美国加州大学Jingjing Li小组的最新研究提出了发育人脑的单细胞蛋白质组学景观。2026年1月27日出版的《自然—生物技术》杂志发表了这项成果。

鉴于在人类大脑皮层研究中观察到的转录物和蛋白质丰度之间的不一致，研究人员开发了一种优化的工作流程，将无标记单细胞质谱法与精确的样品制备相结合，以解决来自发育中的人类大脑的单个细胞的定量蛋白质组学。他们的方法实现了深度蛋白质组学覆盖（每个细胞约800个蛋白质），甚至在未成熟的产前人类小神经元(直径约7-10 μm， ~50 pg蛋白)，捕获主要的脑细胞类型，并在单细胞分辨率下实现蛋白质组范围的表征。小组在细胞类型中记录了广泛的转录组-蛋白质组不一致，特别是在与神经发育障碍相关的基因中。蛋白质表现出比mRNA更高的细胞类型特异性，强调了蛋白质组学水平分析的重要性。通过在蛋白质组学水平上重建从放射状胶质细胞到兴奋性神经元的发育轨迹，课题组人员确定了动态的、特定阶段的蛋白质共表达模块，并确定了中间祖细胞到神经元的转变是与自闭症相关的遗传易感阶段。

据介绍，分析蛋白质丰度和动态在单细胞分辨率在复杂的人体组织是具有挑战性的。

附：英文原文

Title: Single-cell proteomic landscape of the developing human brain

Author: Wu, Tianzhi, Jiang, Lihua, Mukhtar, Tanzila, Wang, Li, Jian, Ruiqi, Wang, Cheng, Trinh, Tiffany, Kriegstein, Arnold R., Snyder, Michael, Li, Jingjing

Issue&Volume: 2026-01-27

Abstract: Profiling protein abundance and dynamics at single-cell resolution in complex human tissues is challenging. Given the discordance between transcript and protein abundance observed in studies of the human cerebral cortex, we developed an optimized workflow that combines label-free single-cell mass spectrometry with precise sample preparation to resolve quantitative proteomes of individual cells from the developing human brain. Our method achieves deep proteomic coverage (~800 proteins per cell) even in small immature prenatal human neurons (diameter~7–10μm, ~50 pg protein), capturing major brain cell types and enabling proteome-wide characterization at single-cell resolution. We document extensive transcriptome–proteome discordance across cell types, particularly in genes associated with neurodevelopmental disorders. Proteins exhibit markedly higher cell-type specificity than their mRNA counterparts, underscoring the importance of proteomic-level analysis. By reconstructing developmental trajectories from radial glia to excitatory neurons at the proteomic level, we identify dynamic, stage-specific protein co-expression modules and pinpoint the intermediate progenitor-to-neuron transition as a genetically vulnerable phase associated with autism.

DOI: 10.1038/s41587-025-02980-7

Source: https://www.nature.com/articles/s41587-025-02980-7