Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander disease severity.
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 articleSubject
BrainAstrocytes
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
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https://hdl.handle.net/10161/21548Published Version (Please cite this version)
10.7554/elife.47789Publication 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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