Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Department of Medicine, Columbia University College of Physicans & Surgeons, New York, NY 10032-3784.
Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):E5703-E5711. doi: 10.1073/pnas.1618417114. Epub 2017 Jun 26.
Alzheimer's disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Aβ peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal-lysosomal and ubiquitin-proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer's disease.
阿尔茨海默病是痴呆症最常见的病因。这种疾病的一个标志是，在受影响个体的大脑中存在含有 Aβ肽（淀粉样斑块）和 tau 蛋白（神经原纤维缠结）的异常沉积物。越来越多的证据表明，这些沉积物的形成与与年龄相关的大量高度表达和易于聚集的蛋白质的失调密切相关，这些蛋白质构成了一个亚稳定的子蛋白质组。为了更详细地了解这种失调的起源，我们通过基因共表达分析，确定了与这些亚稳定蛋白质相关的蛋白质动态平衡系统的特定组成部分。我们的结果揭示了蛋白质运输和清除机制的特殊重要性，包括内体溶酶体和泛素-蛋白酶体系统的特定分支，在维持与阿尔茨海默病相关的亚稳定子蛋白质组的动态平衡方面。
