Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity
Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity
复制标题
人类神经细胞的空间中心体蛋白质组揭示了疾病相关的异质性
DOI：
10.1126/science.abf9088
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发表时间：
2022-06-17
期刊：
影响因子：
56.9
通讯作者：
Goetz，Magdalena
中科院分区：
文献类型：
--
作者：
O'Neill，Adam C.;Uzbas，Fatma;Goetz，Magdalena
中心体为细胞骨架提供细胞内锚，调节细胞分裂、细胞迁移和纤毛形成。我们使用空间蛋白质组学来阐明人类诱导多能干细胞衍生的神经干细胞（NSC）和神经元中心体的蛋白质相互作用网络。中心体相关蛋白主要是细胞类型特异性的，蛋白中枢参与 RNA 动力学。对神经发育疾病队列的分析发现，脑室周围异位 (PH) 患者中 NSC 中心体蛋白的变异明显过多。表达 PH 相关突变体前 mRNA 加工因子 6 (PRPF6) 在发育中的小鼠大脑中再现了心室周围错位，强调了微管相关激酶转录物的错误拼接与中心体位置对于表型至关重要。总的来说，细胞类型特异性中心体相互作用组解释了普遍存在的蛋白质中的遗传变异如何传达大脑特异性表型。
The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell–derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type–specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type–specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.