NOS-JNK-Cdk5 linkage in neurodegeneration of amyotrophic lateral sclerosis.

1.在G93 A转基因小鼠的腰髓Lewy小体样透明包涵体（Lewy body-like hyaline inclusions，LBHI）中，发现内质网（endoplasmic reticulum，ER）分子伴侣葡萄糖调节蛋白78（glucose regulated protein 78，GRP 78）与突变SOD 1共定位。GRP 78在LBHI内呈弥漫性分布，即使在最早出现的LBHI中也呈阳性，提示GRP 78可能与LBHI的形成有关。2.在转基因小鼠剩余的前角细胞核中，核质转运相关蛋白importin beta、importin alpha、组蛋白H1和beta-catenin的免疫反应性降低。此外，我们证明了这些蛋白质在这些细胞的细胞质和LBHI中的异常积累。结果表明，核质转运功能障碍可能参与了转基因小鼠的病理机制。3.自由基清除剂依达拉奉对G93 A SOD 1转基因小鼠的临床疾病进展有显著的抑制作用。病理学上，发现剩余前角细胞的数量与依达拉奉的日剂量成正比。此外，脊髓匀浆中反映氧化应激程度的3-硝基酪氨酸/酪氨酸比值在依达拉奉给药的转基因小鼠中低于对照组。4.我们发现，从野生型小鼠到G93 A转基因小鼠的骨髓内移植（IBM-BMT）改善了其运动功能的下降。接受者的病理学研究显示，移植的细胞迁移到脊髓中，这些细胞的一个子集表达小胶质细胞的标志物Iba-1。

1.We found the immunohistochemical colocalization of endoplasmic reticulum (ER) chaperone, glucose regulated protein 78 (GRP78), with the mutant SOD1 within Lewy body-like hyaline inclusions (LBHIs) in the lumbar spinal cord from G93A transgenic mice. The immunoreactivity was distributed diffusely within LBHIs, and was positive even in those of their earliest emergence, suggesting that GRP78 would be related to LBHI formation.2.We found the reduced immunoreactivity of nucleocytoplasmic transport-related proteins such as importin beta, importin alpha, histone H1, and beta-catenin, in the nucleus of the remaining anterior horn cells of the transgenic mice. Moreover, we demonstrated the abnormal accumulations of these proteins in the cytoplasm of these cells and in LBHIs. Our results suggest that dysfunction of the nucleocytoplasmic transport would be involved in the pathomechanisms of the transgenic mice.3.We found the statistically significant suppressive effect of edaravone, one of the free radical scavengers, on the clinical disease progression of G93A SOD1 transgenic mice. Pathologically, the number of the remaining anterior horn cells was found to be proportional to the daily dose of edaravone. Furthermore, the 3-nitrotyrosine/tyrosine ratio, which reflects the extent of oxidative stress, in the spinal cord homogenates was lower in the edaravone-administered transgenic mice than those of controls.4.We found that intra bone marrow-bone marrow transplantation (IBM-BMT) from wild type mice to G93A transgenic mice ameliorated their decline of motor function. Pathological investigation of the recipients revealed that transplanted cells migrated into the spinal cords and a subset of these cells expressed Iba-1, a marker of microglia.