Phase separation in neurodegenerative disorders: a metabolic perspective on protein aggregation and therapeutic...

Biomolecular condensates formed via liquid-liquid phase separation (LLPS) are increasingly recognised as dynamic organisers of intracellular biochemistry, particularly in neurons where spatially restricted signalling, RNA metabolism, and proteostasis are essential. Aberrant phase transitions of disease-associated proteins, including TDP-43, FUS, tau, and α-synuclein, contribute to protein aggregation and neurodegenerative pathology. Beyond protein-intrinsic sequence features, metabolic state has emerged as an important contextual regulator of condensate assembly, material properties, and liquid-to-solid maturation. Metabolic cues, including ATP availability, NAD⁺/NADH balance, redox state, lipid composition, enzyme-mediated post-translational modifications, and cellular stress responses, can influence the phase behaviour across biochemical, cellular, and disease-model systems. However, direct causal evidence in neurons, animal models, and human neurodegenerative diseases remains uneven and protein-specific. Here, we review LLPS in neurodegenerative disorders from the metabolic perspective, distinguishing established mechanisms from plausible but incompletely validated links. We discuss how pathological condensates may impair RNA metabolism, synaptic function, proteostasis, and cognition, and critically evaluate emerging therapeutic strategies that aim to modulate aberrant phase behaviour. This review therefore provides a cautious framework in which metabolic dysregulation is considered a potential upstream contributor to pathological phase transitions rather than an established master regulator.