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From liquid to solid: New technique uncovers disease-related changes in tiny droplets within our cells

Understanding the behavior of tiny droplets in our cells could aid the search for new treatments. A team of Leiden researchers has developed a method to study how these droplets transition from liquid to solid. This change plays a role in various diseases, including neurodegenerative disorders like Alzheimer's and muscular dystrophy. The findings were in Cell Reports ÌÇÐÄÊÓƵical Science.

They work a bit like oil droplets that spontaneously separate in a glass of water, but inside the cell. These membrane-free structures, known as biomolecular condensates, play a crucial role in processes such as storing molecules and regulating chemical reactions.

However, under certain conditions, they can transition from a liquid to a solid or gel-like state—a change linked to neurodegenerative diseases like Alzheimer's and muscular dystrophy. Until now, there were no effective methods to study these transitions in detail, but Alireza Mashaghi and his team have found a solution.

Reversing harmful processes

Mashaghi says, "We have developed a technology that can measure the transition from liquid to solid in these protein-rich droplets. This opens up new possibilities not only for fundamental research in biology but also for drug development. It is the result of years of work, including the research of our postdoc Aida Naghilouye Hidaji."

Researchers have long struggled to study how condensates change from liquid to solid due to limitations in existing methods. Mashaghi's team has tackled this challenge with a technique called scanning probe microscopy (SPM). This technique employs a tiny probe to scan surfaces at an extremely small scale, allowing scientists to measure the properties of materials, including how soft or stiff they are.

Their approach enables researchers to track individual droplets as they solidify and soften again. Understanding how the latter happens is particularly important, as it could help develop drugs that reverse harmful solidification linked to disease.

Breaking boundaries in biomolecular research

Over the years, Mashaghi's lab has developed various interdisciplinary approaches to studying human diseases. Using single-molecule and structural analysis techniques—including topology studies—the team has investigated disordered proteins involved in muscular dystrophy and cancer. These proteins often form biomolecular condensates and aggregates due to disease, making them key targets for study using the SPM-based method.

"This is a great example of interdisciplinary research, and it puts our faculty in the spotlight within this field," says Mashaghi. "Because our method is widely applicable, we expect it to be used globally. You'll probably hear more from us and our collaborators on this topic later this year."