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The role of neurofilament and mitochondria in the neuronal cell death

神经丝和线粒体在神经细胞死亡中的作用

基本信息

批准号：
10670016
负责人：
GOTOW Takahiro
金额：
$ 1.98万
依托单位：
Koshien University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

We analyzed how neurofilament and mitochondria were altered biochemically as well as morphologically when neuronal cells were degenerated or showed apoptosis, and also how these organelles are associated with such changes of neuronal cells. We used neurons from jimpy and shiverer mutant mice, the model animals for human neurodegenerative diseases, and mice in which NF-H LacZ gene in transfected, and differentiated PC12 cells. In the jimpy mice, in which central axons were dysmyelinated, NFs in the axons were more numerous and irregular and less crossbridged than those in the wild-type control mice. NF-H and NF-M mRNAs were expressed much highly in the jimpy, and more importantly, most increased-axonal NF-H, and also probably NF-M that was not examined in this study, was nonphosphorylated. Thus, because of the absence of the myelin sheath, the disorganized NFs in jimpy axons may be brought about by such abnormal expression and Phosphorylation degree of NF proteins. Concerning the mitoch … More ondria, we found large-expanded mitochondria in NF almost-deficient thin axons of NF-H LacZ gene transfected mice and less-numerous-NF axons in old shiverer mice. Bcl-2 protein in these large-sized mitochondria in the NF-HlacZ transfected mice appeared to increase in amount, which may arrest axonal degeneration shown by impairment of the transport mechanism due to the abnormal accumulation of vesicular structures. This was also supported by the fact that there was no functional change in skeletal cells in these mice, suggesting these mitochondria as well as absence of NF proteins, especially of NF-H, resist the axonal degeneration. In the differentiated PC12 cells, which showed apoptotic change by serum deprivation, Bcl-2 in their mitochondria moved into cytoplasm and/or smooth endoplasmic reticulum, and more importantly, from inner mitochondrial membranes to the outer membranes. In conclusion, when the neuronal cells are degenerating or dying, NFs are disorganized and mitochondria lack Bcl-2 in their inner membranes. Less

我们分析了当神经元细胞变性或出现凋亡时，神经丝和线粒体如何在生物化学和形态学上发生改变，以及这些细胞器如何与神经元细胞的这种变化相关。我们使用的神经元来自jimpy和shiverer突变小鼠，人类神经退行性疾病的模型动物，和小鼠，其中NF-H LacZ基因转染，并分化的PC 12细胞。在jimpy小鼠中，其中央轴突髓鞘发育不良，轴突中的NF比野生型对照小鼠中的NF数量更多且不规则，并且交联较少。NF-H和NF-M mRNA在jimpy中表达非常高，更重要的是，大多数增加的轴突NF-H，也可能是本研究中未检测到的NF-M，是非磷酸化的。因此，由于髓鞘的缺失，这种神经纤维蛋白的异常表达和磷酸化程度可能导致神经纤维在粗糙轴突中的紊乱。关于米托赫 ...更多信息 ondria中，我们发现在NF-H-LacZ基因转染小鼠的NF几乎缺乏的细轴突中有大量膨胀的线粒体，而在老年颤抖小鼠中NF轴突数量较少。在NF-HlacZ转染的小鼠中，这些大尺寸线粒体中的Bcl-2蛋白的量似乎增加，这可能阻止了由于囊泡结构的异常积累而导致的运输机制受损所显示的轴突变性。这也得到了以下事实的支持，即在这些小鼠中骨骼细胞中没有功能变化，表明这些线粒体以及NF蛋白，特别是NF-H的缺乏抵抗轴突变性。在分化的PC 12细胞中，Bcl-2在其线粒体中迁移到细胞质和/或滑面内质网中，更重要的是，从线粒体内膜迁移到外膜。总之，当神经元细胞变性或死亡时，NF紊乱，线粒体内膜缺乏Bcl-2。少