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

• DOI: 10.7554/elife.47789
• Publication Date: 2019-11-04T13:00:19Z
• Authors: Rachel A Battaglia; Adriana S Beltran; Samed Delic; Raluca Dumitru; Jasmine A Robinson; Parijat Kabiraj; Laura E Herring; Victoria J Madden; Namritha Ravinder; Erik Willems; Rhonda A Newman; Roy A Quinlan; James E Goldman; Ming-Der Perng; Masaki Inagaki; Natasha T Snider
• Keywords: GFAP stain

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 cause AxD, but mechanism linking different to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes investigate hypothesis that AxD-causing perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation GFAP-Ser13 patients who died young, independently mutation they carried. iPSC-astrocytes accumulated pSer13-GFAP cytoplasmic aggregates within deep nuclear invaginations, resembling hallmark Rosenthal fibers observed vivo. Ser13 facilitated aggregation was associated with increased proteolysis caspase-6. Furthermore, caspase-6 selectively expressed young patients, correlated presence cleaved novel PTM signature infantile AxD.