近日，美国加州大学洛杉矶分校Baljit S. Khakh团队揭示了星形细胞-神经元亚蛋白组和强迫症机制。相关论文于2023年4月12日在线发表在《自然》杂志上。

研究人员使用细胞特异性和亚区特异性的接近性生物素化来研究体内纹状体星形细胞和神经元的蛋白质组。研究人员评估了星形细胞和神经元的细胞膜和质膜区室，并发现这些细胞在其信号机制的蛋白质水平上有什么不同。研究人员还评估了星形细胞的亚细胞区室，包括突触小结和精细处理，以揭示它们的亚蛋白质组和星形细胞基本信号和稳态功能的分子基础。

值得注意的是，与强迫症（OCD）和重复行为有关的SAPAP3（由Dlgap3编码）在纹状体星形胶质细胞中被高水平检测到，并富集在特定的星形胶质细胞亚区室，它调节肌动蛋白细胞骨架组织。此外，在缺乏SAPAP3的OCD4小鼠模型中，结合行为分析和分子评估的遗传救援实验显示，星形胶质细胞和神经元的SAPAP3对重复性和焦虑相关的OCD样表型有不同的贡献。这些数据确定了星形胶质细胞和神经元在蛋白质水平和主要信号通路上的不同。此外，它们揭示了星形胶质细胞亚蛋白组在生理亚区之间如何变化，以及星形胶质细胞和神经元SAPAP3机制如何对小鼠的强迫症表型作出贡献。

这些数据表明，针对星形胶质细胞和神经元的治疗策略可能有助于探索强迫症和潜在的其他大脑疾病。

据介绍，星形细胞和神经元在大脑中广泛地相互作用。识别星形胶质细胞和神经元的蛋白质组，对于阐明决定它们各自对生理学和疾病的贡献的蛋白质网络至关重要。

附：英文原文

Title: Astrocyte–neuron subproteomes and obsessive–compulsive disorder mechanisms

Author: Soto, Joselyn S., Jami-Alahmadi, Yasaman, Chacon, Jakelyn, Moye, Stefanie L., Diaz-Castro, Blanca, Wohlschlegel, James A., Khakh, Baljit S.

Issue&Volume: 2023-04-12

Abstract: Astrocytes and neurons extensively interact in the brain. Identifying astrocyte and neuron proteomes is essential for elucidating the protein networks that dictate their respective contributions to physiology and disease. Here we used cell-specific and subcompartment-specific proximity-dependent biotinylation1 to study the proteomes of striatal astrocytes and neurons in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and neurons to discover how these cells differ at the protein level in their signalling machinery. We also assessed subcellular compartments of astrocytes, including end feet and fine processes, to reveal their subproteomes and the molecular basis of essential astrocyte signalling and homeostatic functions. Notably, SAPAP3 (encoded by Dlgap3), which is associated with obsessive–compulsive disorder (OCD) and repetitive behaviours2,3,4,5,6,7,8, was detected at high levels in striatal astrocytes and was enriched within specific astrocyte subcompartments where it regulated actin cytoskeleton organization. Furthermore, genetic rescue experiments combined with behavioural analyses and molecular assessments in a mouse model of OCD4 lacking SAPAP3 revealed distinct contributions of astrocytic and neuronal SAPAP3 to repetitive and anxiety-related OCD-like phenotypes. Our data define how astrocytes and neurons differ at the protein level and in their major signalling pathways. Moreover, they reveal how astrocyte subproteomes vary between physiological subcompartments and how both astrocyte and neuronal SAPAP3 mechanisms contribute to OCD phenotypes in mice. Our data indicate that therapeutic strategies that target both astrocytes and neurons may be useful to explore in OCD and potentially other brain disorders.

DOI: 10.1038/s41586-023-05927-7

Source: https://www.nature.com/articles/s41586-023-05927-7