Tarbox Haley E, Branch Audrey, Fried Stephen D
Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
Sci Adv. 2025 Jul 11;11(28):eadt3778. doi: 10.1126/sciadv.adt3778.
Cognitive decline during aging represents a major societal burden, causing both personal and economic hardship in an increasingly aging population. Many studies have found that the proteostasis network, which functions to keep proteins properly folded, is impaired with age, suggesting that there may be many proteins that incur structural alterations with age. Here, we used limited proteolysis mass spectrometry, a structural proteomic method, to globally interrogate protein conformational changes in a rat model of cognitive aging. Specifically, we compared soluble hippocampal proteins from aged rats with preserved cognition to those from aged rats with impaired cognition. We identified a couple hundred proteins as having undergone cognition-associated structural changes (CASCs). We report that CASC proteins are substantially more likely to be nonrefoldable than non-CASC proteins, meaning that they typically cannot spontaneously refold to their native conformations after being chemically denatured. These findings suggest that noncovalent, conformational alterations may be general features in cognitive decline.
衰老过程中的认知衰退是一项重大的社会负担，在人口老龄化日益加剧的情况下，给个人和经济都带来了困难。许多研究发现，负责保持蛋白质正确折叠的蛋白质稳态网络会随着年龄增长而受损，这表明可能有许多蛋白质会随着年龄增长而发生结构改变。在这里，我们使用了一种结构蛋白质组学方法——有限蛋白水解质谱法，来全面研究认知衰老大鼠模型中的蛋白质构象变化。具体而言，我们将认知功能保留的老年大鼠的可溶性海马体蛋白质与认知功能受损的老年大鼠的可溶性海马体蛋白质进行了比较。我们鉴定出数百种发生了与认知相关的结构变化（CASC）的蛋白质。我们报告称，与非CASC蛋白质相比，CASC蛋白质更有可能无法重新折叠，这意味着它们在化学变性后通常无法自发地重新折叠成其天然构象。这些发现表明，非共价的构象改变可能是认知衰退的普遍特征。
