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EBioMedicine. 2019 Feb;40:626-635. doi: 10.1016/j.ebiom.2018.11.067. Epub 2019 Jan 31.

Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS.

Author information

1
Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
2
Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. Electronic address: l.ferraiuolo@sheffield.ac.uk.

Abstract

BACKGROUND:

Astrocytes regulate neuronal function, synaptic formation and maintenance partly through secreted extracellular vesicles (EVs). In amyotrophic lateral sclerosis (ALS) astrocytes display a toxic phenotype that contributes to motor neuron (MN) degeneration.

METHODS:

We used human induced astrocytes (iAstrocytes) from 3 ALS patients carrying C9orf72 mutations and 3 non-affected donors to investigate the role of astrocyte-derived EVs (ADEVs) in ALS astrocyte toxicity. ADEVs were isolated from iAstrocyte conditioned medium via ultracentrifugation and resuspended in fresh astrocyte medium before testing ADEV impact on HB9-GFP+ mouse motor neurons (Hb9-GFP+ MN). We used post-mortem brain and spinal cord tissue from 3 sporadic ALS and 3 non-ALS cases for PCR analysis.

FINDINGS:

We report that EV formation and miRNA cargo are dysregulated in C9ORF72-ALS iAstrocytes and this affects neurite network maintenance and MN survival in vitro. In particular, we have identified downregulation of miR-494-3p, a negative regulator of semaphorin 3A (SEMA3A) and other targets involved in axonal maintenance. We show here that by restoring miR-494-3p levels through expression of an engineered miRNA mimic we can downregulate Sema3A levels in MNs and increases MN survival in vitro. Consistently, we also report lower levels of mir-494-3p in cortico-spinal tract tissue isolated from sporadic ALS donors, thus supporting the pathological importance of this pathway in MNs and its therapeutic potential.

INTERPRETATION:

ALS ADEVs and their miRNA cargo are involved in MN death in ALS and we have identified miR-494-3p as a potential therapeutic target.

FUNDING:

Thierry Latran Fondation and Academy of Medical Sciences.

KEYWORDS:

Amyotrophic lateral sclerosis; Astrocytes; Axonal growth; Extracelular vesicles; Gene therapy; Neurodegeneration; miRNA

PMID:
30711519
DOI:
10.1016/j.ebiom.2018.11.067
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