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 the 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 is 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.
|Williams, Jared R; Trias, Emiliano; Beilby, Pamela R et al. (2016) Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD. Neurobiol Dis 89:1-9|
|Franco, Maria C; Ricart, Karina C; Gonzalez, Analía S et al. (2015) Nitration of Hsp90 on Tyrosine 33 Regulates Mitochondrial Metabolism. J Biol Chem 290:19055-66|
|Adams, Levi; Franco, Maria C; Estevez, Alvaro G (2015) Reactive nitrogen species in cellular signaling. Exp Biol Med (Maywood) 240:711-7|
|Dennys, Cassandra N; Armstrong, JeNay; Levy, Mark et al. (2015) Chronic inhibitory effect of riluzole on trophic factor production. Exp Neurol 271:301-7|
|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|
|Shi, Qingli; Xu, Hui; Yu, Haiqiang et al. (2011) Inactivation and reactivation of the mitochondrial ?-ketoglutarate dehydrogenase complex. J Biol Chem 286:17640-8|
|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|
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