Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
Mol Genet Genomic Med. 2023 Jan;11(1):e2093. doi: 10.1002/mgg3.2093. Epub 2022 Nov 11.
Friedreich's ataxia (FRDA) is an autosomal recessive disease, whereby homozygous inheritance of an expanded GAA trinucleotide repeat expansion in the first intron of the FXN gene leads to transcriptional repression of the encoded protein frataxin. FRDA is a progressive neurodegenerative disorder, but the primary cause of death is heart disease which occurs in 60% of the patients. Several functions of frataxin have been proposed, but none of them fully explain why its deficiency causes the FRDA phenotypes nor why the most affected cell types are neurons and cardiomyocytes.
To investigate, we generated iPSC-derived neurons (iNs) and cardiomyocytes (iCMs) from an FRDA patient and upregulated FXN expression via lentivirus without altering genomic GAA repeats at the FXN locus.
RNA-seq and differential gene expression enrichment analyses demonstrated that frataxin deficiency affected the expression of glycolytic pathway genes in neurons and extracellular matrix pathway genes in cardiomyocytes. Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FRDA cells were supplemented with frataxin.
These results offer novel insight into specific roles of frataxin deficiency pathogenesis in neurons and cardiomyocytes.
弗里德赖希共济失调（FRDA）是一种常染色体隐性疾病，其特征在于 FXN 基因第一内含子中 GAA 三核苷酸重复扩增的纯合子遗传导致编码蛋白 frataxin 的转录抑制。FRDA 是一种进行性神经退行性疾病，但主要死因是心脏病，该病发生在 60%的患者中。已经提出了 frataxin 的几种功能，但没有一种功能能完全解释为什么其缺乏会导致 FRDA 表型，也没有解释为什么受影响最严重的细胞类型是神经元和心肌细胞。
为了进行研究，我们从 FRDA 患者中生成了诱导多能干细胞衍生的神经元（iNs）和心肌细胞（iCMs），并通过慢病毒在不改变 FXN 基因座上基因组 GAA 重复的情况下上调 FXN 表达。
RNA-seq 和差异基因表达富集分析表明，frataxin 缺乏会影响神经元中糖酵解途径基因和心肌细胞中细胞外基质途径基因的表达。与对照相比，这些通路中的基因表达存在差异，当 FRDA 细胞补充 frataxin 时，这些基因的表达恢复到对照水平。
这些结果为 frataxin 缺乏在神经元和心肌细胞发病机制中的特定作用提供了新的见解。
