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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