Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation
Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation
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DOI：
10.15252/msb.20209596
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发表时间：
2020-06-01
影响因子：
9.9
通讯作者：
Ori, Alessandro
中科院分区：
文献类型：
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作者：
Sacramento, Erika Kelmer;Kirkpatrick, Joanna M.;Ori, Alessandro
蛋白质稳态的进行性丧失是衰老的特征，也是神经退行性变的驱动因素。为了定量研究这一过程，我们结合转录组学和蛋白质组学，研究了短寿命脊椎动物Nothobranchius furzericombining脑衰老过程中蛋白质组的动态变化。我们检测到蛋白质和mRNA之间的相关性逐渐降低，主要是由于转录后机制，占年龄调节蛋白质的40%以上。这些变化导致几种蛋白质复合物（包括核糖体）的化学计量逐渐丧失，这些蛋白质复合物显示组装/拆卸受损，并在老年大脑中富集蛋白质聚集体。从机制上讲，我们发现蛋白酶体活性的降低是大脑衰老过程中的早期事件，足以诱导体内蛋白质组学特征的衰老和化学计量的丧失。使用纵向转录组数据，我们表明，生命早期蛋白酶体水平下降的幅度是死亡率的主要危险因素。我们的工作定义了衰老过程中的致病事件，这些事件可以有针对性地防止蛋白质稳态的丧失并延迟与年龄相关的神经退行性变的发生。
A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrateNothobranchius furzericombining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein andmRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometryin vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration.