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• W4387018701 abstract "Abstract Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder caused by reduced frataxin (FXN) levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia with no cure, FRDA lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study identifies long non-coding RNA Tug1 as a potential blood-based FRDA biomarker. In a previous study using a frataxin knockdown mouse model (FRDAkd), we observed several hallmark FRDA symptoms and abnormalities in various tissues. Building on this, we hypothesized that a dual-source approach—comparing the data from peripheral blood samples from FRDA patients with tissue samples from affected areas in FRDAkd mice, tissues usually unattainable from patients—would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of FRDA patients, carriers, and controls, as well as 192 tissue datasets from FRDAkd mice. Blood and tissue samples underwent RNA isolation and qRT-PCR, and frataxin knockdown was confirmed through ELISA. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum and blood samples on an independent set of 45 healthy controls, 45 FRDA patients; 66 heterozygous carriers, and 72 FRDA patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the FRDAkd mouse model (One-way ANOVA, p ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1’s downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of FRDA patients compared to controls (Wilcoxon signed-rank test, p < 0.05). Regression analyses revealed a negative correlation between TUG1 levels and disease onset (p < 0.0037), and positive correlations with disease duration and Functional Disability Stage score (p < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. In summary, this study highlights Tug1 as a crucial blood-based biomarker for FRDA. Tug1’s consistent expression variance across human and mouse tissues is closely associated to disease severity and key FRDA pathways. It also correlates strongly with Fxn levels, making it a promising early, non-invasive marker. TUG1 offers potential for FRDA monitoring and therapeutic development, warranting further clinical research." @default.
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• W4387018701 date "2023-09-25" @default.
• W4387018701 modified "2023-09-30" @default.
• W4387018701 title "Long non-coding RNA TUG1 is down-regulated in Friedreich's ataxia." @default.
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• W4387018701 doi "https://doi.org/10.1101/2023.09.22.558879" @default.
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