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

Battaglia, Rachel A. and Beltran, Adriana S. and Delic, Samed and Dumitru, Raluca and Robinson, Jasmine A. and Kabiraj, Parijat and Herring, Laura E. and Madden, Victoria J. and Ravinder, Namritha and Willems, Erik and Newman, Rhonda A. and Quinlan, Roy Andrew and Goldman, James E. and Perng, Ming-Der and Inagaki, Masaki and Snider, Natasha T. (2019) 'Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander Disease severity.', eLife., 8 . e47789.


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.

Item Type:Article
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Publisher 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.
Date accepted:04 November 2019
Date deposited:14 November 2019
Date of first online publication:04 November 2019
Date first made open access:14 November 2019

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