Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
Cell Rep. 2018 Oct 23;25(4):947-958.e4. doi: 10.1016/j.celrep.2018.09.083.
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.
胶质纤维酸性蛋白（GFAP）突变如何导致亚历山大病（AxD）仍不清楚。我们从两名 AxD 患者中生成了 iPSCs，并纠正了 GFAP 突变，以研究突变型 GFAP 对人星形胶质细胞的影响。AxD 星形胶质细胞显示出 GFAP 聚集，再现了 AxD 的病理特征。RNA 测序表明内质网、囊泡调节和细胞代谢受到影响。通过分析，我们观察到 AxD 星形胶质细胞的内质网和溶酶体呈现扩大和异质形态，并定位于核周。功能上，AxD 星形胶质细胞显示细胞外 ATP 释放受损，这导致钙波传播减弱。这些结果表明，GFAP 中的 AxD 致病突变破坏了细胞内囊泡调节，损害了星形胶质细胞的分泌功能，导致星形胶质细胞功能障碍和 AxD 发病机制。
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