Hepcidin-Ferroportin axis in Friedreich’s Ataxia

One of the open questions in Friedreich’s ataxia (FRDA) is elucidating the role of iron in the development of the disease. In the heart and brain of FRDA, abnormal iron deposits are found in the mitochondria, the cell organelles mostly affected by the disease. Abnormal iron deposition is believed to trigger damage to mitochondria and contribute to disease manifestations. Over the past years, research in other fields identified the protein hepcidin (HAMP) as the main regulator of iron metabolism in the human body. HAMP is produced by the liver and, in conditions of iron excess, binds to ferroportin (FPN), an iron-exporting protein located in the cell membrane. This binding triggers FPN destruction and thus prevents the outflow of the ingested iron from the intestinal cells in the blood. Few studies in autopsies and in mouse models suggested that the HAMP pathway may be altered in FRDA. To explore HAMP involvement in FRDA, Dr. Indelicato designed a pilot study in which she will measure levels of HAMP, iron and copper parameters, erythropoietin and erythroferrone (another human hormone with iron-regulating properties), as well as frataxin and FPN expression in blood cells of FRDA patients, carriers and control subjects. Moreover, Dr. Indelicato will study if iron accumulates in organs other than the nervous system and the heart by means of an MRI examination of the abdomen, which can visualize iron content in the liver, pancreas, and spleen. The aim of this proposal is to elucidate if the whole-body regulation of iron through the key factors HAMP and FNP is impaired in FRDA. These findings will help to guide therapeutic interventions on iron metabolism in FRDA and will help to understand if levels of HAMP may provide indirect information on disease state in FRDA.