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- W2891093550 abstract "Objective: To determine whether decreased expression of mitochondrial ALDH enzymes exacerbates the consequences of oxidative stress in FXN-deficient models and ascertain if ALDH enzymes are valid therapeutic targets for FRDA. Background: Friedreich’s ataxia (FRDA) is the most prevalent inherited ataxia with a population frequency of 1–2:50,000. FRDA is caused by hyperexpansion of GAA repeats in intron 1 of the Frataxin (FXN) gene. Unaffected individuals carry less than 30 triplets, while disease-causing expanded alleles can span up to 2,000 GAA repeats and inhibit expression of the FXN gene. There are currently no effective treatments for FRDA. Frataxin is a mitochondrial protein involved in iron-sulfur (Fe-S) cluster synthesis. Defects in mitochondrial function caused by Frataxin insufficiency contribute to FRDA pathogenesis as indicated by oxidative stress accompanied by increased reactive oxygen species (ROS) formation and decreased bioenergetic capacity. Although, the mechanism linking FXN deficiency to these biological effects remains unclear. Using next-generation RNA sequencing (RNA-seq) to generate gene expression profiles of a large cohort of FRDA and unaffected control fibroblasts (n= 18 and 17, respectively), three mitochondrial aldehyde dehydrogenases (ALDHs) involved in amino acid metabolism and neutralizing lipid peroxidation byproducts, such as the neurotoxic aldehydes malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were identified as significantly downregulated in FRDA samples. Decreased expression of these ALDHs has been linked to cardiovascular and neurodegenerative diseases, but none have yet been considered in the molecular pathogenesis of FRDA. Design/Methods: Fluorescent microscopy along with quantitative colorimetric assays and ELISA tests were used to measure levels of lipid peroxidation byproducts (4-HNE and MDA) in FRDA neuronal cell line models before and after treatment with the ALDH2 activator Alda-1. Results: Treatment with Alda-1 ameliorated the increased lipid peroxidation byproducts observed in FRDA neuronal cells. Conclusions: Based on its effect in cell models, Alda-1 is a suitable candidate to test in FRDA animal models. Study Supported by: Research Training Fellowship in Ataxia (Co-sponsored by American Academy of Neurology, American Brain Foundation and National Ataxia Foundation) National Ataxia Foundation Young Investigator Award Disclosure: Dr. Napierala has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Napierala has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Vertex. Dr. Napierala has received research support from TranslateBio and Biomarin." @default.
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- W2891093550 date "2018-04-10" @default.
- W2891093550 modified "2023-09-27" @default.
- W2891093550 title "Upregulation of Mitochondrial Aldehyde Dehydrogenase Activity Inhibits Lipid Peroxidation in Friedreich’s Ataxia Cells (P1.074)" @default.
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