The ALS-associated TDP-43-M337V mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner

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 the 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 LPS-stimulated microglia. This response was different between male and female microglia. We validated the downregulation of three candidate miRNAs, miR-16-5p, miR-99a-5p, and miR-191-5p by RT-qPCR, and identified their predicted targets, which include primarily neuronal genes associated with dendrites and synapses. 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.