Leiden Physicists Find Protein Fibers Linked to Alzheimer's Grow Outward From Droplet Surfaces
A 12-hour microscope study in Nature Physics overturns the assumption that fibers form inside dense protein droplets, and shows fibers and glass are rival ways for droplets to age.
Physicists at Leiden University have found that the protein fibers tied to neurodegenerative diseases do not grow where scientists long assumed they did. The fibers sprout from the outside of protein droplets, not from within, according to a study published in Nature Physics.
Some proteins linked to diseases such as Alzheimer's and ALS can exist in two forms: liquid droplets, called condensates, and solid amyloid fibers. For about a decade, researchers have known there is a connection between fiber growth from these proteins and neurodegenerative disorders. What was unclear was how the two states relate and where the fibers actually begin. "We wanted to answer an open question: What happens to protein droplets as they age?" said assistant professor Louise Jawerth, who led the work with doctoral candidate Liru Feng.
The droplets look like drops of oil in water, but they are made of protein, and similar droplets exist inside living cells. They are tiny, only about 5 micrometers across, around ten times thinner than a human hair. Feng used a confocal microscope, which builds three-dimensional images with laser light, to watch samples for 12 hours. The record let the team visualize and measure how a droplet ages into each of its two possible solid states, one glassy and one fibrous.
"The results truly surprised us," Jawerth said. "We have often thought that fibers would grow on the inside of the droplets where there is a high concentration of protein, but now we know they don't. They grow from the surface to the outside. Meanwhile, as these fibers grow, we see the droplets themselves shrink and become glasslike."
The analysis showed that fibers and glass are two different solid forms of the same protein, and that they compete. They can exist side by side, but one does not turn into the other. To test this, Feng aged proteins for two days before starting fiber growth. In that case the aged droplets hardly grew any fibers, because they had already settled into the glassy state. The finding means the fate of a droplet depends on which route it takes first.
Because the observations did not fit existing explanations, the team worked with theoretical physicists at the Max Planck Institute to build a new framework that can describe and predict the aging process. "This means new theoretical models are needed to understand and predict these processes," Jawerth said.
She credited the lab's setup for the discovery. It has two confocal microscopes available full-time to the group, something many labs lack. She also praised Feng's ability to make visible something no one else had seen. "It's no simple challenge to make something visible in a microscope that nobody else has seen before," Jawerth said. "Moreover, you need to take this zoo of observations from the microscope and build a new conceptual framework of the underlying physics."
The work is basic research done in a test tube, not a treatment, and it studies droplets of a single protein rather than the crowded interior of a cell. Even so, Jawerth said she expects it to help scientists in neighboring fields read their own data differently. "With our fundamental research on aging proteins, we've created clarity," she said. "I think it immediately will give my fellow researchers, from biologists to doctors, a new view on their data." If fibers form at the droplet surface, researchers who look for the first steps of disease inside droplets may need to look at their edges instead.
