Tang Guomei, Yue Zhenyu, Talloczy Zsolt, Hagemann Tracy, Cho Woosung, Messing Albee, Sulzer David L, Goldman James E
Department of Pathology, Center for Neurobiology and Behavior, Center for Parkinson's Disease and Other Movement Disorders, Columbia University, New York, NY 10032, USA.
Hum Mol Genet. 2008 Jun 1;17(11):1540-55. doi: 10.1093/hmg/ddn042. Epub 2008 Feb 14.
Glial fibrillary acidic protein (GFAP) is the principle intermediate filament (IF) protein in astrocytes. Mutations in the GFAP gene lead to Alexander disease (AxD), a rare, fatal neurological disorder characterized by the presence of abnormal astrocytes that contain GFAP protein aggregates, termed Rosenthal fibers (RFs), and the loss of myelin. All GFAP mutations cause the same histopathological defect, i.e. RFs, though little is known how the mutations affect protein accumulation as well as astrocyte function. In this study, we found that GFAP accumulation induces macroautophagy, a key clearance mechanism for prevention of aggregated proteins. This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is in part responsible for the down-regulation of phosphorylated-mTOR and the subsequent activation of autophagy. Our study suggests that AxD mutant GFAP accumulation stimulates autophagy, in a manner regulated by p38 MAPK and mTOR signaling pathways. Autophagy, in turn, serves as a mechanism to reduce GFAP levels.
胶质纤维酸性蛋白（GFAP）是星形胶质细胞中的主要中间丝（IF）蛋白。GFAP基因突变会导致亚历山大病（AxD），这是一种罕见的致命性神经疾病，其特征是存在含有GFAP蛋白聚集体（称为罗森塔尔纤维，RFs）的异常星形胶质细胞以及髓鞘缺失。所有GFAP突变都会导致相同的组织病理学缺陷，即RFs，尽管对于这些突变如何影响蛋白质积累以及星形胶质细胞功能知之甚少。在本研究中，我们发现GFAP积累会诱导巨自噬，这是预防聚集蛋白的关键清除机制。这种自噬反应受到雷帕霉素哺乳动物靶标（mTOR）的负调控。GFAP积累导致的p38丝裂原活化蛋白激酶（MAPK）激活部分负责磷酸化mTOR的下调以及随后自噬的激活。我们的研究表明，AxD突变体GFAP积累以由p38 MAPK和mTOR信号通路调控的方式刺激自噬。反过来，自噬作为一种降低GFAP水平的机制。
