Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Kofu, Yamanashi Prefecture, 400-8510, Japan.
Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Glia. 2018 May;66(5):1053-1067. doi: 10.1002/glia.23300. Epub 2018 Jan 31.
Alexander disease (AxD) is a rare neurodegenerative disorder caused by gain of function mutations in the glial fibrillary acidic protein (GFAP) gene. Accumulation of GFAP proteins and formation of Rosenthal fibers (RFs) in astrocytes are hallmarks of AxD. However, malfunction of astrocytes in the AxD brain is poorly understood. Here, we show aberrant Ca responses in astrocytes as playing a causative role in AxD. Transcriptome analysis of astrocytes from a model of AxD showed age-dependent upregulation of GFAP, several markers for neurotoxic reactive astrocytes, and downregulation of Ca homeostasis molecules. In situ AxD model astrocytes produced aberrant extra-large Ca signals "AxCa signals", which increased with age, correlated with GFAP upregulation, and were dependent on stored Ca . Inhibition of AxCa signals by deletion of inositol 1,4,5-trisphosphate type 2 receptors (IP3R2) ameliorated AxD pathogenesis. Taken together, AxCa signals in the model astrocytes would contribute to AxD pathogenesis.
亚历山大病（AxD）是一种罕见的神经退行性疾病，由神经胶质纤维酸性蛋白（GFAP）基因的功能获得性突变引起。GFAP 蛋白在星形胶质细胞中的积累和 Rosenthal 纤维（RFs）的形成是 AxD 的标志。然而，AxD 大脑中星形胶质细胞的功能障碍还了解甚少。在这里，我们发现星形胶质细胞中异常的钙反应在 AxD 中起着因果作用。AxD 模型中星形胶质细胞的转录组分析显示，GFAP、几种神经毒性反应性星形胶质细胞标志物随年龄呈上调趋势，而钙稳态分子则下调。原位 AxD 模型星形胶质细胞产生异常的超大钙信号“AxCa 信号”，这些信号随年龄的增长而增加，与 GFAP 的上调相关，并依赖于储存的钙。通过缺失肌醇 1,4,5-三磷酸 2 型受体（IP3R2）抑制 AxCa 信号可改善 AxD 发病机制。总之，模型星形胶质细胞中的 AxCa 信号可能有助于 AxD 的发病机制。
