Clinical aspects and pathology of Alexander disease, and morphological and functional alteration of astrocyte induced by GFAP mutation
Clinical aspects and pathology of Alexander disease, and morphological and functional alteration of astrocyte induced by GFAP mutation
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亚历山大病的临床表现和病理学以及 GFAP 突变引起的星形胶质细胞的形态和功能改变
DOI：
10.1111/j.1440-1789.2011.01268.x
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发表时间：
2011
期刊：
影响因子：
2.3
通讯作者：
Nakagawa M
中科院分区：
文献类型：
--
作者：
Yoshida T;Nakagawa M
亚历山大病（AxD）的病理特征是血管周围和软膜下星形胶质细胞终足的细胞质中存在由GFAP、αB-晶体蛋白和热休克蛋白27组成的罗森塔尔纤维（RF）。由于GFAP突变已在AxD的报告病例中得到证实，因此正在对GFAP突变与发病病理以及临床形式之间的关系进行临床或实验研究。我们进行了一项全国性的调查和临床研究，并将AxD分为三种类型：脑型AxD（1型），主要有婴儿发病，伴有癫痫发作、精神发育迟滞、大头畸形和脑MRI中观察到的上级额叶白色物质异常;延髓脊髓AxD（2型），主要在成人发病，伴有肌无力、反射亢进、延髓或假延髓症状、信号异常，以及在延髓和上颈脊髓的MRI中观察到的萎缩;以及具有两者特征的中间形式（3型）。一项关于GFAP突变和聚集体形成的研究得出结论，GFAP突变降低了GFAP的溶解度。根据我们的细胞模型实验，突变型GFAP的形成取决于GFAP突变的位点。此外，GFAP启动子基因的多态性可能调节GFAP的表达程度;它可能对临床异质性产生影响。最近使用细胞和动物模型的研究表明，AxD的病理不仅涉及中间丝的功能异常，还涉及星形胶质细胞和神经元的功能异常。阐明神经胶质-神经元相互作用将证明这种疾病是非常有趣的。
Alexander disease (AxD) is pathologically characterized by the presence of Rosenthal fibers (RF), which are made up of GFAP, αB‐crystallin and heat shock protein 27, in the cytoplasm of perivascular and subpial astrocyte endfeet. Since GFAP mutation has been confirmed in reported cases of AxD, clinical or experimental research is being conducted on the relationship between GFAP mutation and the onset pathology as well as the clinical form. We conducted a nationwide survey and a clinical study, and classified AxD into three types: cerebral AxD (type 1), which primarily has an infantile onset with presence of seizures, psychomotor developmental retardation, macrocephaly, and abnormalities in the superior frontal cerebral white matter observed in a brain MRI; bulbospinal AxD (type 2), which primarily has an adult onset with presence of muscle weakness, hyperreflexia, bulbar or pseudobulbar symptoms, signal abnormalities, and atrophy observed in an MRI of the medulla oblongata and upper cervical spinal cord; and an intermediate form (type 3) which has the characteristics of both. A research on GFAP mutations and aggregate formation concluded that GFAP mutations decreased the solubility of GFAP. According to our cell model experiment, the formation of mutant GFAP aggravates depending on the site of the GFAP mutation. Furthermore, there is a possibility that polymorphism in the GFAP promoter gene regulates the degree to which GFAP is expressed; it may have an effect on clinical heterogeneity. Recent research using cell and animal models suggests that the pathology of AxD involves not only mere functional abnormalities in intermediate filaments but also functional abnormalities in astrocytes as well as in neurons. Clarification of the glia–neuron interactions will prove the disease to be very interesting.