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

Author:

Christoforidou Eleni1ORCID,Moody Libby1,Joilin Greig1ORCID,Simoes Fabio A.1ORCID,Gordon David2,Talbot Kevin23ORCID,Hafezparast Majid1ORCID

Affiliation:

1. School of Life Sciences, University of Sussex 1 Sussex Neuroscience , , Brighton, BN1 9QG , UK

2. University of Oxford 2 Nuffield Department of Clinical Neurosciences , , Oxford, OX3 9DU , UK

3. Kavli Institute for Nanoscience Discovery, University of Oxford 3 , Oxford, OX1 3QU , UK

Abstract

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 originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), 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, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include 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.

Funder

University of Sussex

Motor Neurone Disease Association

My Name'5 Doddie Foundation

Publisher

The Company of Biologists

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1. First person – Eleni Christoforidou;Disease Models & Mechanisms;2024-05-01

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