期刊
CELL REPORTS
卷 25, 期 4, 页码 947-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.09.083
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类别
资金
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD076892, U54 HD090256]
- NIH-National Institute of Mental Health (NIMH) [MH099587, MH100031]
- NIH-National Institute of Neurological Disorders and Stroke (NINDS) [NS076352, NS086604, NS096282]
- Bleser Family Foundation
- Busta Foundation
- Steenbock professorship
How 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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