An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner

Abstract

Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation may originate from microglia. Furthermore, TDP-43, involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia, and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, miR-16-5p, miR-99a-5p, and miR-191-5p by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and identified their predicted targets, which include primarily genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.

First person – Eleni Christoforidou

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Eleni Christoforidou is first author on ‘ An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner ’, published in DMM. Eleni is a Research Fellow in the lab of Prof. Majid Hafezparast at Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, UK, and is interested in identifying biomarkers for the prognosis and progression of amyotrophic lateral sclerosis (ALS).…”