Vacuolar Leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2
Vacuolar Leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2
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DOI：
10.2353/ajpath.2007.060898
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发表时间：
2007-06-01
影响因子：
6
通讯作者：
Ma, Qiang
中科院分区：
文献类型：
--
作者：
Hubbs, Ann F.;Benkovic, Stanley A.;Ma, Qiang
NFE 2相关因子2（Nrf 2）是一种氧化剂激活的CNC bZip转录因子，与一系列细胞和组织类型（包括中枢神经系统）中的氧化应激和化学损伤防御有关。在这里，我们报告说，在小鼠中的Nrf 2基因的缺失引起空泡（海绵状）白质脑病与广泛的星形胶质细胞增生。白质脑病存在于所有10月龄以上的Nrf 2基因敲除小鼠中，其特征为涉及所有主要脑区的空泡变性，并且在小脑和脑桥的白色束中最明显。白色纤维束中的髓鞘变性归因于髓鞘解旋和髓鞘内囊肿，4-羟基-2-壬烯醛和髓鞘碱性蛋白的双标记免疫荧光定位自由基诱导的髓鞘氧化损伤。此外，Nrf 2基因敲除小鼠的大脑表现出广泛的星形胶质细胞活化，大量的胶质细胞酸性蛋白免疫反应性胶质细胞过程。这项研究揭示了Nrf 2在维持中枢神经系统髓鞘中可能的生理作用。如果这一作用得到证实，它可能为治疗遗传和化学诱导的髓鞘变性疾病提供新的方法。
NFE2-related factor 2 (Nrf2), an oxidant-activated CNC bZip transcription factor, has been implicated in defense against oxidative stress and chemical insults in a range of cell and tissue types, including the central nervous system. Here, we report that deletion of the Nrf2 gene in mice caused vacuolar (spongiform) leukoencephalopathy with widespread astrogliosis. The leukoencephalopathy was present in all Nrf2-null mice more than 10 months of age, was characterized by vacuolar degeneration involving all major brain regions, and was most apparent in the white tracts of the cerebellum and pons. Vacuolar degeneration in white tracts was attributable to myelin unwinding and intramyelinic cysts, and double-label immunofluorescence for 4-hydroxy-2-nonenal and myelin basic protein localized free-radical induced oxidative damage to the myelin sheath. Moreover, the brains of Nrf2-null mice exhibited widespread astrocyte activation with profusion of glial fibrillary acidic protein-immunoreactive glial processes. The study uncovered a possible physiological role for Nrf2 in maintaining central nervous system myelin. if this role is confirmed, it may suggest new approaches to treating genetically and chemically induced myelin degenerative diseases.