Research Grant Award

Alexander P Runko, PhD

NIH/NIDS
Determination of the mitochondrial functional role of frataxin and the mechanisms that underlie the progressive neurodegeneration in Friedreich's ataxia using Drosophila

Friedreich's ataxia (FRDA) is an autosomal recessive disease, first described by the German physician Nikolaus Friedreich in the mid-19th century. This hereditary disease has an estimated incidence of 1 in 30,000 in Caucasians of European descent and is characterized by progressive neuro and cardio-degeneration. It is caused by a large guanine-adenine-adenine (GAA) repeat expansion within the first intron of the frataxin gene, resulting in reduced frataxin expression levels. The frataxin protein has been extensively studied in several organisms and it is proposed to be involved in a range of mitochondrial functions which include the transport or storage of iron, as an antioxidant and biogenesis of iron-sulfur cluster enzymes. Most of the evidence that support these findings are studied with systems that are deficient in or possess reduced frataxin levels, reminiscent of the human disease FRDA. In order to gain further insight into the mitochondrial function frataxin, gain-of-function analyses can be employed, to which the fruit fly Drosophila genetic system is amenable to. This system can examine the effects of frataxin over expression through molecular, biochemical and behavioral analyses. Additionally, frataxin loss-of-function transgenic flies may also be utilized to recapitulate and further examine the neuro-degeneration that occurs with FRDA human patients. These transgenic flies can be subjected to therapeutic rescue or alleviation of pathological disease manifestations through taking advantage of the resourcefulness of Drosophila genetics and application of pharmacological or environmental agents.