Circulating U13 small nucleolar RNA as a candidate biomarker for Huntington's disease

Romano, C.; Romano, S.; Peconi, M.; Fiore, A.; Bellucci, G.; Morena, E.; Troili, F.; Cipollini, V.; Annibali, V.; Giglio, S.; Mechelli, R.; Ferraldeschi, M.; Veneziano, L.; Mantuano, E.; Sani, G.; Vecchione, A.; Umeton, R.; Giubilei, F.; Salvetti, M.; Corbo, R.; Scarabino, D.; Ristori, G.

doi:10.1101/2022.04.22.489178

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bioRxiv · 10.1101/2022.04.22.489178

Circulating U13 small nucleolar RNA as a candidate biomarker for Huntington's disease

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Abstract

Background and ObjectivesFluid biomarkers are a recent field of interest in Huntington disease (HD). We focused on small circulating RNAs from plasma of subjects with prodromal (pre-HD) and overt disease by a two-stage approach: an unbiased investigation by an array method and a validation study to quantify a significant small nucleolar RNA. MethodsThrough Affymetrix Gene-Chip-miRNA-Array we performed an exploratory study on 9 HD patients, 8 healthy subjects (HS) and 5 psychiatric patients (PP; who share drugs with HD patients, to control for iatrogenic effects). Through real time PCR we validated the results in an independent population of 24 HD patients, 15 pre-HD, 24 PP, 28 Alzheimers disease (AD) patients (added to control the disease-specificity of our finding) and 23 HS. A bioinformatic analysis was also performed to interpret our finding. ResultsThe microarray results showed a significant signal for U13 small nucleolar RNA (SNORD13) that was increased in plasma of HD patients compared to controls (fold change, 1.54, p =0.003 HD vs. HS, and fold change 1.44 p = 0.0026 HD vs. PP). In the validation population the significant increase in HD patients was evident compared to both pre-HD and the three control groups (p<0.00001). The plasma levels of SNORD13 correlated with the status of mutant huntingtin carrier and the disease duration (respectively R=0.69; p<0.000001; R=0.49; p=0.015). Through receiver operating characteristic (ROC) curve analysis, we showed high accuracy of plasmatic SNORD13 in discriminating HD patients from pre-HD and control groups (AUC=0.963), outperforming values reported in another study for intrathecal or plasmatic mutant huntingtin and neurofilament light chain as biomarkers of overt HD. The bioinformatic analysis on SNORD13 interactome and pathway analysis showed enrichments for factors involved in nuclear functions beyond the ribosome biogenesis. DiscussionWe report the unprecedented finding of a potential role of small nucleolar RNAs in HD. Circulating SNORD13 seems a good biomarker for clinical purposes. It seems to be specific for HD and to peripherally report a plausible tipping point in the pathogenic cascade at neuronal level, possibly paving the way for new therapeutic targets.

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Romano, C., Romano, S., Peconi, M., Fiore, A., Bellucci, G., Morena, E., Troili, F., Cipollini, V., Annibali, V., Giglio, S., Mechelli, R., Ferraldeschi, M., Veneziano, L., Mantuano, E., Sani, G., Vecchione, A., Umeton, R., Giubilei, F., Salvetti, M., Corbo, R., Scarabino, D., Ristori, G.. 2022-04-22. Circulating U13 small nucleolar RNA as a candidate biomarker for Huntington's disease. https://doi.org/10.1101/2022.04.22.489178

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