SOD1G93A Astrocyte-Derived Extracellular Vesicles Induce Motor Neuron Death by a miRNA-155-5p-Mediated Mechanism

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motor neuron (MN) degeneration. Astrocytes surrounding MNs are known to modulate ALS progression. When cocultured with astrocytes overexpressing the ALS-linked mutant Cu/Zn superoxide dismutase...

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Bibliographic Details
Published in:ASN neuro 2023-01, Vol.15, p.17590914231197527-17590914231197527
Main Authors: Marton, Soledad, Miquel, Ernesto, Acosta-Rodríguez, Joaquín, Fontenla, Santiago, Libisch, Gabriela, Cassina, Patricia
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Astrocytes
Cell death
Cell size
Exosomes
Extracellular vesicles
Genomes
MicroRNAs
miRNA
mRNA
Neurodegeneration
Neurodegenerative diseases
Neurotoxicity
Protein transport
RNA transport
Signal transduction
The Role of Glial Cells in the Nervous System in Health and Disease
Therapeutic targets
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Summary:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motor neuron (MN) degeneration. Astrocytes surrounding MNs are known to modulate ALS progression. When cocultured with astrocytes overexpressing the ALS-linked mutant Cu/Zn superoxide dismutase (SOD1G93A) or when cultured with conditioned medium from SOD1G93A astrocytes, MN survival is reduced. The exact mechanism of this neurotoxic effect is unknown. Astrocytes secrete extracellular vesicles (EVs) that transport protein, mRNA, and microRNA species from one cell to another. The size and protein markers characteristic of exosomes were observed in the EVs obtained from cultured astrocytes, indicating their abundance in exosomes. Here, we analyzed the microRNA content of the exosomes derived from SOD1G93A astrocytes and evaluated their role in MN survival. Purified MNs exposed to SOD1G93A astrocyte-derived exosomes showed reduced survival and neurite length compared to those exposed to exosomes derived from non-transgenic (non-Tg) astrocytes. Analysis of the miRNA content of the exosomes revealed that miR-155-5p and miR-582-3p are differentially expressed in SOD1G93A exosomes compared with exosomes from non-Tg astrocytes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicates that miR-155-5p and miR-582-3p predicted targets are enriched in the neurotrophin signaling pathway. Importantly, when levels of miR-155-5p were reduced by incubation with a specific antagomir, SOD1G93A exosomes did not affect MN survival or neurite length. These results demonstrate that SOD1G93A-derived exosomes are sufficient to induce MN death, and miRNA-155-5p contributes to this effect. miRNA-155-5p may offer a new therapeutic target to modulate disease progression in ALS.
ISSN:1759-0914
1759-0914
DOI:10.1177/17590914231197527