Toward understanding of Friedreich's ataxia
J Am Chem Soc Jan. 16, 2013
Feb. 11, 2013
In partnership with two research groups from the CEA, Hélène Puccio’s team at the IGBMC unveiled the role of a protein called frataxin in the biosynthesis of iron-sulfur clusters. These results present a major advance in understanding the pathophysiology of Friedreich's Ataxia, a rare genetic disorder. A study published December 20th, 2012 in the Journal of the American Chemical Society.
Involved in many biological functions, such as transcription, translation, replication of DNA, generation of energy or control of cellular iron content, iron-sulfur clusters are essential chemical groups for life. Formed by assembly of iron and sulfide ions, they provide through their chemical properties, specific functions to proteins they are associated with. The biosynthesis of iron-sulfur clusters occurs in the mitochondria through a multi-protein complex, one of the most conserved cellular machinery during evolution. Present throughout the animal kingdom, this machinery is present from bacteria to humans and is the cause of many diseases, such as ataxia, encephalopathy, anemia, or myopathies, when it fails.
Initially implicated in Friedreich's ataxia, the function of frataxin, one of the four proteins of the complex, has raised interest of the scientific community for over a decade. Various studies have shown its involvement in cellular iron metabolism and more recently in the synthesis of iron-sulfur clusters. The study performed by Hélène Puccio’s group in collaboration with two teams from the CEA, has now revealed the role of frataxin in the first step of iron-sulfur cluster biosynthesis. The researchers compared in an interdisciplinary approach combining molecular biology, biochemistry and biophysics, the activity of the complex in the presence and absence of frataxin.
Scientists have highlighted the role of the protein during the assembly of the cluster’s building blocks. It controls the entry of the iron in the complex through the activation of the cysteine desulfurase, an enzyme which provides the sulfur atoms, showing for the first time that iron-sulfur clusters are formed by the simultaneous entrance of its two constitutive elements. Moreover, they have shown that frataxin protects the newly formed iron-sulfur cluster in the complex, within the protein scaffold ISCU, by preventing the dissociation of the complex structure and then allowing the cluster transfer to mitochondrial proteins.
Beyond the understanding of an essential process common to all forms of life, this study reveals the function of frataxin, the protein deficient in Friedreich's ataxia. This rare disorder that combines a progressive neurodegenerative disorder, cardiomyopathy and an increase incidence in diabetes, affects one birth out of 50,000. Currently, therapeutic strategies attempt to reduce the negative effects arising from the loss of functional frataxin. A better understanding of the role of the protein is essential for the design of more effective drugs that would directly target the cause of the disorder, by creating, for example, molecules that could mimick the biological properties of frataxin.