Abstract
Friedreich’s ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets.
Highlights
Friedreich’s ataxia (FRDA) is a neurodegenerative disorder caused by an intronic GAA expansion within FXN, the gene encoding frataxin [1]
Frataxin deficiency in Drosophila leads to metal accumulation Iron accumulation occurs in several tissues of FRDA patients [9,10,11,12] and in models of disease [14,27,28,29]
Atomic emission spectroscopic analysis revealed an increase in iron levels but that zinc, copper, manganese and aluminum were increased in the FRDA flies relative to control animals (Fig 1A)
Summary
Friedreich’s ataxia (FRDA) is a neurodegenerative disorder caused by an intronic GAA expansion within FXN, the gene encoding frataxin [1]. A total of 130 candidate lines from the VDRC and BSC selected for genes in metal homeostasis pathways were used to identify genetic modifiers of the external eye structure and the motor performance phenotypes induced by frataxin knockdown in Drosophila.
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