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

Mariah L. Hoye, Melissa R. Regan, Leah A. Jensen, Allison M. Lake, Linga V. Reddy, Svetlana Vidensky, Jean Philippe Richard, Nicholas J. Maragakis, Jeffrey D. Rothstein, Joseph D. Dougherty, Timothy M. Miller

Research output: Contribution to journalArticlepeer-review

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 microRNAmediated 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.

Original languageEnglish (US)
Pages (from-to)2561-2575
Number of pages15
JournalBrain
Volume141
Issue number9
DOIs
StatePublished - Sep 1 2018

Keywords

  • ALS
  • extracellular miRNA
  • miR-218
  • neuron-glia communication
  • non-cell autonomous

ASJC Scopus subject areas

  • Clinical Neurology

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