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Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

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Final rept. 1 Sep 2011-31 Aug 2013

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Iron accumulation and deposition have been reported in patients with amyotrophic lateral sclerosis ALS. Previous work in mutant SOD1 mice mouse models of ALS have indicated that iron chelation with a chemical agent extends lifespan. Therefore, we propose the use of apo-ferritin, the iron-storage protein ferritin that is iron-poor, as a natural ionophore to sequester excess iron and redistribute it. The overall hypothesis is that infusion of apo-ferritin protein into the brain will provide neuroprotection by limiting the availability of excess iron to catalyze free-radical production. The most significant findings from this project are 1. Infusion of artificial cerebrospinal fluid aCSF containing nutrients, including H-ferritin, increases lifespan and delays onset of disease in SOD1G93A mice 2. This effect is not achieved by infusion of saline, suggesting that there is more than just a mechanical benefit to increasing flow of CSF 3 In an accelerated disease model of ALS where mice carry both the HFEH67D allelic variant, present in 30 of ALS patients, and the SOD1G93A mutation, infusion of aCSF with or without H-ferritin is not beneficial. The high rate of oxidative stress in these animals may be too great for an infusion strategy 4. Infusion of H-ferritin protein encapsulated in liposomes is even more effective at delaying onset and extending lifespan than H-ferritin protein directly infused. The potential clinical significance of this work is that increasing turn-over of cerebrospinal fluid, and providing H-ferritin in a manner that may be more likely to be taken up by cells, appear to be viable therapeutic options for ALS patients.

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  • Biochemistry

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