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

journal contribution
posted on 2024-05-14, 14:18 authored by Eleni ChristoforidouEleni Christoforidou, Libby Moody, Greig JoilinGreig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid HafezparastMajid Hafezparast
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.

History

Publication status

  • Accepted

File Version

  • Accepted version

Journal

Dis Model Mech

ISSN

1754-8403

Publisher

The Company of Biologists

Page range

dmm.050638

Department affiliated with

  • Neuroscience Publications
  • Biochemistry Publications

Institution

University of Sussex

Full text available

  • Yes

Peer reviewed?

  • Yes