Long non-coding RNA is downregulated in Friedreich's ataxia.

Friedreich's ataxia is a neurodegenerative disorder caused by reduced frataxin 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, Friedreich's ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes , a long non-coding RNA, as a promising blood-based biomarker for Friedreich's ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreich's ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreich's ataxia patients with tissue samples from affected areas in Friedreich's ataxia knockdown 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 Friedreich's ataxia patients, carriers and controls and 192 tissue data sets from Friedreich's ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreich's ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreich's ataxia patients. and emerged as potential blood-based biomarkers, confirmed in the Friedreich's ataxia knockdown mouse model (one-way ANOVA, ≤ 0.05). was consistently downregulated after knockdown and correlated strongly with levels ( = 0.71 during depletion, = 0.74 during rescue). showed a similar but tissue-specific pattern. Further validation of 's downstream targets strengthened its biomarker candidacy. In additional human samples, levels were significantly downregulated in both whole blood and serum of Friedreich's ataxia patients compared with controls (Wilcoxon signed-rank test, < 0.05). Regression analyses revealed a negative correlation between fold-change and disease onset ( < 0.0037) and positive correlations with disease duration and functional disability stage score ( < 0.04). This suggests that elevated levels correlate with earlier onset and more severe cases. This study identifies as a potential blood-based biomarker for Friedreich's ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreich's ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. holds potential for Friedreich's ataxia monitoring and therapeutic development, meriting additional research.