Journal
EBIOMEDICINE
Volume 40, Issue -, Pages 626-635Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2018.11.067
Keywords
Astrocytes; Neurodegeneration; Gene therapy; Axonal growth; Extracelular vesicles; miRNA; Amyotrophic lateral sclerosis
Funding
- Thierry Latran Fondation [FTLAAP2016/FERRAIUOLO/Astrocyte secretome]
- MND Association [Bonanno/Apr16/848-791, Hautbergue/Apr16/846-79]
- MRC NIRG [MR/R024162/1]
- Royal Society International Exchanges grant [IEC\R3\170,103]
- AMS/Wellcome Trust
- MRC [1812144, MR/R024162/1] Funding Source: UKRI
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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 postmortem 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. Crown Copyright (C) 2019 Published by Elsevier B.V.
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