Biomolecular Condensates and Phase Separation in Neural Signaling and Disease

Liquid-liquid phase separation is emerging as a fundamental organizing principle in neural cells. Biomolecular condensates are dynamic, membraneless assemblies formed when proteins and nucleic acids bearing intrinsically disordered regions or multivalent interaction motifs demix from the surrounding cytoplasm or nucleoplasm, concentrating signaling molecules, transcription factors, and RNA-processing machinery into functionally distinct compartments without the need for enclosing membranes. In the nervous system, this process drives the assembly of structures such as postsynaptic densities, presynaptic active zones, RNA transport granules, stress granules, and nuclear bodies. Their formation and dissolution are dynamically regulated by neuronal activity, post-translational modifications, and intracellular signaling cascades, enabling rapid and reversible responses to physiological demands. Proteins such as TDP-43 and FUS are established components of condensates including stress granules and RNA-processing bodies, where they contribute to RNA metabolism under normal conditions. Tau and alpha-synuclein also undergo phase separation, though whether this reflects a primary physiological role, an early step in pathological aggregation, or both remains an active area of investigation. When the mechanisms governing condensate assembly and dissolution are disrupted, these proteins can undergo aberrant phase transitions and mature into solid-like aggregates, linking dysregulated phase separation to the molecular pathogenesis of ALS, frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative conditions.

This Research Topic invites studies on the molecular mechanisms which govern condensate assembly, composition, and regulation in the nervous system, and that connect condensate biology to neural function in health and disease. By integrating biophysical, structural, and cell-biological perspectives, this collection aims to establish how phase separation interfaces with canonical signaling pathways to shape synaptic plasticity, gene expression, and neuronal homeostasis.

We welcome studies that address these questions through approaches including biochemical reconstitution, live-cell and super-resolution imaging, proteomics, genetic perturbation, and computational modeling, and spanning experimental systems from neuronal cultures and organoids to animal models and patient-derived tissues. Contributions developing or applying novel tools to visualize, quantify, or therapeutically modulate condensate dynamics are especially encouraged where they shed light on neural function or disease mechanisms.