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Brain. 2018 Sep 1;141(9):2561-2575. doi: 10.1093/brain/awy182.

Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis.

Author information

1
Department of Neurology, Washington University School of Medicine; St. Louis, MO, USA.
2
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
Department of Genetics, Washington University School of Medicine; St. Louis, MO, USA.
4
Department of Psychiatry, Washington University School of Medicine; St. Louis, MO, USA.

Abstract

We recently demonstrated that microRNA-218 (miR-218) is greatly enriched in motor neurons and is released extracellularly in amyotrophic lateral sclerosis model rats. To determine if the released, motor neuron-derived miR-218 may have a functional role in amyotrophic lateral sclerosis, we examined the effect of miR-218 on neighbouring astrocytes. Surprisingly, we found that extracellular, motor neuron-derived miR-218 can be taken up by astrocytes and is sufficient to downregulate an important glutamate transporter in astrocytes [excitatory amino acid transporter 2 (EAAT2)]. The effect of miR-218 on astrocytes extends beyond EAAT2 since miR-218 binding sites are enriched in mRNAs translationally downregulated in amyotrophic lateral sclerosis astrocytes. Inhibiting miR-218 with antisense oligonucleotides in amyotrophic lateral sclerosis model mice mitigates the loss of EAAT2 and other miR-218-mediated changes, providing an important in vivo demonstration of the relevance of microRNA-mediated communication between neurons and astrocytes. These data define a novel mechanism in neurodegeneration whereby microRNAs derived from dying neurons can directly modify the glial phenotype and cause astrocyte dysfunction.

PMID:
30007309
PMCID:
PMC6113638
[Available on 2019-09-01]
DOI:
10.1093/brain/awy182

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