MicroRNA-23a-3p Is Upregulated in Plasma Exosomes of Bulbar-onset ALS Patients and Targets ERBB4

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease related to the progressive death of motor neurons. Understanding the pathogenesis of ALS continues to provide considerable challenges. Bulbar -onset ALS involves faster functional loss and shorter survival time than spinal cord-onset ALS. However, debate is ongoing regarding typical plasma miRNA changes in ALS patients with bulbar onset. Exosomal miRNAs have not yet been described as a tool for bulbar-onset ALS diagnosis or prognosis prediction. In this study, candidate exosomal miRNAs were identified by small RNA sequencing using samples from patients with bulbar-onset ALS and healthy controls. Potential pathogenic mechanisms were identified through enrichment analysis of target ge-nes for differential miRNAs. Expression of miR-16-5p, miR-23a-3p, miR-22-3p, and miR-93-5p was significantly up -regulated in plasma exosomes from bulbar-onset ALS patients compared with healthy control subjects. Among them, miR-16-5p and miR-23a-3p were significantly lower in spinal-onset ALS patients than those with bulbar -onset. Furthermore, up-regulation of miR-23a-3p in motor neuron-like NSC-34 cells promoted apoptosis and in-hibited cell viability. This miRNA was found to directly target ERBB4 and regulate the AKT/GSK3b pathway. Col-lectively, the above miRNAs and their targets are related to the development of bulbar-onset ALS. Our research indicates that miR-23a-3p might have an effect on motor neuron loss observed in bulbar-onset ALS and may be a novel target for the therapy of ALS in the future.& COPY; 2023 The Author(s). Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

In this study, candidate exosomal miRNAs were identified from patients with bulbar-onset ALS, and miR-16-5p, miR-23a-3p, miR-22-3p, and miR-93-5p were found to be significantly up-regulated in plasma exosomes from ALS patients. Among them, miR-23a-3p was shown to promote apoptosis and inhibit cell viability. The results suggest that these miRNAs and their targets are closely related to the development of bulbar-onset ALS.