In a preprint, protein “droplets” slowed amyloid fibril growth in stress granule models
In a preprint, protein “droplets” slowed amyloid fibril growth in stress granule models
On September 4, Research Square published a preprint describing twelve engineered condensates, which are droplets composed of proteins and nucleic acids. In these models, three proteins capable of forming amyloid fibrils became more than 50 times as concentrated inside the droplets, while detectable fibril growth began later.
A stress granule is a temporary collection of proteins and RNA that a cell assembles under stress. These assemblies resemble droplets without membranes. Proteins encounter one another more frequently inside them than in the surrounding solution. Stress granules have therefore been linked to amyloid, which consists of ordered protein fibrils that accumulate in several neurodegenerative diseases.
Such assemblies can also have a different outcome. In experiments with RNASEK, an excess of circular RNAs converted stress granules into toxic aggregates. The new preprint shows how condensate composition, the condensate interface, and viscoelasticity can delay the appearance of amyloid fibrils.
The authors studied hnRNPA1, tau, and FUS, three proteins capable of forming these fibrils. The condensates drew soluble molecules of these proteins out of the surrounding liquid. Optical sections and electron microscopy showed visible fibrils mainly outside the droplets and at their interfaces. A fibril elongates by incorporating individual protein molecules. When fewer of these molecules are available outside the droplet, fibril growth slows.
A separate process occurs at the droplet interface. When the protein concentration outside the droplet is low, a fibril nucleus can form at the interface. At a higher concentration, nucleation can also occur in the surrounding solution. The authors added a variant of hnRNPA1 lacking the region that initiates fibril assembly. This variant reduced the density of the protein under study at the interface without measurably changing condensate viscosity, and the delay before fibril growth increased.
Viscoelasticity is a property of the internal protein-RNA network. The network flows while also resisting deformation. More viscoelastic condensates released one of the hnRNPA1 variants under study into the surrounding solution more slowly. The fibrils that formed outside consequently had less protein available for elongation, so their growth began later.
The starting point was a 2025 study of a simple condensate formed from a region of hnRNPA1. Its interior retained the protein, while its interface could accelerate fibril nucleation. The new preprint tested this model in twelve multicomponent systems. The authors then observed the same direction of effect in condensates composed of G3BP1 and polyA RNA, as well as in granules made from cell lysate, which contains material released from disrupted cells. In living human cells, the authors measured the mechanical properties of the granules. They monitored amyloid fibril growth in reconstituted systems and in granules made from cell lysate.
In these models, fibril formation depends on the protein’s location, its density at the interface, and the rate of exchange between the droplet and the surrounding solution.