Friedreich’s ataxia and tight iron utilization

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Friedreich’s ataxia is a genetic disease, where there are expansions of GAA trinucleotide repeats in intron 1 of both frataxin alleles. Gait and limb ataxia, dysarthria and loss of lower limb reflexes are clinical features Friedrich’s ataxia.

Mice models of Friedreich’s ataxia have been developed in which the gene for frataxin in is mutated, where the mice exhibit a progressive Friedreich’s ataxia-like pathology. Frataxin binds iron which assists in iron-sulfur cluster biogenesis.

Giving mice, with ataxia due to mutations in genes for frataxin, iron from iron carbonyl by gavage three times a day could be a treatment for such an ataxia as iron carbonyl given by gavage three times a day could tightly regulate iron utilization, making iron constantly available thereby making the frataxin protein less required or even redundant. As the iron chelator, desferal decreases expressiot of frataxin, carbonyl iron given by gavage three times a day to mice could also increase expression of the gene for frataxin.

As deferiprone, an iron chelator, can worsen ataxia in patients with Friedreich’s ataxia iron carbonyl given three times a day to humans could be part of a treatment for Friedreich’s ataxia. Prior to any clinical trials in humans, carbonyl iron, given by gavage three times a day from birth to mice with mutated frataxin genes, would have to stop a Friedreich’s ataxia-like pathology from developing and/or treat in mice, a Friedreich’s ataxia-like pathology after mice with mutated frataxin genes develope a Friedreich’s ataxia-like pathology.

Difficulties in iron-sulfur cluster formation can lead to iron accumulation in mitochondria

In Friedreich ataxia iron-sulfur clusters are not formed, due to deficiencies in frataxin which results in iron accumulation in mitochondria. The relevant point is that problems in iron-sulfur cluster formation can be associated with iron accumulation in mitochondria and iron toxicity. The point I have been making is that there are difficulties in synthesizing iron-sulfur clusters in many neurological illnesses due to dysregulation of the transsulfuration pathway which synthesizes L-cysteine. L-cysteine supplies sulfur for iron-sulfur cluster formation.

Iron chelators are now being investigated as treatments for Alzheimer’s disease and Parkinson’s disease. If iron is being accumulated in cells in Alzheimer’s disease and Parkinson’s disease due to difficulties in iron-sulfur cluster formation then iron chelators would not be appropriate treatments. Iron-sulfur cluster formation is increased by supplemental iron. Iron chelators by decreasing iron would decrease iron–sulfur cluster formation leading to iron accumulation in mitochondria and iron toxicity.