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，由于在年幼婴儿中观察到的严重髓鞘形成不足或在较大儿童中观察到的脱髓鞘而被归类为脑白质营养不良。这种疾病的病理特征是罗森塔尔纤维，在整个CNS的星形胶质细胞中积累的中间丝和小的热休克蛋白。对GFAP基因进行测序，发现迄今为止检查的13名患者中有12名编码区发生单碱基变化，预测非保守氨基酸取代。所有的突变都是杂合子，表明一种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原发性遗传性疾病的第一例，星形胶质细胞是脊椎动物中枢神经系统中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、星形胶质细胞骨架破坏、星形胶质细胞功能障碍和中枢神经系统中少突胶质细胞严重后果的方法。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，生物化学，细胞和形态学的方法来解决这些问题。该计划将连接四个实验室;其中三个已经有了生产性相互作用的证明记录，第四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，思想的交叉受精以及实验室成员之间的定期沟通和会议，促进扩大对神经胶质丝功能障碍在疾病中的作用的努力。这些研究有望对胶质纤维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有新的见解。

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.