Micro-RNAs from Plasma-Derived Small Extracellular Vesicles as Potential Biomarkers for Tic Disorders Diagnosis

Abstract

Tic disorders (TDs) are a series of childhood neuropsychiatric disorders characterized by involuntary motor and/or vocal tics and commonly comorbid with several other psychopathological and/or behavioral disorders (e.g., attention deficit hyperactivity disorder and obsessive–compulsive disorder), which indeed aggravate clinical symptoms and complicate diagnosis and treatment. Micro-RNAs (miRNAs) derived from small extracellular vesicles (sEVs) have been recognized as novel circulating biomarkers of disease. To identify specific miRNAs derived from plasma sEVs for TDs’ diagnosis and prognosis, we used official EV isolation and purification methods to characterize the plasma-derived EV miRNAs from children with different types of TDs. Nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis of EV surface markers were applied to confirm the features and quality of sEVs. The RNA sequencing (RNA-seq) approach was adapted to identify novel circulating sEVs-derived miRNAs with altered expression levels in paired comparisons of TDs versus healthy controls (HCs), transient tic disorder (TTD) versus chronic motor or vocal tic disorder (CTD), and TTD versus Tourette Syndrome (TS). GO term and KEGG pathway were performed for functional analysis and the receiver operator curve analysis was followed to test the diagnosis efficacy of differentially expressed miRNAs (DEMs) derived from plasma sEVs among paired groups, namely, TDs versus HCs, TTD versus CTD, and TTD versus TS. As a result, 10 miRNAs (hsa-let-7a, hsa-let-7b, hsa-let-7c, hsa-let-7e, hsa-let-7f, hsa-miR-25-3p, hsa-miR-29a-3p, hsa-miR-30b-5p, hsa-miR-125b-5p, and hsa-miR-1469) have demonstrated a significantly different expression signature in the TDs group compared to HCs with excellent area under curve (AUC) values of 0.99, 0.973, 0.997, 1, 0.99, 0.997, 0.987, 0.993, 0.977, and 0.997, respectively, and the diagnostic efficacy of miRNAs was also estimated for discriminating TTD from CTD or TS. In our research, we finally obtained several potential sEVs-derived miRNA biomarkers to assess the diagnosis and prognosis of TDs.

The SIK1/CRTC2/CREB1 and TWIST1/PI3K/Akt/GSK3β signaling pathways mediated by microRNA-25-3p are altered in the schizophrenic rat brain

“…MiR-25 was reported to be involved in epilepsy, Parkinson's disease, cerebral ischemia, multiple sclerosis, panic disorder, alexithymia, and tic disorders (Guo et al, 2014;Zhang et al, 2016;Nuzziello et al, 2018;Min et al, 2019;Van der Auwera et al, 2022; Wang et al, 2022;Zhou and Qiao, 2022). The present study demonstrated that miR-25 might also be associated with schizophrenia, further confirming the role of miR-25 in neuropsychiatric diseases and suggesting that miR-25-3p might be a potential therapeutic target or a diagnosis biomarker of schizophrenia.…”

“…Previous studies showed that miR-25 is involved in the pathogenesis of various diseases, such as acute myocardial infarction, left ventricular hypertrophy, heart failure, diabetes mellitus, diabetic nephropathy, tubulointerstitial nephropathy, and asthma bronchiale (Sárközy et al, 2018). Moreover, miR-25 was found to play a critical role in the pathogenesis of a range of neuropsychiatric diseases, including epilepsy (Li et al, 2020), Parkinson's disease (Chen et al, 2020), cerebral ischemia (Guo et al, 2014;Zhang et al, 2016;Zhou and Qiao, 2022), multiple sclerosis (Nuzziello et al, 2018), panic disorder (Min et al, 2019), alexithymia (Van der Auwera et al, 2022), and tic disorders (Wang et al, 2022). It was also reported that sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2), a downstream target of miR-25, was elevated in the brains of patients with schizophrenia (Earls et al, 2012), suggesting a potential connection between miR-25 and schizophrenia.…”

Association of elevated plasma CCL5 levels with high risk for tic disorders in children

“…Tics tend to be refractory to medical treatments and non-medical interventions, and most patients experience relapses that often persist into adulthood. Prediction and management of the risk for TD onset and relapse rely largely on biomarkers which, however, are severely lacking ( 4 ).…”