INTRACELLULAR PROTEIN DEGRADATION IN AGED AND ALZHEIMER'S DISEASE CELLS

衰老和阿尔茨海默病细胞的细胞内蛋白质降解

• 批准号: 6218756
• 负责人: George N. DeMartino
• 金额: $ 15.74万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6218756
• 关键词: Alzheimer's disease; adenosine triphosphate; aging; cell free system; endopeptidases; enzyme activity; fibroblasts; human tissue; intracellular; neurofibrillary tangles; proteasome; protein degradation; protein structure; tissue /cell culture; ubiquitin

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.

衰老和阿尔茨海默病（AD）的特点是积累 异常蛋白质和与泛素结合的蛋白质。一种功能 正常细胞中泛素的存在可作为分子标记 异常或结构损坏的细胞蛋白质的降解。因此， 对异常或异常退化的一种合理解释 结构受损的细胞蛋白质。因此，一种合理的解释 老年细胞和 AD 细胞中泛素化蛋白的积累是 蛋白水解系统的缺陷通常导致它们 降解。我们已经确定并广泛研究了一个广泛的 分布式蛋白酶命名为蛋白酶体，它似乎是 降解泛素化蛋白质的蛋白酶。我们还确定了 并研究了两种可能控制的特定蛋白酶体调节蛋白 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 细胞内蛋白质降解的过程以及一种或多种 蛋白酶体催化的泛素依赖性蛋白水解的成分 途径解释了这一缺陷。因此，我们建议确定 培养中的衰老细胞或 AD 细胞的蛋白质降解率是否 低于年轻或正常对照者。我们还将测量 这些物质的无细胞提取物中蛋白酶体系统的活性 细胞并定量各种成分蛋白质的水平。这些 研究应该确定蛋白质降解的改变是否是一个 老化或 AD 细胞的特征并识别可能的分子 造成这种缺陷的基础。