MRC National Institute for Medical Research, London
Science for Health
Shedding light on a neurodegenerative genetic disease
07 April 2009
Friedreich's ataxia (FA) was first diagnosed in 1863 by the German clinician after whom the disease is named but the gene responsible for FA was discovered only in 1996. We now know that FA patients have gene mutations which limit the production of a protein called frataxin. Frataxin is an important protein which functions in the energy producing factories of the cell, called mitochondria, but its precise function has been somewhat elusive so far.
It has been established for a long time that frataxin takes part in two important metabolic pathways related to iron, an element that is at the same time essential for life but also insoluble and toxic. It has been thought that frataxin acts as an iron chaperone, a substance which carries iron, and that it is involved with the formation of iron-sulphur clusters. These are necessary for the functioning of the mitochondria and thus for energy production in the cell.
Annalisa Pastore (picture), in NIMR's Division of Molecular Structure, has shown that frataxin is not just a chaperone but an inhibitor of the iron-sulphur cluster formation process. It regulates the formation of such clusters to match the number of available acceptors, in response to the concentration of iron. Friedreich's ataxia patients, who have only reduced quantities of frataxin, therefore lack this important regulatory process. Without it, too many iron-sulphur clusters are formed and, being unstable species, they decompose. This causes the accumulation of insoluble iron which precipitates in the cell, as is observed in the tissues of FA patients. This in turn causes metabolic damage that leads to cell death.
Dr Pastore said:
Frataxin is known to function in the mitochondria, the energy-producing factories of the cell, but until now we did not know how frataxin worked. Our research allows us a completely new perspective into understanding Friedreich's Ataxia which will hopefully help us find a cure for this debilitating disease.
Julie Greenfield from Ataxia UK, the support organisation for people with Friedreich's ataxia, welcomed these findings and said:
This research will further our understanding of the disease mechanism and provide useful information for the development of treatments.
Friedreich's ataxia is a genetic disorder which affects about one individual per 50,000 in the UK. It is a debilitating, life-shortening, degenerative neuro-muscular disorder. It is associated with the loss of coordination (ataxia) in the limbs, increased incidence of diabetes, and hypertrophic cardiomyopathy, which is a serious heart condition.
Symptoms can be observed from childhood or in young adulthood. Childhood onset of FA is usually between the ages of five and fifteen and tends to be associated with a more rapid progression. The mental capabilities of people with Friedreich's ataxia remain completely intact until the later stages. There are currently no treatments for FA.
Original article
The research findings are published in full in:
Salvatore Adinolfi, Clara Iannuzzi, Filippo Prischi, Chiara Pastore, Stefania Iametti, Stephen R Martin, Franco Bonomi and Annalisa Pastore (2009)
Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS
Nature Structural and Molecular Biology Epub ahead of print. Publisher abstract
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