A simple model system can disassemble fibrils and study therapeutic drugs for neurodegenerative diseases

The causes of many diseases, such as Alzheimer’s disease and Parkinson’s disease, are found at the molecular level, or proteins, in our bodies. In healthy systems, these proteins are responsible for numerous physiological functions.

They can also assemble into groups of many proteins to perform specific tasks. Once the job is done, they split up again and go their separate ways. But when large clusters of 100 or more proteins form so-called fibrils, which are bundles of long filament-like aggregates of proteins, the attraction between the proteins becomes so strong that they can no longer separate from each other.

The resulting plaque can cause a variety of problems. For example, when fibrils accumulate in the brain, they can increase intracranial pressure and cause neurodegenerative diseases.

First achievement of fibril collapse

Fibril formation is generally an irreversible process in both the human body and synthetic systems. Professor Shikha Dhiman from Johannes Gutenberg University Mainz (JGU) in Germany and Professor Lu Su from Leiden University in the Netherlands have recently succeeded in creating a model system that can break down fibrils into individual components or droplets.

Two PhD students were also involved in this project. students Mohit Kumar from Mainz and Helen Duis from Leiden. “This is the first model system that successfully reverses this process without a chemical reaction,” Dhiman reported. The results of this study will be published in the Journal of the American Chemical Society.

Within fibrils, single units are held together by noncovalent bonds, such as hydrogen bridges. Although they are not particularly strong in themselves, it is the large number of bonds and their order that give fibrils their great stability. So the researchers decided to use a little trick. They added a substance that embeds itself inside the fibrils, creating pocket-like formations that destabilize the fibril structure.

“What we’re actually doing is introducing competing binding partners. These form bonds with single units, and the interactions between the units become redundant and the fibrils start to collapse. ,” Deaman explained.

Model system allows systematic investigation

A particularly interesting feature of the model system is that all the parameters that can be changed can be systematically studied one by one. Until recently, researchers thought that individual proteins came together to form fibrils. However, recently this concept has been rejected. Rather, some proteins accumulate with water and salt to form droplets, and proteins are placed on the surface of these droplets. This is an important intermediate state in the actual formation of fibrils.

In contrast to fibrils, these droplets can take on normal functions in the body and can even break down to release the protein again.

“Our model system was able to map all three states: individual single units, droplets, and fibrils,” said JGU Chemistry Professor and CoM2Life (Communicating Biomaterials: Convergence Center for Life) professor. Senior Researcher Shikha Dhiman explained. -Soft materials, biological systems, etc.) research networks.

Basic foundation for developing innovative treatments

In the long term, this model system will support the development of drugs to treat a variety of diseases, especially neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Unlike complex systems such as cells, all parameters of a model system can be easily investigated to answer different questions. What causes protein droplets to aggregate to form fibrils? How can this process be regulated? How are fibrils broken down into short fibers?

Once researchers have solved these basic questions, they will be able to investigate the cellular level based on large-scale screening of active substances. “The potential in terms of therapeutic applications is huge,” emphasized Lu Su, assistant professor at the Leiden Academic Research Center.

“We hope that drugs developed based on this model will be used for targeted degradation of pathological fibrils, relieving symptoms and improving patient outcomes.”