Figueiredo-Pereira M E, Cohen G
Department of Biological Sciences, Hunter College of City University of New York, NY 10021, USA.
Mol Biol Rep. 1999 Apr;26(1-2):65-9. doi: 10.1023/a:1006909918866.
One of the hallmarks of neurodegeneration is the accumulation of ubiquitinated proteins in intraneuronal inclusions in the cytosol, endosomes/lysosomes and nuclei of affected cells. The relationship between inclusion production and cell viability is not well understood. On the one hand inclusions may be beneficial and result from an attempt of the cell to isolate a subclass of ubiquitinated proteins that are not effectively degraded. On the other hand, the inclusions may impede normal cell function contributing to cell death. To address this issue we treated mouse neuronal HT4 cells with three toxic agents cadmium, zinc and H2O2, and investigated their effects on glutathione homeostasis, on accumulation of ubiquitinated proteins and on cell viability. The three treatments induce oxidative stress manifested by decreases in glutathione (GSH) and/or increases in protein mixed disulfides (PrSSG). After an overnight recovery period in the absence of treatment, GSH and PrSSG were restored to almost normal levels. However, the levels of ubiquitinated proteins were significantly increased, and cell viability was sharply reduced. These results suggest that the ubiquitin-proteasome pathway is recruited for removal of proteins that are oxidatively modified. However, if the ubiquitinated proteins are not efficiently degraded, they accumulate in the cell and contribute to a decrease in cell viability.
神经退行性变的一个标志是泛素化蛋白在受影响细胞的胞质溶胶、内体/溶酶体和细胞核中的神经元内包涵体中积累。包涵体产生与细胞活力之间的关系尚未完全了解。一方面，包涵体可能是有益的，是细胞试图隔离一类未被有效降解的泛素化蛋白的结果。另一方面，包涵体可能会阻碍正常细胞功能，导致细胞死亡。为了解决这个问题，我们用三种有毒试剂镉、锌和过氧化氢处理小鼠神经元HT4细胞，并研究它们对谷胱甘肽稳态、泛素化蛋白积累和细胞活力的影响。这三种处理诱导了氧化应激，表现为谷胱甘肽（GSH）减少和/或蛋白质混合二硫键（PrSSG）增加。在无处理的过夜恢复期后，GSH和PrSSG恢复到几乎正常水平。然而，泛素化蛋白水平显著增加，细胞活力急剧下降。这些结果表明，泛素-蛋白酶体途径被用于清除氧化修饰的蛋白质。然而，如果泛素化蛋白没有被有效降解，它们就会在细胞中积累，并导致细胞活力下降。
