Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• MicroRNA-218 (miR-218) is enriched in motor neurons and released extracellularly in amyotrophic lateral sclerosis (ALS) models.
• The functional role of extracellular, neuron-derived miR-218 in ALS pathogenesis is not well understood.

Purpose of the Study:

• To investigate the functional role of extracellular miR-218 released from motor neurons on neighboring astrocytes in the context of ALS.
• To determine if miR-218 uptake by astrocytes affects glial function, specifically glutamate transport.

Main Methods:

• Examined the effect of extracellular miR-218 on astrocyte glutamate transporter expression (EAAT2).
• Analyzed mRNA targets of miR-218 in ALS astrocytes.
• Administered antisense oligonucleotides to inhibit miR-218 in ALS model mice.

Main Results:

• Extracellular miR-218 is taken up by astrocytes and downregulates the glutamate transporter EAAT2.
• miR-218 binding sites are enriched in mRNAs translationally downregulated in ALS astrocytes.
• Inhibition of miR-218 in vivo ameliorated EAAT2 loss and other miR-218-mediated changes in ALS mice.

Conclusions:

• Motor neuron-derived miR-218 can alter astrocyte phenotype and function, contributing to neurodegeneration in ALS.
• This study defines a novel mechanism of microRNA-mediated intercellular communication in neurodegenerative diseases.
• Targeting miR-218 may offer a therapeutic strategy for ALS by restoring astrocyte function.