Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1
| Autor: | Yongjie Yang, Lydie Morel, Seng Kah Ng, Jeffrey D. Rothstein, Melissa R. Regan, Svetlana Vidensky, Christine Esau, Haruki Higashimori |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Immunoblotting
Mice Transgenic Biology Exosomes Biochemistry Mice Glutamates Neurobiology microRNA Translational regulation medicine Animals Humans Molecular Biology Cells Cultured Regulation of gene expression Mice Knockout Neurons Messenger RNA Superoxide Dismutase Amyotrophic Lateral Sclerosis Glutamate receptor Cell Biology Molecular biology Microvesicles Corpus Striatum Endocytosis MicroRNAs Microscopy Electron medicine.anatomical_structure HEK293 Cells nervous system Excitatory Amino Acid Transporter 2 Gene Expression Regulation Spinal Cord Astrocytes Gene Knockdown Techniques Protein Biosynthesis Signal transduction Astrocyte Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 288(10) |
| ISSN: | 1083-351X |
| Popis: | Perisynaptic astrocytes express important glutamate transporters, especially excitatory amino acid transporter 2 (EAAT2, rodent analog GLT1) to regulate extracellular glutamate levels and modulate synaptic activation. In this study, we investigated an exciting new pathway, the exosome-mediated transfer of microRNA (in particular, miR-124a), in neuron-to-astrocyte signaling. Exosomes isolated from neuron-conditioned medium contain abundant microRNAs and small RNAs. These exosomes can be directly internalized into astrocytes and increase astrocyte miR-124a and GLT1 protein levels. Direct miR-124a transfection also significantly and selectively increases protein (but not mRNA) expression levels of GLT1 in cultured astrocytes. Consistent with our in vitro findings, intrastriatal injection of specific antisense against miR-124a into adult mice dramatically reduces GLT1 protein expression and glutamate uptake levels in striatum without reducing GLT1 mRNA levels. MiR-124a-mediated regulation of GLT1 expression appears to be indirect and is not mediated by its suppression of the putative GLT1 inhibitory ligand ephrinA3. Moreover, miR-124a is selectively reduced in the spinal cord tissue of end-stage SOD1 G93A mice, the mouse model of ALS. Subsequent exogenous delivery of miR-124a in vivo through stereotaxic injection significantly prevents further pathological loss of GLT1 proteins, as determined by GLT1 immunoreactivity in SOD1 G93A mice. Together, our study characterized a new neuron-to-astrocyte communication pathway and identified miRNAs that modulate GLT1 protein expression in astrocytes in vitro and in vivo. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|