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Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis.
- Source :
-
Brain : a journal of neurology [Brain] 2018 Sep 01; Vol. 141 (9), pp. 2561-2575. - Publication Year :
- 2018
-
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 :
- Amino Acid Transport System X-AG genetics
Amino Acid Transport System X-AG physiology
Animals
Astrocytes metabolism
Cells, Cultured
Disease Models, Animal
Down-Regulation
Excitatory Amino Acid Transporter 2 genetics
Excitatory Amino Acid Transporter 2 physiology
Glutamic Acid metabolism
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
MicroRNAs genetics
MicroRNAs physiology
Motor Neurons metabolism
Motor Neurons physiology
Neuroglia metabolism
Amyotrophic Lateral Sclerosis genetics
Astrocytes physiology
MicroRNAs metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2156
- Volume :
- 141
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Brain : a journal of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 30007309
- Full Text :
- https://doi.org/10.1093/brain/awy182