F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; The Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
Cell. 2024 Aug 8;187(16):4193-4212.e24. doi: 10.1016/j.cell.2024.05.058. Epub 2024 Jun 27.
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.
神经免疫相互作用介导细胞间通讯，并构成关键的大脑功能。小胶质细胞，中枢神经系统常驻巨噬细胞，通过直接的物理相互作用和分子的分泌来调节大脑。其中一种分泌因子，补体蛋白 C1q，有助于在发育和疾病模型中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。在这里，我们报告 C1q 以年龄依赖的方式与神经元核糖核蛋白（RNP）复合物相互作用。纯化的 C1q 蛋白在体外经历 RNA 依赖性液-液相分离（LLPS），并且 C1q 与神经元 RNP 复合物在体内的相互作用依赖于 RNA 和内吞作用。缺乏 C1q 的小鼠在体内表现出特定于年龄的神经元蛋白合成改变和恐惧记忆消退受损。总之，我们的发现揭示了 C1q 的一种生物物理特性，该特性构成了 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。
