Ferraiuolo, L. orcid.org/0000-0001-9118-5714, Meyer, K., Sherwood, T. et al. (12 more authors) (2016) Oligodendrocytes contribute to motor neuron death in ALS via SOD1 dependent mechanism. Proceedings of the National Academy of Sciences, 113 (42). E6496-E6505. ISSN 1091-6490
Abstract
Oligodendrocytes have recently been implicated in the pathophysiology of ALS. Here we show that, in vitro, mutant SOD1 mouse oligodendrocytes induce wild-type motor neuron hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls, sporadic and familial ALS patients using two different reprogramming methods. All ALS oligodendrocyte lines induced motor neuron death through conditioned medium and in co-culture. Conditioned medium-mediated motor neuron death was associated with decreased lactate production and release, while toxicity in co-culture was lactate independent, demonstrating that motor neuron survival is not only mediated by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in motor neuron rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, while it was ineffective in differentiated oligodendrocytes. Early SOD1 knockdown, in fact, rescued lactate impairment and cell toxicity in all lines tested with exclusion of samples carrying C9orf72 repeat expansions. These did not respond to SOD1 knockdown nor showed lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type some damage might be irreversible. In addition, we demonstrate that C9ORF72 patients represent an independent patient group that might not respond to the same treatment.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 National Academy of Sciences. This is an author produced version of a paper subsequently published in PNAS. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Oligodendrocytes; neurodegeneration; lactate; amyotrophic lateral sclerosis |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Funding Information: | Funder Grant number MOTOR NEURONE DISEASE ASSOCIATION Ferraiuolo/Nov14/900-790 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 08 Aug 2016 12:58 |
Last Modified: | 15 Nov 2016 17:20 |
Published Version: | https://doi.org/10.1073/pnas.1607496113 |
Status: | Published |
Publisher: | National Academy of Sciences |
Refereed: | Yes |
Identification Number: | 10.1073/pnas.1607496113 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:103431 |