Mutation of the frataxin gene, encoding FRDA, is responsible for Freidrich's ataxia, a neurodegenerative disease. Affected tissues from these patients contain excess mitochondrial iron but lack mitochondrial iron proteins and respiratory complexes. Likewise, the loss-of-function mutation of Yh1p, the yeast frataxin homolog, leads to markedly comprised growth, iron accumulation in mitochondria, and a deficiency of numerous mitochondrial iron proteins and respiratory complexes. An FRDA fusion protein (Y34-FRDA) in which the first 39 amino acid have been replaced have been replaced with the first 34 amino acids of Yfh1p results in a chimera able to complement several of the yh1 mutant phenotypes. Complementation of the yfh1 phenotype by Y34-FRDA suggests that frataxin exerts its effects via a pathway similar to that of the yeast pathway. This result forms the basis of the proposal.
The aim of this proposal is to determine the functional role of FRDA in iron homeostasis using yeast as the model system. To accomplish this, FRDA will be expressed from the inducible GAL1 promoter and temperature sensitive FRDA mutants will be generated. These tolls will be used to determine the order of events that occur following the depletion of inactivation of FRDA in the yfh1 mutant. Changes in iron accumulation in total cells, mitochondria, and cytosol; changes in iron association with Fe-S proteins; differences in protein levels of Fe-S proteins; the acquisition of mitochondrial DNA damage; and the loss of respiratory protein complexes will be measured over time. Delineating those events that occur as a direct result of the loss of FRDA function, versus toxic iron accumulation, will provide a basis for understanding the etiology of, and suggest treatments for, Freidreich's ataxia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32NS011166-02
Application #
6559428
Study Section
Biological Sciences 2 (BIOL)
Program Officer
Podskalny, Judith M
Project Start
2000-09-29
Project End
Budget Start
2001-09-29
Budget End
2002-09-28
Support Year
2
Fiscal Year
2002
Total Cost
$41,996
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107