| Autor: |
André Varcianna, Monika A. Myszczynska, Lydia M. Castelli, Brendan O'Neill, Yeseul Kim, Jordan Talbot, Sophie Nyberg, Immanuelle Nyamali, Paul R. Heath, Matthew J. Stopford, Guillaume M. Hautbergue, Laura Ferraiuolo |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
EBioMedicine, Vol 40, Iss , Pp 626-635 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2352-3964 |
| DOI: |
10.1016/j.ebiom.2018.11.067 |
| Popis: |
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: Astrocytes, Neurodegeneration, Gene therapy, Axonal growth, Extracelular vesicles, miRNA, Amyotrophic lateral sclerosis |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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