Ed Grabczyk, PhD

Research in the Grabczyk lab focuses on key aspects of Friedreich ataxia (FRDA), a relentlessly progressive neurodegenerative disease. The ataxia is incapacitating and the associated cardiomyopathy is often fatal. FRDA is caused by an unstable GAA•TTC repeat expansion in the first intron of the FXN gene that reduces frataxin expression. The degree of repression correlates with the length of the repeat, but it is unclear how transcription is reduced. Frataxin is a nuclear encoded mitochondrial protein with a role in iron-sulfur (Fe•S) cluster assembly. Insufficient frataxin causes mitochondrial dysfunction, most severely affecting cells with high metabolic rates. The variable onset of neurodegeneration and cardiomyopathy in FRDA patients stems from a combination of reduced ATP production and increased reactive oxygen species (ROS) damage. Currently there is no effective treatment for FRDA. Most FRDA patients have intact frataxin coding sequences, so the transcript deficiency is an obvious target for therapeutic intervention.

The FXN locus has 5 exons spread over about 38 kilobases on chromosome 9. The GAA•TTC repeat located 1 kb from the first exon in the first intron is represented here by a shaded triangle. Numbers to the left of the triangle indicate the triplets in the normal (6-30), the asymptomatic (30-100) and the disease range (>100). The repeat adds (GAA)_n to the primary transcript.  

A primary goal in our lab is to understand why GAA•TTC repeats expand, and how the expansion impairs gene expression in FRDA. We have engineered a series of unique dual reporter vectors in human cell lines to dissect the gene repression mechanism, and to serve as high-throughput tests of candidate FRDA therapies. Our cell lines also allow us to study how factors such as transcription and DNA repair influence repeat stability. We are particularly interested in probing the role DNA structures may have in attracting enzymes of DNA repair, recombination and chromatin modification. We hope that understanding how transcription elongation is impaired in FRDA will lead to a treatment, and that understanding why DNA repeats expand or contract will lead to a cure.  

The aerobic function of FRDA cells can resemble aged cells. In a second area of research, we are exploring the relationship between frataxin expression and iron and oxygen metabolism. Insufficient frataxin slows replacement of Fe•S clusters, which heightens sensitivity to ROS. Slowed replacement in respiratory complexes I, II and III compromises OXPHOS and increases ROS. Cytosolic aconitase, in the absence of its Fe•S cluster, becomes Iron Regulatory Protein 1 and alters iron metabolism. Oxidative stress from outside the cell can send this cycle spinning out of control. Understanding how frataxin modulates iron homeostasis and mitochondrial function should provide insights helpful to other conditions that lead to similar declines in aerobic function and increases in ROS.

Projects in all these areas of interest are currently active in the lab.

Dr. Grabczyk earned his BS at UCLA and his PhD at Harvard University.  He did post-doctoral work at Massachusetts General Hospital and at the National Institutes of Health before coming to the LSU Health Sciences Center.