Signature of miRNAs derived from the circulating exosomes of patients with amyotrophic lateral sclerosis

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder (NDS) with unclear pathophysiology and few therapeutic options. Mutations in SOD1 and C9orf72 are the most common in Asian and Caucasian patients with ALS, respectively. Aberrant (microRNAs) miRNAs found in patients with gene-mutated ALS may be involved in the pathogenesis of gene-specific ALS and sporadic ALS (SALS). The aim of this study was to screen for differentially expressed miRNAs from exosomes in patients with ALS and healthy controls (HCs) and to construct a miRNA-based diagnostic model to classify patients and HCs.MethodsWe compared circulating exosome-derived miRNAs of patients with ALS and HCs using the following two cohorts: a discovery cohort (three patients with SOD1-mutated ALS, three patients with C9orf72-mutated ALS, and three HCs) analyzed by microarray and a validation cohort (16 patients with gene-mutated ALS, 65 patients with SALS, and 61 HCs) confirmed by RT-qPCR. The support vector machine (SVM) model was used to help diagnose ALS using five differentially expressed miRNAs between SALS and HCs.ResultsA total of 64 differentially expressed miRNAs in patients with SOD1-mutated ALS and 128 differentially expressed miRNAs in patients with C9orf72-mutated ALS were obtained by microarray compared to HCs. Of these, 11 overlapping dysregulated miRNAs were identified in both groups. Among the 14 top-hit candidate miRNAs validated by RT-qPCR, hsa-miR-34a-3p was specifically downregulated in patients with SOD1-mutated ALS, while hsa-miR-1306-3p was downregulated in ALS patients with both SOD1 and C9orf72 mutations. In addition, hsa-miR-199a-3p and hsa-miR-30b-5p were upregulated significantly in patients with SALS, while hsa-miR-501-3p, hsa-miR-103a-2-5p, and hsa-miR-181d-5p had a trend to be upregulated. The SVM diagnostic model used five miRNAs as features to distinguish ALS from HCs in our cohort with an area under receiver operating characteristic curve (AUC) of 0.80.ConclusionOur study identified aberrant miRNAs from exosomes of SALS and ALS patients with SOD1/C9orf72 mutations and provided additional evidence that aberrant miRNAs were involved in the pathogenesis of ALS regardless of the presence or absence of the gene mutation. The machine learning algorithm had high accuracy in predicting the diagnosis of ALS, shedding light on the foundation for the clinical application of blood tests in the diagnosis of ALS, and revealing the pathological mechanisms of the disease.

SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity

“…However, the valuable information derived from our detailed computational analysis could be used for the identification of alternative biomarkers for diagnosis and/or prognosis. Indeed, it has recently been proposed that accurate expression profiling of disease-associated miRNAs (MDAs) combined with machine learning or deep learning strategies can serve as an innovative diagnostic tool for various physiological disorders in patients 64 , 65 , including certain types of sclerosis 66 , Lyssavirus infection 67 , and COVID-19 68 . Hence, this comprehensive study might provide, once the regulatory pathways involved in the sncRNA-mediated response are characterized, a new perspective for the development of innovative therapeutic and/or prophylactic strategies for the control and management of SARS-CoV-2 infection.…”

Lnc-HIBADH-4 regulates autophagy-lysosome pathway in amyotrophic lateral sclerosis by targeting Cathepsin D

“…We identi ed and validated lnc-HIBADH-4 as one of the most signi cantly downregulated lncRNAs in ALS patients. Several miRNAs [14,18], including miR-181, have been found to be differentially expression in peripheral blood cells and may serve as novel biomarkers when combined with NfL [13]. Although several studies have investigated the mechanisms of lncRNAs in the pathogenesis of ALS, their potential as diagnostic and prognostic biomarkers remain unknown [38][39][40].…”

“…Several miRNAs could serve as diagnostic and prognostic biomarkers for ALS [13][14][15][16][17][18]. Also, AAVdelivered miRNAs could provide potential for a targeted therapy for ALS patients carrying SOD1 variant [19,20].…”

Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions

“…Particularly, due to the nature of EVs and their superior cargoes and stability in biofluids, EVs have garnered great interest in the non-invasive diagnosis of ALS [267][268][269][270][271][272]. When it comes to EVs as biomarkers for ALS, many researchers have focused on dysregulated miRNAs [273]. Banack et al confirmed previous studies reporting that miR-146a-5p is up-regulated while miR-4454 is down-regulated in the blood plasma-derived EVs of ALS patients compared to healthy controls [267].…”