Abstract 15669: Frataxin Deficiency-Dependent Gene Expression in Friedreich Ataxia Ipsc-Neurons and Cardiomyocytes

Abstract

Introduction: Friedreich's ataxia (FA) is an autosomal recessive disease where expanded GAA trinucleotide repeat expansion in the first intron of the FXN gene results in transcriptional repression of the encoded protein, frataxin. FA is a progressive neurodegenerative disorder, but a primary cause of morbidity and mortality is hypertrophic cardiomyopathy, occurring 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. Hypothesis: We hypothesize that frataxin deficiency plays unique roles in FA-affected neural and cardiac cells. Methods: We generated induced pluripotent stem cell (iPSC)-derived neurons (iNs) and cardiomyocytes (iCMs) from an FA patient and normalized FXN expression via lentivirus without altering genomic GAA repeats at the FXN locus. Then we performed transcriptional profile and differential expression analysis to identify the dysregulated genes and enriched pathways. Results: Differential expression analysis identified 127 differentially expressed genes between transduced and non-transduced iNs (37 upregulated and 90 downregulated). The most significant enriched processes and pathways for iNs were Glycolysis (GO:0006096, KEGG:00010), ATP generation (GO:0006757), and ADP and Pyruvate metabolic processes (GO:0046031, GO:0006090). 417 genes were differentially expressed between transduced and non-transduced iCMs (320 upregulated and 97 downregulated). Enrichment analyses for iCMs demonstrated that frataxin deficiency affected the extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), and extracellular matrix receptor interaction (KEGG:04512). Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FA cells were supplemented with frataxin. Conclusions: These results offer novel insight into specific roles of frataxin deficiency pathogenesis in neurons and cardiomyocytes. Glucose metabolism appears preferentially perturbed in neurons while pathways leading to fibrosis may play an important role in cardiac tissue.