Amyloid Regulatory Networks

CBET-1262729-阿尔茨海默氏症、帕金森氏症和糖尿病等疾病在病因、症状和进展方面明显不同。然而，它们有一个共同的特征：蛋白质在受影响的器官上沉积。每种疾病沉积的蛋白质都是独一无二的，它们的正常形状和功能也明显不同。然而，在每一种情况下，蛋白质都会经历形状和结构的变化，导致它们粘在一起形成纤维状聚集体。将正常的可溶性蛋白质转化为不可溶的纤维聚集体的过程称为淀粉样蛋白形成。每种疾病中的沉淀物主要由一种蛋白质组成，这种蛋白质对每种疾病都是独一无二的；换句话说，沉淀物是通过“自身”联系形成的。这种自结合是蛋白质在淀粉样蛋白形成过程中的某个时刻采用的结构特征的结果。这些结构特征出现在淀粉样蛋白途径上的所有蛋白质中，位于途径的中间点，无论是什么疾病。结构特征的相似性可能导致“非我”关联：两个都处于相似中间点的不同蛋白质之间的关联。一对这样的蛋白质，转甲状腺蛋白(与老年性系统性淀粉样变性有关)和β-淀粉样蛋白(阿尔茨海默病)的数据清楚地表明，这种非自身联系确实存在。此外，转甲状腺素与β-淀粉样蛋白的结合阻止了β-淀粉样蛋白的聚集，更重要的是，阻止了β-淀粉样蛋白杀死神经细胞。在这个项目中，淀粉样蛋白致病蛋白之间的非自身关联的检查将扩展到转甲状腺蛋白和β-淀粉样蛋白之外。大约100对不同的蛋白质将被探测，以确定这些蛋白质是否相互作用。如果答案是肯定的，将进行实验以确定参与相互作用的蛋白质的特定部分，并测量相互作用对淀粉样蛋白形成途径进展的影响。这个项目背后的假设是，存在一个调控网络，这个网络包含许多淀粉样蛋白，并且“非我”相互作用在干预“自我”相互作用方面很重要。与转甲状腺素和β-淀粉样蛋白一样，这种“非我”相互作用可能会阻止“自我”相互作用所产生的毒性。如果成功，科学家将不再认为蛋白质聚集是涉及单一蛋白质的孤立事件，而是认为蛋白质聚集是相互作用的蛋白质网络，共同调节彼此的自我关联。该项目的结果可能有助于为抗击这些蛋白质聚集障碍提供创新的新战略。

CBET-1262729MurphyDiseases such as Alzheimer's, Parkinson's, and diabetes are distinctly different in etiology, symptoms, and progression. Yet they share one common feature: the deposition of proteins on affected organs. The deposited proteins are unique to each disease, and their normal shape and function are distinctly different. Yet, in each case, the proteins undergo a change in shape and structure, causing them to stick together into clumps of fibrillar aggregates. The process of converting normal soluble proteins to insoluble fibrillar aggregates is called amyloidogenesis. The deposits in each disease are comprised mainly of a single protein, unique to each disorder; in other words, the deposits are formed through 'self' association. This self-association arises as a result of the structural features that the proteins adopt at some point during the amyloidogenesis process. These structural features arise in all proteins on the amyloid pathway, at an intermediate point along the pathway, no matter what the disease. The similarity of structural features could lead to 'non-self' association: association between two different proteins that are both at a similar intermediate point. Data with one pair of such proteins, transthyretin (involved in senile systemic amyloidosis) and beta-amyloid (Alzheimer's disease), demonstrate clearly that such non-self association does exist. Furthermore, the binding of transthyretin to beta-amyloid halts beta-amyloid aggregation and, more importantly, prevents beta-amyloid from killing neuron cells. In this project, the examination of non-self association between amyloidogenic proteins will be expanded beyond transthyretin and beta-amyloid. About 100 different pairs of proteins will be probed to determine if the proteins interact. If the answer is yes, experiments will be conducted to define the specific parts of the proteins that are involved in the interaction, and to measure the effect of the interaction on progress along the amyloidogenesis pathway. The hypothesis underlying this project is that a regulatory network exists, that this network contains many amyloidogenic proteins, and that 'non-self' interactions are important in intervening in 'self' interactions. As with transthyretin and beta-amyloid, such 'non-self' interactions may prevent the toxicity that arises due to 'self' interaction. If successful, no longer will scientists think about protein aggregation as an isolated event involving a single protein, but rather, as a network of interacting proteins that co-regulate each other's self-association. Results from this project could contribute innovative new strategies for combating these protein aggregation disorders.