Hippocampal gene expression in the GFAP-R237H rat model of Alexander disease at early and late stages of disease

Alexander disease is a rare neurodegenerative disorder caused by mutations in the gene for glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes in the central nervous system. GFAP mutation causes a toxic gain-of-function and protein aggregation, ultimately leading to gliosis, astrocyte dysfunction, and neurodegeneration. To better understand the disease process, a rat model has been generated to mimic the common R239H mutation observed in the human disease (R237H in the rat). This study focuses on hippocampus, a brain region with a heavy burden of pathology, to determine the impact of GFAP mutation at presymptomatic (3 weeks of age) and severe stages ( 8 weeks of age) of disease. Transcription profiling shows progressive neuroinflammation and neurodegeneration.亚历山大病（Alexander disease）是一种罕见的神经退行性疾病，由中枢神经系统星形胶质细胞的主要中间丝蛋白——胶质纤维酸性蛋白（glial fibrillary acidic protein, GFAP）编码基因的突变引发。GFAP突变会导致毒性功能获得与蛋白质聚集，最终引发胶质增生、星形胶质细胞功能异常及神经退行性变。为更好地解析该疾病的发病进程，研究人员构建了可模拟人类疾病常见R239H突变（对应大鼠体内的R237H突变）的大鼠模型。本研究聚焦于病理负荷较重的脑区海马体，分别在疾病症状前（3周龄）与重症阶段（8周龄）探究GFAP突变带来的影响。转录谱分析结果显示，疾病进程伴随进行性神经炎症与神经退行性变。