期刊
BRAIN
卷 141, 期 -, 页码 2561-2575出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awy182
关键词
ALS; miR-218; extracellular miRNA; neuron-glia communication; non-cell autonomous
资金
- ALS
- Target ALS
- National Institute of Neurological Disorders and Stroke [K08NS074194, R01NS078398, F31NS092340]
- Robert Packard Center for ALS Research
- University of Missouri Spinal Cord Injury/Disease Research Program
- Hope Center for Neurological Disorders
- NIH T35 NHLBI training grant [T35 HL007815]
- NARSAD Independent Investigator grant from the Brain and Behavior Research Foundation [R01 NS102272]
- Departments of Neurology and Psychiatry at Washington University School of Medicine
- Washington University School of Medicine
- Children's Discovery Institute of Washington University
- St. Louis Children's Hospital
- Foundation for Barnes-Jewish Hospital
- National Institute for Neurological Disorders and Stroke [NS086741]
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.
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