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

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.

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© 2019, Battaglia et al.

Déclaration de conflit d'intérêts

RB, AB, SD, RD, JR, PK, LH, VM, RQ, JG, MP, MI No competing interests declared, NR, EW, RN are paid employees of ThermoFisher Scientific, whose products were used to complete parts of the study. ThermoFisher Scientific had no role in the study design, data analysis, decision to publish, or preparation of the manuscript. NS is a member of the Scientific Advisory Board for Elise's Corner Fund, which supported part of this work