INTRACELLULAR PROTEIN DEGRADATION IN AGED AND ALZHEIMER'S DISEASE CELLS

衰老和阿尔茨海默病（AD）的特征在于 异常蛋白质和与泛素结合的蛋白质。一个功能 泛素在正常细胞中的作用是作为一种分子标记， 异常或结构受损的细胞蛋白质的降解。因此，在本发明中， 一个合理的解释退化的异常或 结构受损的细胞蛋白质。因此，一个合理的解释是 在老年和AD细胞中泛素化蛋白的积累是 蛋白水解系统中的缺陷通常导致其 降解我们已经确定并广泛研究了 一种叫做蛋白酶体的分布式蛋白酶，它似乎是 降解泛素化蛋白质的蛋白酶。我们还确定 研究了两种特定的蛋白酶体调节蛋白， 它在完整细胞中的活性。这项工作的目的是测试 假设衰老和/或AD细胞在细胞内具有一般缺陷， 细胞内蛋白质降解的过程，并且一个或多个 蛋白酶体催化的泛素依赖性蛋白水解的组分 pathway解释了这一缺陷。因此，我们建议确定 培养中的老年或AD细胞的蛋白质降解速率是否 低于年轻或正常对照组。我们还将测量 蛋白酶体系统在这些相同的无细胞提取物中的活性 细胞并定量各种组分蛋白质的水平。这些 研究应该确定蛋白质降解的改变是否是 老年或AD细胞的特征，并确定可能的分子 这种缺陷的基础。

Aging and Alzheimer's Disease (AD) are characterized by the accumulation of aberrant proteins and proteins conjugated to ubiquitin. One function of ubiquitin in normal cells is to serve as a molecular marker for the degradation of abnormal or structurally damaged cellular proteins. Thus, one reasonable explanation for the degradation of abnormal or structurally damaged cellular proteins. Thus, one reasonable explanation for the accumulation of ubiquitinated proteins in aged and AD cells is a defect in the proteolytic system normally responsible for their degradation. We have identified and extensively studied a widely distributed protease named the proteasome, that appears to be the protease that degrades ubiquitinated proteins. We have also identified and studied two specific proteasome regulatory proteins that may control its activity in intact cells. The purpose of this work is to test the hypothesis that aging and/or AD cells have a general defect in the process of intracellular protein degradation and that one or more components of the proteasome-catalyzed ubiquitin-dependent proteolytic pathway accounts for this defect. Therefore, we propose to determine whether rates of protein degradation in aged or AD cells in culture are lower than those in young or normal controls. We will also measure the activity of the proteasome system in cell free extracts from these same cells and quantitate level of the various component proteins. These studies should determine whether altered protein degradation is a characteristic of aged or AD cells and identify a possible molecular basis for such a defect.