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- Title
Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis.
- Authors
Hoye, Mariah L; Regan, Melissa R; Jensen, Leah A; Lake, Allison M; Reddy, Linga V; Vidensky, Svetlana; Richard, Jean-Philippe; Maragakis, Nicholas J; Rothstein, Jeffrey D; Dougherty, Joseph D; Miller, Timothy M
- 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.
- Subjects
GENETICS of amyotrophic lateral sclerosis; MICRORNA; ANIMAL models of amyotrophic lateral sclerosis; MOTOR neurons; ASTROCYTES; ANTISENSE genetics; NEUROGLIA; PHYSIOLOGY
- Publication
Brain: A Journal of Neurology, 2018, Vol 141, Issue 9, p2561
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awy182