PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) is a heterogeneous age-dependent neurodegenerative disorder. Its hallmarks involve abnormal proteostasis, which triggers proteotoxicity and induces neuronal dysfunction. The 26S proteasome is an ATP-dependent proteolytic nanomachine of the ubiquitin-proteasome system (UPS) and contributes to eliminating these abnormal proteins. This study focused on the relationship between proteasome and AD, the hub genes of proteasome, PSMC6, and 7 genes of α-ring, are selected as targets to study. The following three characteristics were observed: 1. The total number of proteasomes decreased with AD progression because the proteotoxicity damaged the expression of proteasome proteins, as evidenced by the downregulation of hub genes. 2. The existing proteasomes exhibit increased activity and efficiency to counterbalance the decline in total proteasome numbers, as evidenced by enhanced global coordination and reduced systemic disorder of proteasomal subunits as AD advances. 3. The synergy of PSMC6 and α-ring subunits is associated with AD. Synergistic downregulation of PSMC6 and α-ring subunits reflects a high probability of AD risk. Regarding the above discovery, the following hypothesis is proposed: The aggregation of pathogenic proteins intensifies with AD progression, then proteasome becomes more active and facilitates the UPS selectively targets the degradation of abnormal proteins to maintain CNS proteostasis. In this paper, bioinformatics and support vector machine learning methods are applied and combined with multivariate statistical analysis of microarray data. Additionally, the concept of entropy was used to detect the disorder of proteasome system, it was discovered that entropy is down-regulated continually with AD progression against system chaos caused by AD. Another conception of the matrix determinant was used to detect the global coordination of proteasome, it was discovered that the coordination is enhanced to maintain the efficiency of degradation. The features of entropy and determinant suggest that active proteasomes resist the attack caused by AD like defenders, on the one hand, to protect themselves (entropy reduces), and on the other hand, to fight the enemy (determinant reduces). It is noted that these are results from biocomputing and need to be supported by further biological experiments.
摘要：
阿尔茨海默病(AD)是一种异质性的年龄依赖性神经退行性疾病。它的标志涉及异常的蛋白质停滞，触发蛋白毒性并诱导神经元功能障碍。26S蛋白酶体是泛素-蛋白酶体系统（UPS）的ATP依赖性蛋白水解纳米机器，有助于消除这些异常蛋白质。本研究主要探讨蛋白酶体与AD的关系,蛋白酶体的中心基因，PSMC6和7个α环基因，被选为研究目标。观察到以下三个特征:1.蛋白酶体的总数随着AD的进展而减少，因为蛋白质毒性破坏了蛋白酶体蛋白的表达，hub基因的下调证明了这一点。2.现有的蛋白酶体表现出增加的活性和效率，以抵消总蛋白酶体数量的下降。随着AD的进展，蛋白酶体亚基的整体协调性增强和系统性疾病减少。3.PSMC6和α环亚基的协同作用与AD相关。PSMC6和α环亚基的协同下调反映了AD风险的高概率。关于上述发现，提出了以下假设：致病蛋白的聚集随着AD的进展而加剧，然后蛋白酶体变得更活跃，并促进UPS选择性靶向异常蛋白的降解，以维持CNS蛋白的稳定。在本文中,应用生物信息学和支持向量机学习方法，并结合微阵列数据的多元统计分析。此外,熵的概念被用来检测蛋白酶体系统的紊乱，人们发现，随着AD的发展，熵不断下调，而不是由AD引起的系统混乱。矩阵行列式的另一个概念用于检测蛋白酶体的整体协调，已发现，协调增强，以保持降解效率。熵和决定因素的特征表明，活性蛋白酶体抵抗由AD引起的攻击，一方面,为了保护自己（熵减少），另一方面,与敌人作战(决定因素减少)。注意,这些是来自生物计算的结果,并且需要进一步的生物实验来支持。
