Multidimensional Dynamics of the Proteome in the Neurodegenerative and Aging Mammalian Brain.
Multidimensional Dynamics of the Proteome in the Neurodegenerative and Aging Mammalian Brain.
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DOI：
10.1016/j.mcpro.2021.100192
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Frank RAW
中科院分区：
文献类型：
--
作者：
Andrews B;Murphy AE;Stofella M;Maslen S;Almeida-Souza L;Skehel JM;Skene NG;Sobott F;Frank RAW
大脑中任何给定蛋白质的数量取决于其合成和破坏的速率，而合成和破坏的速率受不同的细胞机制调节。在这里，我们将活体小鼠的代谢标记与整体蛋白质组分析相结合，以同时量化神经退行性小鼠模型中蛋白质的通量和数量。在多个模型中，蛋白质周转的增加与病理的增加相关。该方法区分合成介导的蛋白质表达变化和降解介导的蛋白质表达变化。在阿尔茨海默病的 AppNL-F 敲入小鼠模型中，合成和降解失衡导致周转率增加，聚集在与突触小泡回收（Dnm1、Cltc、Rims1）和线粒体（Fis1、Ndufv1）相关的蛋白质上。与疾病模型相反，野生型小鼠的衰老导致蛋白质回收广泛减少，并与自噬通量减少相关。总体而言，这种简单的多维方法能够全面绘制蛋白质组动力学图谱，并识别小鼠疾病模型和其他活体动物测试环境中受影响的蛋白质。多维蛋白质组学筛选检测小鼠疾病模型的不平衡。多种症状性神经退行性变小鼠模型中蛋白质组周转增加。健康老龄化与全球蛋白质周转率下降有关。神经退行性疾病的特征是大脑中聚集蛋白的异常积累。使用体内脉冲同位素标记，我们筛选了多种神经退行性疾病小鼠模型中蛋白质周转率和丰度变化的蛋白质组。这些数据表明，受病理影响的组织的疾病状态的特征是蛋白质组范围内蛋白质周转和修复的增加。相比之下，在健康的野生型小鼠中，哺乳动物大脑的衰老与蛋白质周转的整体放缓有关。
The amount of any given protein in the brain is determined by the rates of its synthesis and destruction, which are regulated by different cellular mechanisms. Here, we combine metabolic labeling in live mice with global proteomic profiling to simultaneously quantify both the flux and amount of proteins in mouse models of neurodegeneration. In multiple models, protein turnover increases were associated with increasing pathology. This method distinguishes changes in protein expression mediated by synthesis from those mediated by degradation. In the AppNL-F knockin mouse model of Alzheimer’s disease, increased turnover resulted from imbalances in both synthesis and degradation, converging on proteins associated with synaptic vesicle recycling (Dnm1, Cltc, Rims1) and mitochondria (Fis1, Ndufv1). In contrast to disease models, aging in wild-type mice caused a widespread decrease in protein recycling associated with a decrease in autophagic flux. Overall, this simple multidimensional approach enables a comprehensive mapping of proteome dynamics and identifies affected proteins in mouse models of disease and other live animal test settings. Multidimensional proteomic screen to detect imbalances in mouse models of disease. Increased proteome turnover in multiple symptomatic neurodegeneration mouse models. Healthy aging is associated with a global decrease in protein turnover. Neurodegenerative diseases are characterized by the abnormal accumulation of aggregated proteins in the brain. Using in vivo pulse isotope labeling, we screened the proteome for changes in protein turnover and abundance in multiple mouse models of neurodegeneration. These data suggest that the disease state of pathologically affected tissue is characterized by a proteome-wide increase in protein turnover and repair. In contrast, in healthy wild-type mice, aging in the mammalian brain is associated with a global slowdown in protein turnover.
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DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
DOI：
10.1126/science.aaa4484
发表时间：
2015-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Das I;Krzyzosiak A;Schneider K;Wrabetz L;D'Antonio M;Barry N;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A
影响因子：
82.9
作者：
Jucker, Mathias
通讯作者：
Jucker, Mathias
影响因子：
5.7
作者：
Guerreiro, Rita;Hardy, John
通讯作者：
Hardy, John
影响因子：
3.4
作者：
Basisty N;Meyer JG;Schilling B
通讯作者：
Schilling B