Comprehensive analysis of gene expression patterns in Friedreich's ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers

Author:

Napierala Jill Sergesketter1ORCID,Li Yanjie1,Lu Yue2,Lin Kevin2,Hauser Lauren A.3,Lynch David R.3,Napierala Marek14ORCID

Affiliation:

1. University of Alabama at Birmingham, Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, 1825 University Blvd., Birmingham, Alabama 35294, USA

2. University of Texas MD Anderson Cancer Center, Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, Science Park, Smithville, Texas 78957, USA

3. Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia, Abramson Research Center Room 502, Philadelphia, PA 19104, USA

4. Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, 61-704, Poland

Abstract

ABSTRACT Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients homozygous for GAA expansions have low FXN mRNA and protein levels when compared with heterozygous carriers or healthy controls. Frataxin is a mitochondrial protein involved in iron–sulfur cluster synthesis, and many FRDA phenotypes result from deficiencies in cellular metabolism due to lowered expression of FXN. Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking. Peripheral tissues, including blood cells, buccal cells and skin fibroblasts, can readily be isolated from FRDA patients and used to define molecular hallmarks of disease pathogenesis. For instance, FXN mRNA and protein levels as well as FXN GAA-repeat tract lengths are routinely determined using all of these cell types. However, because these tissues are not directly involved in disease pathogenesis, their relevance as models of the molecular aspects of the disease is yet to be decided. Herein, we conducted unbiased RNA sequencing to profile the transcriptomes of fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Bioinformatic analyses revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins in FRDA fibroblasts. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in FRDA fibroblasts. Finally, comparison of genes differentially expressed in FRDA fibroblasts to three previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease. When performed on statistically meaningful sample group sizes, unbiased global profiling analyses utilizing peripheral tissues are critical for the discovery and validation of FRDA disease biomarkers.

Funder

National Institute of Neurological Disorders and Stroke

Muscular Dystrophy Association

Friedreich's Ataxia Research Alliance

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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