Derailed protein turnover in the aging mammalian brain.

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Systems Biology Pub Date : 2024-02-01 Epub Date: 2024-01-05 DOI:10.1038/s44320-023-00009-2
Nalini R Rao, Arun Upadhyay, Jeffrey N Savas
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Abstract

Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.

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哺乳动物大脑衰老过程中的蛋白质周转失调。
高效的蛋白质周转对细胞平衡和器官功能至关重要。蛋白质失去平衡是衰老的一个标志,最终导致蛋白质周转严重失调。为了研究蛋白质随年龄变化的动态变化,我们在小鼠体内进行了连续的代谢稳定同位素标记。首先,我们发现与心脏和肝脏组织相比,大脑蛋白质组在衰老过程中经历了独特的动态周转波动。其次,大脑蛋白质组在衰老过程中的蛋白质周转趋势显示出性别差异,这种差异与细胞区隔密切相关。接下来,对不溶性蛋白质组的平行分析表明,一些细胞区系的蛋白质周转受阻,部分原因是折叠错误。最后,我们发现与年龄相关的蛋白酶体活性波动与核心蛋白水解亚基的周转有关,这一点可以通过药物抑制蛋白酶体活性来重现。综上所述,我们的研究提供了一个蛋白质组范围内的跨衰老过程蛋白质周转图谱,并揭示了单个蛋白酶体亚基的周转与年龄相关的蛋白酶体活性下降之间的联系。
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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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