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Biomolecular condensates (BMCs) are membrane-less protein compartments with physiological and pathological relevance. The formation of BMCs is driven by a process known as liquid–liquid phase separation (LLPS), a field that has largely focused on the study of micron-sized condensates. However, there have been recent studies showing that proteins that undergo LLPS also form nanometer-sized condensates. These nanometer-sized condensates, or nanocondensates, are distinct from microcondensates and potentially exhibit more relevance in cell biology. The field of nanocondensate research is in its infancy, with limited biophysical studies of these structures. Here, we studied condensate formation and dissolution of wild-type and disease-linked (hyperphosphorylated and missense mutated) Tau. We investigated the effects of solution condition modulation on nanocondensate formation and dissolution, and observed that Tau condensation is strongly regulated by electrostatic forces and less affected by hydrophobic disruption. We observed that all three Tau variants studied shared condensate formation properties when in solution conditions with the same ionic strength. However, hyperphosphorylated and missense-mutated Tau exhibited higher resistance to dissolution compared to wild-type Tau. This study uncovers additional distinctions between different types of condensates, which provides further insight into the distinctions between physiological and pathological condensates. Full article

Biomolecular condensates (BMCs) exhibit physiological and pathological relevance in biological systems. Both liquid and solid condensates play significant roles in the spatiotemporal regulation and organization of macromolecules and their biological activities. Some pathological solid condensates, such as Lewy Bodies and other fibrillar aggregates, have been hypothesized to originate from liquid condensates. With the prevalence of BMCs having functional and dysfunctional roles, it is imperative to understand the mechanism of biomolecular condensate formation and initiation. Using the low-complexity domain (LCD) of heterogenous ribonuclear protein A1 (hnRNPA1) as our model, we monitored initial assembly events using dynamic light scattering (DLS) while modulating pH and salt conditions to perturb macromolecule and condensate properties. We observed the formation of nanometer-sized BMCs (nano-condensates) distinct from protein monomers and micron-sized condensates. We also observed that conditions that solubilize micron-sized protein condensates do not solubilize nano-condensates, indicating that the balance of forces that stabilize nano-condensates and micron-sized condensates are distinct. These findings provide insight into the forces that drive protein phase separation and potential nucleation structures of macromolecular condensation. Full article