Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the...

Area of Science:

• Neuroscience
• Molecular Biology
• Immunology

Background:

• Neuroimmune interactions are crucial for brain function.
• Microglia, the brain's immune cells, communicate via physical contact and secreted molecules.
• The complement protein C1q is implicated in synapse elimination and increases with age.

Purpose of the Study:

• To investigate the age-dependent interaction of C1q with neuronal ribonucleoprotein (RNP) complexes.
• To explore the biophysical properties of C1q, specifically its role in liquid-liquid phase separation (LLPS).
• To determine the functional consequences of C1q-RNA interactions on neuronal processes and memory.

Main Methods:

• In vitro experiments with purified C1q protein to assess RNA-dependent liquid-liquid phase separation (LLPS).
• In vivo studies examining the interaction of C1q with neuronal RNP complexes, assessing RNA and endocytosis dependence.
• Analysis of C1q-deficient mice to evaluate age-specific alterations in neuronal protein synthesis and fear memory extinction.

Main Results:

• C1q protein undergoes RNA-dependent liquid-liquid phase separation (LLPS) in vitro.
• The interaction between C1q and neuronal RNP complexes in vivo is dependent on both RNA and endocytosis.
• Mice lacking C1q exhibited age-specific changes in neuronal protein synthesis and impaired fear memory extinction.

Conclusions:

• C1q possesses a biophysical property enabling RNA- and age-dependent interactions with neuronal components.
• C1q plays a significant role in intracellular neuronal processes, including protein synthesis and memory.
• These findings highlight a novel mechanism linking neuroinflammation, RNA metabolism, and cognitive function during aging.