Alexander disease: mechanisms, modifiers, and therapeutics

描述：Alexander病是一种罕见的、典型的致命的儿童神经退行性疾病，由编码III型中间丝蛋白GFAP的基因杂合突变引起。这种疾病的病理特征是罗森塔尔纤维，这是一种细胞质包涵体，含有中间丝和小的热休克蛋白，积聚在整个中枢神经系统的星形胶质细胞中。我们小组之前的研究表明，GFAP突变是几乎所有Alexander病的原因，并将这一信息迅速转化为临床实践，作为诊断的标准。然而，GFAP突变导致星形胶质细胞功能障碍和疾病的机制尚不清楚。该项目的目标是开发新的人脑星形胶质细胞模型系统，研究突变型GFAP和过量的GFAP对神经元发育、活性和功能的影响，并研究错误折叠的蛋白质从脑中清除的途径。此外，我们将识别和表征疾病表型的遗传修饰因素，并测试潜在的治疗策略。我们的研究跨越了遗传学、生化、细胞学、生理学和形态学的方法来解决这些问题，并包括从无脊椎动物到人类的各种模型系统。该计划将连接四个实验室，一个使用人类诱导的多能干细胞，一个使用果蝇，两个使用小鼠模型。一个行政核心将协调财务报告，监测IACUC的批准，并支持各小组之间以及与内部和外部咨询委员会的沟通。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，通过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GFAP在疾病中的作用的重点努力。这些研究有望对GFAP毒性的后果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。我们希望这类研究最终将有助于减轻星形胶质细胞功能障碍的破坏性影响的策略。

DESCRIPTION: Alexander disease is a rare and typically fatal neurodegenerative disease of childhood that results from heterozygous mutations in the gene encoding the type III intermediate filament protein GFAP. The pathological signature of the disorder is the Rosenthal fiber, a cytoplasmic inclusion containing intermediate filaments and small heat shock proteins that accumulates in astrocytes throughout the CNS. Prior investigations by our group have let to the acceptance of GFAP mutations as the cause for nearly all cases of Alexander disease, and the rapid translation of this information to clinical practice as the standard for diagnosis. However, the mechanisms by which GFAP mutations cause astrocyte dysfunction and disease remain unclear. The goals of this Program Project are to develop novel model systems of human astrocytes, investigate the impact of mutant GFAP and GFAP excess in astrocytes on neuronal development, viability, and function, and study the pathways by which mis-folded proteins are cleared from the brain. In addition, we will identify and characterize genetic modifiers of disease phenotype and test potential strategies for treatment. Our studies span genetic, biochemical, cellular, physiological, and morphological approaches to these questions, and include model systems ranging from invertebrate through human. The Program will link four laboratories, one using human induced pluripotent stem cells, one using Drosophila, and two using mouse models. An administrative core will coordinate financial reporting, monitor IACUC approvals, and support communication between the groups as well as with the internal and external advisory committees. The Program will promote a focused effort on the role of GFAP in disease, by fostering sharing of reagents, animals, and results among the four labs, through cross-fertilization of ideas, and by regular communication and meetings among laboratory members. These studies promise novel insights into the consequences of GFAP toxicity and the role of astrocytes in brain function and disease. Our hope is that such studies will ultimately lea to strategies for mitigating the devastating effects of astrocyte dysfunction.