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，属于白质营养不良症，因为在年幼的婴儿中看到严重的髓鞘减少或在较大的儿童中看到脱髓鞘。这种疾病的病理特征是罗森塔尔纤维，一种中间纤维和小热休克蛋白在整个中枢神经系统星形胶质细胞中的积累。GFAP基因测序显示编码区的单碱基变化，预测13例患者中有12例出现非保守性氨基酸取代。所有突变都是杂合的，表明显性的功能获得机制。因此，亚历山大病代表了星形胶质细胞（脊椎动物中枢神经系统的主要细胞类型之一）原发性遗传疾病的第一个例子。本项目的目标是研究GFAP突变导致包涵体、星形胶质细胞骨架破坏、星形胶质细胞功能障碍和中枢神经系统少突胶质细胞严重后果的途径。我们将继续对具有不寻常临床表现的亚历山大病患者进行遗传学研究，以阐明与GFAP突变相关的疾病范围；开发携带与人类相同突变的动物模型；并探索干扰突变蛋白影响的潜在方法。我们的研究跨越分子，生化，细胞和形态学的方法来解决这些问题。该方案将连接四个实验室；其中三个已经证明了富有成效的相互作用的记录，第四组将在研究灯丝组装方面带来独特的专业知识。该计划将通过促进四个实验室之间共享试剂、动物和结果、思想的交流以及实验室成员之间的定期交流和会议，促进对神经胶质丝功能障碍在疾病中的作用的扩大研究。这些研究有望对胶质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.