Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

Abstract

Friedreich’s ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.

Genetically Regulated Gene Expression in the Brain Associated With Chronic Pain: Relationships With Clinical Traits and Potential for Drug Repurposing

“…DCAKD encodes a protein linked to neurodevelopment ( 57 ) that is expressed widely in the brain ( 58 ), and MCP-GREX of this gene in the caudate basal ganglia was negatively associated with cardiac dysrhythmia ( Table 4 ). Previous studies indicate a relationship between magnetic resonance imaging markers of cerebral small vessel disease and DCAKD ( 59 ) and Friedrich’s ataxia ( 60 ), a disease of progressive neurodegeneration, heart, and spinal problems ( 61 , 62 ). Heart rate variability is thought to represent hyperarousal and has been linked to emotion regulation and chronic pain ( 63 , 64 ).…”

Co-expression Network Analysis Reveals Novel Genes Underlying Alzheimer’s Disease Pathogenesis

“…Previously, evidence has shown that the ENO2 gene promoter drives high-level transgene expression in differentiated neurons throughout the central nervous system of transgenic zebrafish (Bai et al, 2007). Friedreich's ataxia (FA) is a neurodegenerative disease, and a recent study showed that ENO2 is a marker of mitochondrial function and/or myelination status in FA patients (McMackin et al, 2019). In addition, expression of ENO2 was reportedly linked to prognosis for several cancers, including colorectal cancer (Pan et al, 2020), lung cancer (Liu et al, 2020), and pancreatic cancer (Zheng et al, 2020).…”

Antioxidant Therapies and Oxidative Stress in Friedreich’s Ataxia: The Right Path or Just a Diversion?

“…However, these studies are based on cell types that might be not relevant to analyze neuronal features that are monitored in the clinical scales. In order to bypass this problem, Gino Cortopassi's team have compared the transcriptomic signatures of lymphoblasts and fibroblasts from patients with RNA-seq data from murine frataxin-deficient DRG neurons [209]. This approach allowed the identification in all 3 cell types of common alterations, that might become future biomarkers, in genes involved in mitochondrial stress, apoptosis, oxidative stress, and selenium metabolism.…”