Stress-Induced Membraneless Organelles in Neurons: Bridging Liquid-Liquid Phase Separation and Neurodevelopmental Dysfunction.

Liquid-liquid phase separation (LLPS) in cell biology has revolutionized our understanding of how cells organize biochemical reactions and structures through dynamic, membraneless organelles (MLOs). In neurons, LLPS-driven processes are particularly important for regulating synaptic plasticity, RNA metabolism, and responses to environmental stressors. Over the past decade, LLPS has gained increasing attention in neurobiology as a framework to interpret altered synaptic functions in various neurodevelopmental disorders (NDDs). These diseases comprise a diverse spectrum of clinical and pathological symptoms (e.g., global developmental delay, impaired cognitive and mental functions, as well as social withdrawal). Recent studies have highlighted how mutations in proteins containing intrinsically disordered regions (IDRs)-key drivers of LLPS-can alter condensate properties, resulting in persistent or defective MLO formation. These aberrant assemblies may disrupt RNA transport, splicing, and translation in developing neurons, thereby contributing to disorder pathology. IDRs are known to be enriched in membraneless components, such as stress granules, nuclear paraspeckles, and P-bodies, where they play crucial role in the formation, maintenance, and function of protein-RNA networks. This review explores the role of stress-induced MLOs in the nervous system, the molecular principles governing their formation, and how their dysfunction bridges the gap between environmental stress responses and neurodevelopmental impairment.