美国波士顿儿童医院Beth Stevens和Nicole Scott-Hewitt共同合作，近期取得重要工作进展。他们研究提出，小胶质源性C1q与神经元核糖核蛋白复合物相互作用影响衰老大脑中的蛋白质稳态。相关研究成果2024年6月27日在线发表于《细胞》杂志上。
据介绍，神经免疫相互作用介导细胞间通讯，是大脑关键功能的基础。小胶质细胞是中枢神经系统中的巨噬细胞，通过直接的物理相互作用和分子的分泌来调节大脑。一种这样的分泌因子，补体蛋白C1q，在发育和疾病模型中都有助于补体介导的突触消除，但大脑C1q蛋白水平在整个衰老过程中显著增加。
研究人员报道了C1q与神经元核糖核蛋白（RNP）复合物以年龄依赖的方式相互作用。纯化的C1q蛋白在体外进行RNA依赖性液-液相分离（LLPS），并且C1q在体内与神经元RNP复合物的相互作用依赖于RNA和内吞作用。缺乏C1q的小鼠体内神经元蛋白合成发生年龄特异性改变，恐惧记忆消退受损。
总之，这一研究揭示了C1q的生物物理特性，这是RNA和年龄依赖性神经元相互作用的基础，并证明了C1q在关键的细胞内神经元过程中的作用。
附：英文原文
Title: Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain
Author: Nicole Scott-Hewitt, Matthew Mahoney, Youtong Huang, Nils Korte, T. Yvanka de Soysa, Daniel K. Wilton, Emily Knorr, Kevin Mastro, Allison Chang, Allison Zhang, David Melville, Monica Schenone, Christina Hartigan, Beth Stevens
Issue&Volume: 2024-06-27
Abstract: Neuroimmune interactions mediate intercellular communication and underlie critical brain functions. Microglia, CNS-resident macrophages, modulate the brain through direct physical interactions and the secretion of molecules. One such secreted factor, the complement protein C1q, contributes to complement-mediated synapse elimination in both developmental and disease models, yet brain C1q protein levels increase significantly throughout aging. Here, we report that C1q interacts with neuronal ribonucleoprotein (RNP) complexes in an age-dependent manner. Purified C1q protein undergoes RNA-dependent liquid-liquid phase separation (LLPS) in vitro, and the interaction of C1q with neuronal RNP complexes in vivo is dependent on RNA and endocytosis. Mice lacking C1q have age-specific alterations in neuronal protein synthesis in vivo and impaired fear memory extinction. Together, our findings reveal a biophysical property of C1q that underlies RNA- and age-dependent neuronal interactions and demonstrate a role of C1q in critical intracellular neuronal processes.
DOI: 10.1016/j.cell.2024.05.058
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00639-1