Precisely measured protein lifetimes in the brain of aged mice

Aging, which is associated with protein homeostasis defects, is one of the most prominent risk factors for neurodegenerative disorders and the regulation of protein homeostasis is essential for brain health. While several studies have addressed changes in protein abundance due to aging, little is known about differences in protein stability in the mammalian brain proteome. In particular, pre-symptomatic alterations of protein stability might be instrumental for understanding the pathological alterations that occur during neurodegeneration. To explore these alterations, we measured proteome turnover with a pulse-SILAC approach in aged mice from total cortex and cerebellum homogenates and from the respective synaptic-enriched fraction. We compared the stability of young and aged proteomes. Our analyses revealed several differences and the large dataset that we created will serve as a resource for the community to develop approaches that explore these alterations with diagnostic and therapeutic purposes.

衰老与蛋白质稳态（protein homeostasis）缺陷紧密相关，是神经退行性疾病最显著的风险因素之一；而蛋白质稳态的调控对于大脑健康至关重要。尽管已有多项研究探讨了衰老引发的蛋白质丰度变化，但目前对哺乳动物脑蛋白质组（proteome）中蛋白质稳定性的差异仍知之甚少。尤为关键的是，蛋白质稳定性的症状前改变或许有助于理解神经退行性病变过程中发生的病理变化。为探究此类改变，本研究采用脉冲SILAC（pulse-SILAC）技术，对衰老小鼠的全皮层、小脑匀浆及其对应的突触富集组分进行了蛋白质组更新速率的检测。我们对比了年轻与衰老小鼠蛋白质组的稳定性。本研究的分析结果揭示了多项差异，我们所构建的大型数据集将可为科研社区开发用于探索此类改变的诊断与治疗方法提供宝贵资源。