 6747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Yan and J. N. Barrett
Purification from Bovine Serum of a Survival-Promoting Factor for Cultured Central Neurons and Its Identification as Selenoprotein-P
J. Neurosci.,
November 1, 1998;
18(21):
8682 - 8691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Lipton and P. Nicotera
{blacksquare} REVIEW : Excitotoxicity, Free Radicals, Necrosis, and Apoptosis
Neuroscientist,
September 1, 1998;
4(5):
345 - 352.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. Ara, S. Przedborski, A. B. Naini, V. Jackson-Lewis, R. R. Trifiletti, J. Horwitz, and H. Ischiropoulos
Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
PNAS,
June 23, 1998;
95(13):
7659 - 7663.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Estevez, N. Spear, J. A. Thompson, T. L. Cornwell, R. Radi, L. Barbeito, and J. S. Beckman
Nitric Oxide-Dependent Production of cGMP Supports the Survival of Rat Embryonic Motor Neurons Cultured with Brain-Derived Neurotrophic Factor
J. Neurosci.,
May 15, 1998;
18(10):
3708 - 3714.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gonzalez-Zulueta, L. M. Ensz, G. Mukhina, R. M. Lebovitz, R. M. Zwacka, J. F. Engelhardt, L. W. Oberley, V. L. Dawson, and T. M. Dawson
Manganese Superoxide Dismutase Protects nNOS Neurons from NMDA and Nitric Oxide-Mediated Neurotoxicity
J. Neurosci.,
March 15, 1998;
18(6):
2040 - 2055.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Park, E. J. Morris, L. Stefanis, C. M. Troy, M. L. Shelanski, H. M. Geller, and L. A. Greene
Multiple Pathways of Neuronal Death Induced by DNA-Damaging Agents, NGF Deprivation, and Oxidative Stress
J. Neurosci.,
February 1, 1998;
18(3):
830 - 840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Estevez, N. Spear, S. M. Manuel, R. Radi, C. E. Henderson, L. Barbeito, and J. S. Beckman
Nitric Oxide and Superoxide Contribute to Motor Neuron Apoptosis Induced by Trophic Factor Deprivation
J. Neurosci.,
February 1, 1998;
18(3):
923 - 931.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Keller, M. S. Kindy, F. W. Holtsberg, D. K. St. Clair, H.-C. Yen, A. Germeyer, S. M. Steiner, A. J. Bruce-Keller, J. B. Hutchins, and M. P. Mattson
Mitochondrial Manganese Superoxide Dismutase Prevents Neural Apoptosis and Reduces Ischemic Brain Injury: Suppression of Peroxynitrite Production, Lipid Peroxidation, and Mitochondrial Dysfunction
J. Neurosci.,
January 15, 1998;
18(2):
687 - 697.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Villa, W. Henzel, M Sensenbrenner, C. Henderson, and B Pettmann
Calpain inhibitors, but not caspase inhibitors, prevent actin proteolysis and DNA fragmentation during apoptosis
J. Cell Sci.,
January 3, 1998;
111(6):
713 - 722.
[Abstract]
[PDF]
|
|
|
|
|
|
|
G. D. Ghadge, J. P. Lee, V. P. Bindokas, J. Jordan, L. Ma, R. J. Miller, and R. P. Roos
Mutant Superoxide Dismutase-1-Linked Familial Amyotrophic Lateral Sclerosis: Molecular Mechanisms of Neuronal Death and Protection
J. Neurosci.,
November 15, 1997;
17(22):
8756 - 8766.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Ayata, G. Ayata, H. Hara, R. T. Matthews, M. F. Beal, R. J. Ferrante, M. Endres, A. Kim, R. H. Christie, C. Waeber, et al.
Mechanisms of Reduced Striatal NMDA Excitotoxicity in Type I Nitric Oxide Synthase Knock-Out Mice
J. Neurosci.,
September 15, 1997;
17(18):
6908 - 6917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. T. Gobbel, T. Y.-Y. Chan, and P. H. Chan
Nitric Oxide- and Superoxide-Mediated Toxicity in Cerebral Endothelial Cells
J. Pharmacol. Exp. Ther.,
September 1, 1997;
282(3):
1600 - 1607.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
I. Kruman, A. J. Bruce-Keller, D. Bredesen, G. Waeg, and M. P. Mattson
Evidence that 4-Hydroxynonenal Mediates Oxidative Stress-Induced Neuronal Apoptosis
J. Neurosci.,
July 1, 1997;
17(13):
5089 - 5100.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Troy, L. Stefanis, L. A. Greene, and M. L. Shelanski
Nedd2 Is Required for Apoptosis after Trophic Factor Withdrawal, But Not Superoxide Dismutase (SOD1) Downregulation, in Sympathetic Neurons and PC12 Cells
J. Neurosci.,
March 15, 1997;
17(6):
1911 - 1918.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Friedman, S. Thakur, L. Seidman, and A. B. Rabson
Regulation of Nerve Growth Factor mRNA by Interleukin-1 in Rat Hippocampal Astrocytes Is Mediated by NFkappa B
J. Biol. Chem.,
December 6, 1996;
271(49):
31115 - 31120.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Derossi, S. Calvet, A. Trembleau, A. Brunissen, G. Chassaing, and A. Prochiantz
Cell Internalization of the Third Helix of the Antennapedia Homeodomain Is Receptor-independent
J. Biol. Chem.,
July 26, 1996;
271(30):
18188 - 18193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. H. Chan
Role of Oxidants in Ischemic Brain Damage
Stroke,
June 1, 1996;
27(6):
1124 - 1129.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
A. L. Hughes, L. Gollapudi, T. L. Sladek, and K. E. Neet
Mediation of Nerve Growth Factor-driven Cell Cycle Arrest in PC12 Cells by p53. SIMULTANEOUS DIFFERENTIATION AND PROLIFERATION SUBSEQUENT TO p53 FUNCTIONAL INACTIVATION
J. Biol. Chem.,
November 22, 2000;
275(48):
37829 - 37837.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Delledonne, J. Zeier, A. Marocco, and C. Lamb
Signal interactions between nitric oxide and reactive oxygen intermediates in the plant hypersensitive disease resistance response
PNAS,
November 6, 2001;
98(23):
13454 - 13459.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Milhavet, H. E. M. McMahon, W. Rachidi, N. Nishida, S. Katamine, A. Mange, M. Arlotto, D. Casanova, J. Riondel, A. Favier, et al.
Prion infection impairs the cellular response to oxidative stress
PNAS,
December 5, 2000;
97(25):
13937 - 13942.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
