INTRACELLULAR PROTEIN DEGRADATION IN AGED AND ALZHEIMER'S DISEASE CELLS

衰老和阿尔茨海默病(AD)的特点是积聚 异常蛋白质和与泛素结合的蛋白质。一种功能 泛素在正常细胞中的表达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， 一种合理的解释来解释异常或异常的退化 结构受损的细胞蛋白质。因此，一个合理的解释是 在衰老和AD细胞中泛素化蛋白的积累 蛋白分解系统中的缺陷通常是导致它们 退化。我们已经确定并广泛研究了一种 被命名为蛋白酶体的分布式蛋白酶，似乎是 降解泛素化蛋白质的蛋白酶。我们还确认了 并研究了两种特定的蛋白酶体调节蛋白，它们可能控制 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 细胞内蛋白质降解的过程以及一个或多个 蛋白酶体催化的泛素依赖蛋白水解酶的组成 通路解释了这一缺陷。因此，我们建议确定 无论是老年细胞还是培养中的AD细胞的蛋白质降解率 低于年轻或正常对照组。我们还将测量 这些化合物的无细胞提取物中蛋白酶体系统的活性 细胞和各种成分蛋白的定量水平。这些 研究应该确定改变的蛋白质降解是否是一种 衰老或阿尔茨海默病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.