Protein Glycation and the Proteasome: Role in Neurological Diseases and Aging

描述(申请人提供)：与其他器官相似，大脑功能会随着年龄的增长而下降。事实上，认知和运动功能的下降是正常衰老的特征之一，会导致学习和记忆的变化，以及平衡和协调的缺陷。年龄也是包括阿尔茨海默病(AD)在内的各种神经疾病的最大风险因素。由于许多西方国家的平均年龄正在增加，因此正在寻找减少衰老对大脑功能影响的方法 新的紧迫感。据推测，导致大脑功能随年龄增长而下降的因素包括蛋白质加工过程中的变化。这是如何和为什么发生的尚不清楚，但我们假设它与甲基乙二醛(MG)的增加密切相关，从而导致蛋白质糖化。糖类在蛋白质中的非酶加成会导致晚期糖基化终末产物(AGEs)的形成。虽然糖化蛋白的增强形成最初与糖尿病有关，但现在人们认识到，这种蛋白修饰在正常衰老过程中也会增加，并在阿尔茨海默病(AD)等依赖年龄的神经退行性疾病中加剧。镁是AGE形成的主要反应性醛之一。它是糖酵解的副产品，但也可以直接或间接从饮食来源获得。许多因素被认为在衰老过程中起作用，包括氧化还原稳态、蛋白质加工、线粒体功能和免疫反应的改变。尽管这些变化看起来相当不同，但人们假设它们由一个共同的因素MG联系在一起。支持这一观点的是，糖酵解率的降低被证明可以延长寿命，而蛋白质加工，特别是蛋白酶体功能的损害对培养细胞和动物模型的衰老都有负面影响。最近的证据表明，MG可以通过修饰特定的蛋白酶体亚基，直接和间接地抑制蛋白酶体的活性。此外，MG和泛素都可以共价修饰赖氨酸残基上的蛋白质。由于依赖泛素的途径是去除许多聚集的、错误折叠的或氧化的蛋白质所必需的，因此蛋白质的糖基化可能会阻碍泛素 依存性退化。因此，进一步假设MG蛋白糖基化的年龄依赖性增加和蛋白酶体功能的年龄依赖性降低是直接相关的，并导致认知功能障碍。这项拟议的研究旨在使用细胞培养研究和AD的动物模型来验证这一假设。

DESCRIPTION (provided by applicant): Similar to other organs, brain function declines with age. Indeed, a decline in both cognitive and motor functions is one of the characteristics of normal aging, resulting in changes in learning and memory as well as deficits in balance and coordination. Age is also the single greatest risk factor for a variety of neurological disorders including Alzheimer's disease (AD). Since the average age in many Western countries is increasing, identifying approaches for reducing the effects of aging on brain function is taking on a new urgency. Among the factors that have been proposed to contribute to the decrease in brain function with age are alterations in protein processing. How and why this occurs is unclear but we hypothesize that it is tightly linked to increases in methylglyoxal (MG) and, in consequence, protein glycation. The non-enzymatic addition of sugars to proteins results in the formation of advanced glycation end- products (AGEs). Although the enhanced formation of glycated proteins was initially associated with diabetes, it is now recognized that this protein modification is also increased during normal aging and is exacerbated in age-dependent neurodegenerative diseases such as Alzheimer's disease (AD). MG is one of the major reactive aldehydes responsible for AGE formation. It is a by-product of glycolysis but can also be obtained both directly and indirectly from dietary sources. Multiple factors have been proposed to contribute to the aging process including alterations in redox homeostasis, protein processing, mitochondrial function and the immune response. Although these alterations appear to be quite diverse, it is hypothesized that they are linked by a common factor, MG. In support of this idea, a reduction in the glycolytic rate has been shown to increase longevity while impairments in protein processing and especially proteasome function have negative effects on aging both in cultured cells and in animal models. Recent evidence suggests that MG can both directly and indirectly inhibit proteasome activity via modification of specific proteasome subunits. Furthermore, both MG and ubiquitin covalently modify proteins on lysine residues. Since ubiquitin-dependent pathways are required for the removal of many aggregated, misfolded, or oxidized proteins, it is possible that the glycation of proteins can hinder ubiquitin dependent degradation. Thus, it is further hypothesized that age-dependent increases in MG-protein glycation and age-dependent decreases in proteasome function are directly linked and contribute to cognitive dysfunction. The proposed research is designed to test this hypothesis using both cell culture studies and an animal model of AD.