Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17803-8. doi: 10.1073/pnas.1103141108. Epub 2011 Oct 3.
Recent studies highlight astrocytes as key drivers of motor neuron (MN) degeneration and disease propagation in mutant human superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis. However, in vivo analysis of specific astrocytic influence in amyotrophic lateral sclerosis has proven difficult because mSOD1 is ubiquitously expressed throughout the CNS of rodent models studied. Here, we transplanted SOD1(G93A) glial-restricted precursor cells--glial progenitors capable of differentiating into astrocytes--into the cervical spinal cord of WT rats to reveal how mutant astrocytes influence WT MNs and other cells types (microglia and astrocytes) in an in vivo setting. Transplanted SOD1(G93A) glial-restricted precursor cells survived and differentiated efficiently into astrocytes. Graft-derived SOD1(G93A) astrocytes induced host MN ubiquitination and death, forelimb motor and respiratory dysfunction, reactive astrocytosis, and reduced GLT-1 transporter expression in WT animals. The SOD1(G93A) astrocyte-induced MN death seemed in part mediated by host microglial activation. These findings show that mSOD1 astrocytes alone can induce WT MN death and associated pathological changes in vivo.
最近的研究强调了星形胶质细胞作为突变型超氧化物歧化酶 1（mSOD1）介导的肌萎缩侧索硬化症中运动神经元（MN）变性和疾病传播的关键驱动因素。然而，由于 mSOD1 在研究的啮齿动物模型的中枢神经系统中广泛表达，因此对肌萎缩侧索硬化症中特定星形胶质细胞影响的体内分析一直很困难。在这里，我们将 SOD1(G93A) 神经胶质限制前体细胞——能够分化为星形胶质细胞的神经胶质祖细胞——移植到 WT 大鼠的颈脊髓中，以揭示突变型星形胶质细胞如何在体内影响 WT MN 以及其他细胞类型（小胶质细胞和星形胶质细胞）。移植的 SOD1(G93A) 神经胶质限制前体细胞存活并有效地分化为星形胶质细胞。源自移植物的 SOD1(G93A) 星形胶质细胞诱导宿主 MN 泛素化和死亡、前肢运动和呼吸功能障碍、反应性星形胶质细胞增生以及 WT 动物中 GLT-1 转运蛋白表达减少。SOD1(G93A) 星形胶质细胞诱导的 MN 死亡似乎部分是由宿主小胶质细胞激活介导的。这些发现表明，mSOD1 星形胶质细胞本身就可以在体内诱导 WT MN 死亡和相关的病理变化。
