Phenotypic conversions of "protoplasmic" to "reactive" astrocytes in Alexander disease.
Phenotypic conversions of "protoplasmic" to "reactive" astrocytes in Alexander disease.
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DOI：
10.1523/jneurosci.4506-12.2013
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发表时间：
2013-04-24
期刊：
影响因子：
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通讯作者：
Goldman JE
中科院分区：
文献类型：
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作者：
Sosunov AA;Guilfoyle E;Wu X;McKhann GM 2nd;Goldman JE
亚历山大病（AxD）是由GFAP杂合突变引起的星形胶质细胞的原发性疾病，GFAP编码主要的星形胶质细胞中间丝蛋白，胶质细胞酸性蛋白（GFAP）。AxD中的星形胶质细胞显示肥大，GFAP大量增加，以及罗森塔尔纤维，含有GFAP和小热休克蛋白的细胞质蛋白内含物的积累。为了研究GFAP突变对星形胶质细胞形态学和生理学的影响，我们在AxD的三种小鼠模型中检测了海马星形胶质细胞，AxD是一种转基因系（GFAPTg），其中正常人GFAP以几个拷贝表达，敲入系（GFAPTg），（GFap+/R236 H），其中一个GFap基因携带R236 H突变，以及由这两个品系交配衍生的小鼠（GFAPTg; GFap+/R236 H）。我们报告了所有细胞系中星形胶质细胞表型的变化，其中GFAPTg;GFAP+/R236 H中的变化最严重，导致原生质星形胶质细胞转化为由于远端细突起减少而失去丛状形态的细胞，并变得多核和肥大。星形胶质细胞激活mTOR级联，获得CD 44并失去GLT-1。改变的星形胶质细胞在表型上显示出微异质性，甚至邻近细胞。星形胶质细胞还显示谷氨酸转运体电流减少，显著去极化，并且不与相邻星形胶质细胞偶联。因此，GFAP在AxD小鼠星形胶质细胞中的积累启动了正常的原生质星形胶质细胞向显示严重“反应性”特征的星形胶质细胞的转化，其中许多可能对邻近的神经元和少突胶质细胞有害。
Alexander Disease (AxD) is a primary disorder of astrocytes, caused by heterozygous mutations in GFAP, which encodes the major astrocyte intermediate filament protein, glial fibrillary acidic protein (GFAP). Astrocytes in AxD display hypertrophy, massive increases in GFAP, and the accumulation of Rosenthal fibers, cytoplasmic protein inclusions containing GFAP and small heat shock proteins. To study the effects of GFAP mutations on astrocyte morphology and physiology we have examined hippocampal astrocytes in three mouse models of AxD, a transgenic line (GFAPTg) in which the normal human GFAP is expressed in several copies, a knock-in line (Gfap+/R236H) in which one of the Gfap genes bears an R236H mutation, and a mouse derived from the mating of these two lines (GFAPTg; Gfap+/R236H). We report changes in astrocyte phenotype in all lines, with the most severe in the GFAPTg;Gfap+/R236H, resulting in the conversion of protoplasmic astrocytes to cells that have lost their bushy-like morphology because of a reduction of distal fine processes, and become multinucleated and hypertrophic. Astrocytes activate the mTOR cascade, acquire CD44 and lose GLT-1. The altered astrocytes display a microheterogeneity in phenotypes, even neighboring cells. Astrocytes also show diminished glutamate transporter current, are significantly depolarized, and not coupled to adjacent astrocytes. Thus, the accumulation of GFAP in the AxD mouse astrocytes initiates a conversion of normal, protoplasmic astrocytes to astrocytes that display severely “reactive” characteristics, many of which may be detrimental to neighboring neurons and oligodendrocytes.