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

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Date
2019-11-04
Authors
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 A
Goldman, James E
Perng, Ming-Der
Inagaki, Masaki
Snider, Natasha T
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(16 total)
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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.
Type
Journal article
Subject
Brain
Astrocytes
Cell Line
Intermediate Filaments
Humans
Alexander Disease
Glial Fibrillary Acidic Protein
Caspases
Severity of Illness Index
Binding Sites
Phosphorylation
Mutation
Adult
Infant
Induced Pluripotent Stem Cells
Proteolysis
Biomarkers
Permalink
https://hdl.handle.net/10161/21548
Published Version (Please cite this version)
10.7554/elife.47789
Publication Info
Battaglia, Rachel A; Beltran, Adriana S; Delic, Samed; Dumitru, Raluca; Robinson, Jasmine A; Kabiraj, Parijat; ... Snider, Natasha T (2019). Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander disease severity. eLife, 8. 10.7554/elife.47789. Retrieved from https://hdl.handle.net/10161/21548.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Samed Delic

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