SUMMARYHow mutations in glial fibrillary acidic protein (GFAP) cause Alexander
disease (AxD) remains elusive. We generated iPSCs from two AxD patients and
corrected the GFAP mutations to examine the effects of mutant GFAP on human
astrocytes. AxD astrocytes displayed GFAP aggregates, recapitulating the
pathological hallmark of AxD. RNA sequencing implicated the endoplasmic
reticulum, vesicle regulation, and cellular metabolism. Corroborating this
analysis, we observed enlarged and heterogeneous morphology coupled with
perinuclear localization of endoplasmic reticulum and lysosomes in AxD
astrocytes. Functionally, AxD astrocytes showed impaired extracellular ATP
release, which is responsible for attenuated calcium wave propagation. These
results reveal that AxD-causing mutations in GFAP disrupt intracellular vesicle
regulation and impair astrocyte secretion, resulting in astrocyte dysfunction
and AxD pathogenesis.
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