Alexander disease: cellular and molecular mechanisms

亚历山大病是一种罕见的、致命的退行性疾病，被归类为脑白质营养不良，原因是幼儿出现严重的髓鞘减少或年龄较大的儿童出现脱髓鞘。这种疾病的病理特征是罗森塔尔纤维，在整个中枢神经系统的星形胶质细胞中积聚着中间细丝和小的热休克蛋白。对GFAP基因进行测序发现，在迄今检查的13名患者中，有12名患者的编码区发生了单碱基变化，预测了非保守的氨基酸替换。所有突变都是杂合的，这表明了一种显性的功能获得机制。因此，亚历山大病是第一例星形胶质细胞原发遗传障碍的例子，星形胶质细胞是脊椎动物中枢神经系统的主要细胞类型之一。本计划项目的目标是研究GFAP突变导致包涵体、星形胶质细胞细胞骨架破坏、星形胶质细胞功能障碍和中枢神经系统少突胶质细胞的严重后果的方法。我们将继续对临床表现不寻常的Alexander病患者进行遗传学研究，以澄清与GFAP突变相关的疾病的范围；开发携带与人类中已发现的突变相同的突变的动物模型；并探索干扰突变蛋白影响的潜在方法。我们的研究跨越了分子、生化、细胞和形态方法来解决这些问题。该计划将连接四个实验室；其中三个实验室已经有了经过验证的生产性相互作用的记录，第四个小组将带来研究细丝组装的独特专业知识。该计划将通过促进四个实验室之间的试剂、动物和结果的共享、思想的交流以及实验室成员之间的定期交流和会议，促进关于神经胶质细丝功能障碍在疾病中的作用的进一步努力。这些研究有望对胶质细丝在星形胶质细胞细胞生物学中的作用以及星形胶质细胞在大脑功能和疾病中的作用提供新的见解。

Alexander disease is a rare, fatal degenerative disease, classified among the leukodystrophies because of the severe hypomyelination seen in young infants or the demyelination seen in older children. The pathological signature of the disorder is the Rosenthal fiber, an accumulation of intermediate filaments and small heat shock proteins in astrocytes throughout the CNS. Sequencing the GFAP gene revealed single base changes in the coding region, predicting, non-conservative amino acid substitutions, in 12 of 13 patients examined to date. All mutations are heterozygous, suggesting a dominant, gain-of-function mechanism. Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate central nervous system. The goals of this Program Project are to investigate the means by which GFAP mutations lead to inclusion bodies, disruption of the astrocyte cytoskeleton, astrocyte, dysfunction, and severe consequences for oligodendrocytes in the central nervous system. We will continue genetic studies of Alexander disease patients with unusual clinical presentations to clarify the range of disorders associated with GFAP mutations; develop animal models carrying the same mutations as those identified in humans; and explore potential approaches for interfering with the effects of the mutant protein. Our studies span molecular, biochemical, cellular, and morphological approaches to these questions. The Program will link four laboratories; three of these already have a proven record of productive interactions, and a fourth group will bring unique expertise in studying filament assembly. The Program will promote an expanded effort on the role of glial filament dysfunction in disease, by fostering sharing of reagents, animals, and results between the four labs, cross-fertilization of ideas, and regular communication and meetings among laboratory members. These studies promise novel insights into the role of glial filaments in the cell biology of astrocytes, and the role of astrocytes in brain function and disease.