Ed Grabczyk, PhD

The long-term goal of our research is to develop therapies for degenerative conditions associated with aging.  We currently study the molecular biology and biochemistry of Friedreich ataxia (FRDA).  Although it can strike in childhood, FRDA has attributes that pertain to other neurodegenerative diseases and to pathologic conditions of aging:  1) An unstable trinucleotide repeat that can expand with age.  2) Reduced mitochondrial function and lower Fe•S enzyme activities.  3) Increased sensitivity of Fe•S enzymes to ROS.  4) Disrupted iron homeostasis and mitochondrial iron accumulation.  

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 may reflect continued somatic expansion of the repeat.  Cell loss stems from a combination of reduced ATP production and increased ROS sensitivity.  One percent of the population carries an expanded repeat in one FXN allele, making it the most common triplet expansion known.  The GAA•TTC repeat expanded from an Alu element, suggesting a vast reservoir for other such expansions.

A primary goal in our lab is to understand why GAA•TTC repeats expand, and how the expansion impairs gene expression in FRDA.  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. 

Projects in 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.