Our long-term goal is to understand how mutations to SOD can increase oxidative stress and cause the death of motor neurons in amyotrophic lateral sclerosis (ALS). We have shown that endogenous formation of peroxynitrite by the diffusion-limited reaction between superoxide and nitric oxide induces apoptosis in cultured embryonic rat motor neurons deprived of trophic support. Both inhibitors of nitric oxide synthesis as well as Cu.Zn superoxide dismutase (SOD) delivered intracellularly with liposomes protect motor neurons from apoptosis. These data indicate that the interaction between nitric oxide and superoxide has a role in motor neuron apoptosis. Mutations to SOD are implicated in the selective degeneration of motor neurons in ALS and expression of ALS- SOD mutants in transgenic mice produces motor neuron disease. A common phenotype among the ALS-SOD mutations so far investigated is to decrease the affinity for zinc. We have shown that zinc-deficient SOD is both less efficient at scavenging superoxide and a better catalyst of tyrosine nitration. Furthermore, the copper in zinc-deficient SOD can act as a non-specific one-electron oxidase, robbing electrons from antioxidants like ascorbate and glutathione that can be transferred to oxygen to produce superoxide. In the presence of NO, zinc-deficient SOD can catalyze the formation of peroxynitrite. In the previous cycle of funding, we have shown that zinc-deficient SOD induces apoptosis in motor neurons by a nitric oxide-dependent mechanism. For the renewal, our first aim is to further investigate the mechanisms by which zinc-deficient SODs can kill cultured motor neurons and to determine what can protect motor neurons from this toxicity.
Our second aim i s to characterize the source or sources of superoxide induced in motor neurons by trophic factor withdrawal.
Our third aim i s to test the role of tyrosine nitration by peroxynitrite in the death of motor neurons induced by either trophic factor deprivation or by zinc-deficient SOD. Completion of the specific aims will provide a mechanistic basis for explaining how motor neurons are particularly vulnerable to SOD mutations and establish a link between sporadic and familial SODs.
|Franco, María C; Estévez, Alvaro G (2014) Tyrosine nitration as mediator of cell death. Cell Mol Life Sci 71:3939-50|
|Viera, Liliana; Radmilovich, Milka; Vargas, Marcelo R et al. (2013) Temporal patterns of tyrosine nitration in embryo heart development. Free Radic Biol Med 55:101-8|
|Franco, Maria Clara; Ye, Yaozu; Refakis, Christian A et al. (2013) Nitration of Hsp90 induces cell death. Proc Natl Acad Sci U S A 110:E1102-11|
|Magrané, Jordi; Sahawneh, Mary Anne; Przedborski, Serge et al. (2012) Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci 32:229-42|
|Sahawneh, Mary Anne; Ricart, Karina C; Roberts, Blaine R et al. (2010) Cu,Zn-superoxide dismutase increases toxicity of mutant and zinc-deficient superoxide dismutase by enhancing protein stability. J Biol Chem 285:33885-97|
|Estevez, Alvaro G (2007) Good science shows the way. Highlight Commentary on "Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice--a model of familial amyotrophic lateral sclerosis". Free Radic Biol Med 43:163-4|
|Ye, Yaozu; Quijano, Celia; Robinson, Kristine M et al. (2007) Prevention of peroxynitrite-induced apoptosis of motor neurons and PC12 cells by tyrosine-containing peptides. J Biol Chem 282:6324-37|
|Lu, Liang; Zheng, Lei; Viera, Liliana et al. (2007) Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. J Neurosci 27:7929-38|
|Schonhoff, Christopher M; Matsuoka, Masaaki; Tummala, Hemachand et al. (2006) S-nitrosothiol depletion in amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:2404-9|
|Shacka, J J; Sahawneh, M A; Gonzalez, J D et al. (2006) Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells. Cell Death Differ 13:1506-14|
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