Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Thomas McDonald, Ph.D.

Committee Member

Derek Wildman, Ph.D.

Committee Member

Sami Noujaim, Ph.D.

Committee Member

Thomas Taylor-Clark, Ph.D.


Frataxin, Transcriptional Profile, Lentivirus, Glycolysis, Extracellular Matrix


Friedreich's ataxia (FA) is an autosomal recessive disease caused, in most cases, by a GAA trinucleotide repeat expansion in the first intron of the frataxin (FXN) gene, which results in transcriptional repression of the encoded protein frataxin. FA is a progressive neurodegenerative disorder, but the primary cause of death is hypertrophic cardiomyopathy, which occurs in 60% of the patients. Several functions of frataxin have been proposed, but none of them can fully explain why its deficiency causes the FA phenotypes nor why the most affected cell types are neurons and cardiomyocytes. It is possible that frataxin affects neural and cardiac cells in different ways and that the GAA expansion has a pathological effect independent of frataxin. However, this is also unknown. To fill this gap, I investigated the hypothesis that frataxin deficiency plays a unique role in different FA-affected tissues.

In the first part of this study, I generated induced pluripotent stem cells (iPSC)-derived neurons (iNs) and cardiomyocytes (iCMs) from an FA patient and an unrelated control, and performed RNA-seq and differential gene expression analysis. Results demonstrated that the dysregulated genes of FA iNs were involved in nervous system development, supporting neuronal differentiation, specification, and maturation. On the other hand, the dysregulated genes in FA iCMs play roles in fibrosis, iron overload, and cardiac remodeling.

In the second part of this study, I upregulated FXN expression via lentivirus without altering genomic GAA repeats at the FXN locus in the FA iNs and iCMs. RNA-seq and differential gene expression analyses demonstrated that frataxin deficiency affected the expression of glycolytic pathway genes in neurons and extracellular matrix pathways genes in cardiomyocytes. Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FA cells were supplemented with frataxin.

These results offer novel insight into the specific roles of frataxin deficiency pathogenesis in neurons and cardiomyocytes using patient-specific iPSCs. By exploring the dysregulated genes using FA-derived cells from different patients, generating isogenic cell lines, and obtaining cellular phenotypes to test disease mechanisms, we will be one step closer to understanding and finding a cure for FA.

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