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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Battaglia, RA; Beltran, AS; Delic, S; Dumitru, R; Robinson, JA; Kabiraj, P; Herring, LE; Madden, VJ; Ravinder, N; Willems, E; Newman, RA; Quinlan, RA; Goldman, JE; Perng, M-D; Inagaki, M; Snider, NT

Published Date

  • November 2019

Published In

Volume / Issue

  • 8 /

Start / End Page

  • e47789 -

PubMed ID

  • 31682229

Pubmed Central ID

  • PMC6927689

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

International Standard Serial Number (ISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/elife.47789


  • eng