A novel SOD1-dependent mechanism for the iron-induced production of toxic SOD1 and oxidative stress that initiates ALS

Free iron is highly toxic and the blood-derived iron initiates early motor-neuron degeneration upon breakdown of blood-spinal cord barrier. Iron is currently known to trigger oxidative stress by Fenton chemistry but no report implies that iron manifests its toxicity through CuZn-superoxide dismutase (SOD1), the central antioxidant enzyme in all human tissues that carries >180 ALS-causing mutations. Here, by NMR we show that Zn2+ play an irreplaceable role in the maturation of the nascent hSOD1, and further decipher for the first time that out of 11 other cations only Fe2+ has the Zn2+-like capacity to induce folding to form the Fe2+-bound hSOD1. This acts to reduce or even block the maturation of wild-type and ALS-causing mutant hSOD1, consequently trapping SOD1 in toxic forms and provoking oxidative stress. Our study establishes a novel SOD1-dependent mechanism for iron to manifest cellular toxicity that contributes to pathogenesis of neurodegenerative diseases, aging and even more.

Renal redox response to normal pregnancy in the rat

Normal pregnancy involves increased renal sodium reabsorption, metabolism, and oxygen consumption, which can cause increased oxidative stress (OS). OS can decrease nitric oxide (NO) bioavailability and cause pregnancy complications. In this study we examined the NO synthases (NOS) and redox state in the kidney cortex and aorta in early (E), mid (M), and late (L) pregnant (P) ( days 3, 12, 20) and 2–4 days postpartum (PP) rats compared with virgin rats (V). Protein abundance of endothelial NOS (eNOS) was unchanged and neuronal NOS (nNOS)α fell at LP in the kidney cortex. Kidney cortex nNOSβ was elevated at MP, LP, and PP. No changes in aortic NOS isoforms were observed. Kidney cortex nitrotyrosine (NT) abundance decreased in EP, MP, and PP, whereas aortic NT increased in EP, MP, and PP. The NADPH oxidase subunit p22phox decreased in the kidney cortex at EP while aortic p22phox increased in EP and LP. No changes in kidney cortex NADPH-dependent superoxide production or hydrogen peroxide levels were noted. Kidney cortex cytosolic (CuZn) superoxide dismutase (SOD) was unchanged, while mitochondrial SOD decreased at EP and extracellular SOD decreased at MP and LP in the kidney cortex. Despite falls in abundance of kidney cortex SODs, total antioxidant capacity (TAC) was elevated in EP, MP, and PP in the kidney cortex. Aortic CuZn SOD deceased at PP, while the other aortic SODs and aortic TAC did not change. Data from this study suggest that the kidney cortex is protected from OS during normal rat pregnancy via an increase in antioxidant activity.