Insights into the identification of a molecular signature for amyotrophic lateral sclerosis exploiting integrated microRNA profiling of iPSC-derived motor neurons and exosomes

• Published in: Cellular and molecular life sciences : CMLS Vol. 79; no. 3; p. 189
• Main Authors: Rizzuti, Mafalda, Melzi, Valentina, Gagliardi, Delia, Resnati, Davide, Meneri, Megi, Dioni, Laura, Masrori, Pegah, Hersmus, Nicole, Poesen, Koen, Locatelli, Martina, Biella, Fabio, Silipigni, Rosamaria, Bollati, Valentina, Bresolin, Nereo, Comi, Giacomo Pietro, Van Damme, Philip, Nizzardo, Monica, Corti, Stefania
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2022; Springer Nature B.V
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - cerebrospinal fluid; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Biochemistry; Biological properties; Biological samples; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Cell Biology; Cell Communication - genetics; Cells, Cultured; Cerebrospinal fluid; Degeneration; Deregulation; Exosomes; Exosomes - genetics; Gene Expression Regulation; Human performance; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - physiology; Life Sciences; metabolism; microRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Molecular modelling; Motor neurons; Motor Neurons - pathology; Motor Neurons - physiology; Neurodegeneration; Neurodegenerative diseases; Neurons; Original; Original Article; Pathogenesis; Ribonucleic acid; RNA; therapeutics; ALS; Motor neurons; miRNA; Exosomes; CSF
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-022-04217-1

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by progressive degeneration of motor neurons (MNs). Most cases are sporadic, whereas 10% are familial. The pathological mechanisms underlying the disease are partially understood, but it is increasingly being recognized that alterations in RNA metabolism and deregulation of microRNA (miRNA) expression occur in ALS. In this study, we performed miRNA expression profile analysis of iPSC-derived MNs and related exosomes from familial patients and healthy subjects. We identified dysregulation of miR-34a, miR-335 and miR-625-3p expression in both MNs and exosomes. These miRNAs regulate genes and pathways which correlate with disease pathogenesis, suggesting that studying miRNAs deregulation can contribute to deeply investigate the molecular mechanisms underlying the disease. We also assayed the expression profile of these miRNAs in the cerebrospinal fluid (CSF) of familial (fALS) and sporadic patients (sALS) and we identified a significant dysregulation of miR-34a-3p and miR-625-3p levels in ALS compared to controls. Taken together, all these findings suggest that miRNA analysis simultaneously performed in different human biological samples could represent a promising molecular tool to understand the etiopathogenesis of ALS and to develop new potential miRNA-based strategies in this new propitious therapeutic era.