Physicists Uncover New Model for Fibre Growth in Neurodegenerative Disease

'We wanted to answer an open question: what happens to protein droplets as they age?' Assistant Professor Louise Jawerth explains. 'They look just like drops of oil in water, but they are droplets of proteins inside cells, also called condensates. Scientists have only relatively recently come to understand how they develop. Our findings on how they age - published in Nature Physics today - add an important piece to the puzzle.'

The droplets are very complex materials; they are liquid-like, and it is known that these can turn into solids that are glassy or fibrous. Jawerth: 'For ten years or so, we know that there is a link between the fibre growth from these proteins and neurodegenerative disorders like Alzheimer or ALS. Our goal was to visualise, quantify and model this ageing process, and we succeeded in doing so'.

Unveiling the mystery

PhD Candidate Liru Feng shows us how small these protein droplets are: 'They are only about 5 micrometres across - around ten times thinner than the width of a human hair.' With a confocal microscope, Feng monitored the samples in 3D for 12 hours. They revealed and quantified the development of the liquid droplets into both possible solid states: glassy and fibrous.

The team did not expect to uncover a new whole paradigm of fibre growth, but they did.

New paradigm of fibre growth

'The results truly surprised us', says Jawerth. 'We have often thought that fibres 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 fibres grow, we see the droplets themselves shrink and become glassy-like.'

Two competing ways of ageing

In their data analysis the physicists showed that the fibres and glassy-like state are two different solid forms of the same protein. They represent two competing ways in which the protein system can age. This means that they can exist side by side, but one does not directly change into the other. Feng: 'In our experiments we made this visible by first ageing the proteins for two days before initiating fibre growth. You see that this way, the aged droplets hardly grow any fibres.'

'This means new theoretical models are needed to understand and predict these processes', concludes Jawerth. Together with theoretical physicists at the Max Planck Institute the team developed these new theoretical frameworks.

Full-time experimenting

'Key to our success was the fact that our lab has two confocal microscopes that are available full-time for our group. These microscopes use laser light to create detailed images of cells and tissues. A luxury that many other groups don't have,' according to Jawerth. 'Also, Feng is clearly a very talented experimentalist. It's no simple challenge to make something visible in a microscope that nobody else has seen before. Moreover, you need to take this zoo of observations from the microscope and build a new conceptual framework of the underlying physics. To answer the question: what do all these observations tell us?'

A new view on existing data

'With our fundamental research on ageing proteins, we've created clarity. I think it immediately will give my fellow researchers - from biologists to doctors - a new view on their data. Cells are extraordinarily complex systems, and if we are also confused - on top of this complexity - about the way simple cell elements like proteins function, then resolving the bigger questions is impossible. Now we know what's happening in proteins, we are ready to take the next steps.'

Healthy or unhealthy ageing

'We don't yet know the healthy versus unhealthy routes for ageing protein droplets, Jawerth concludes. At this moment in time, our work suggests that the glassy state of ageing may have a different, perhaps even healthy, function within brains cells. While the fibres are possibly the unhealthy alternative. Mind you, we don't know yet if these fibres are the main reason brain cells degenerate. By clarifying how the fundamental processes work, we can at least more clearly analyse the complex data we get when we look into cells. In our lab, we made an important step towards this goal.'