Peroxynitrite is a powerful oxidant that initiates apoptosis in diverse cell types. The applicant has shown that peroxynitrite produced by the diffusion-limited reaction between superoxide and nitric oxide induces apoptosis in cultured embryonic rat motor neuron deprived of atrophic support. Both inhibitors of nitric oxide synthesis and wild type Cu/Zn superoxide dismutase (SOD) delivered intracellularly with liposomes protect trophic factor deprived motor neurons from apoptosis. Mutations to superoxide dismutase are implicated in the selective degeneration of motor neurons in ALS and expression of SOD mutants associated with ALS induces neuronal apoptosis in cultures. The applicant has previously suggested that the main function of SOD mutants results from increased catalysis of tyrosine nitration by peroxynitrite. SOD can catalyze nitration of tyrosine and protein by peroxynitrite to form 3-nitrotyrosine. Nitration can disrupt both tyrosine kinase signal transduction and the assembly of structural proteins. Tyrosine nitration occurs in ALS and other neurodegenerative disorders including Parkinson's Disease, multiple sclerosis and Alzheimer's Disease. The common phenotype among all ALS/SOD mutations so far investigated is a decreased affinity for zinc. Zinc deficient SOD is both less efficient at scavenging superoxide and is also a better catalyst of tyrosine nitration. In the present application the applicant hypothesizes that motor neurons under stress increase the rates of both nitric oxide and superoxide production which makes these neurons particularly vulnerable to zinc-deficient SOD. The applicant proposes to investigate the induction of neuronal nitric oxide synthase in cultured rat embryonic motor neurons deprived of trophic support and characterize the sources of superoxide in motor neurons. Using efficient pH sensitive liposomes to deliver SOD with defined metal contents to motor neurons, the applicant will examine the role of zinc-deficient SOD in initiating apoptosis in motor neurons and whether nitric oxide is necessary for the toxicity of ALS mutant SOD. Completion of the specific aims will help explain why motor neurons are particularly vulnerable to mutations in SOD associated with ALS.
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| 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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