TY - JOUR T1 - A novel SOD1-dependent mechanism for the iron-induced production of toxic SOD1 and oxidative stress that initiates ALS JF - bioRxiv DO - 10.1101/018846 SP - 018846 AU - Liangzhong Lim AU - Jianxing Song Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/05/01/018846.abstract N2 - 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 and carries >180 ALS-causing mutations. Here, by NMR we show that Zn2+ play an irreplaceable role in the maturation of the nascent hSOD1, and decipher for the first time that Fe2+ has the Zn2+-like capacity in triggering the 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 provoking oxidative stress and trapping SOD1 in toxic forms. Our study thus establishes a novel SOD1-dependent mechanism for iron to manifest its cellular toxicity which contributes to pathogenesis of neurodegenerative diseases, aging or even more. ER -