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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

Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander Disease severity Thumbnail


Authors

Rachel A Battaglia

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

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., …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 Mar 28, 2024
Journal eLife
Publisher eLife Sciences Publications
Peer Reviewed Peer Reviewed
Volume 8
Article Number e47789
DOI https://doi.org/10.7554/elife.47789

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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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