Rachel A Battaglia
Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander Disease severity
Battaglia, Rachel A; Beltran, Adriana S; Delic, Samed; Dumitru, Raluca; Robinson, Jasmine A; Kabiraj, Parijat; Herring, Laura E; Madden, Victoria J; Ravinder, Namritha; Willems, Erik; Newman, Rhonda A; Quinlan, Roy Andrew; Goldman, James E; Perng, Ming-Der; Inagaki, Masaki; Snider, Natasha T
Authors
Adriana S Beltran
Samed Delic
Raluca Dumitru
Jasmine A Robinson
Parijat Kabiraj
Laura E Herring
Victoria J Madden
Namritha Ravinder
Erik Willems
Rhonda A Newman
Roy Quinlan r.a.quinlan@durham.ac.uk
Emeritus Professor
James E Goldman
Ming-Der Perng
Masaki Inagaki
Natasha T Snider
Abstract
Alexander Disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD.
Citation
Battaglia, R. A., Beltran, A. S., Delic, S., Dumitru, R., Robinson, J. A., Kabiraj, P., Herring, L. E., Madden, V. J., Ravinder, N., Willems, E., Newman, R. A., Quinlan, R. A., Goldman, J. E., Perng, M.-D., Inagaki, M., & Snider, N. T. (2019). Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander Disease severity. eLife, 8, Article e47789. https://doi.org/10.7554/elife.47789
Journal Article Type | Article |
---|---|
Acceptance Date | Nov 4, 2019 |
Online Publication Date | Nov 4, 2019 |
Publication Date | Nov 4, 2019 |
Deposit Date | Nov 13, 2019 |
Publicly Available Date | Nov 14, 2019 |
Journal | eLife |
Publisher | eLife Sciences Publications |
Peer Reviewed | Peer Reviewed |
Volume | 8 |
Article Number | e47789 |
DOI | https://doi.org/10.7554/elife.47789 |
Public URL | https://durham-repository.worktribe.com/output/1277503 |
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Accepted Journal Article
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Copyright Statement
© 2019, Battaglia et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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