Novel Approach to Combat Protein-Related Diseases

Researchers from Mainz and Leiden universities have devised a simple model system that can be used to break down fibrils, the cause of several diseases like Alzheimer's and Parkinson's disease, into their constituent single units or liquid droplets.

Many diseases, such as Alzheimer's and Parkinson's, can be traced back to the molecular level in the human body, specifically proteins. In a healthy system, these proteins perform a variety of physiological roles. They may also form groups made up of multiple proteins to perform certain tasks. Once that duty is completed, they break up and go their separate ways.

However, if bigger clusters of a hundred or more proteins form so-called fibrils, which are bundles of long, filament-like protein accumulations, the attraction between the proteins becomes so strong that they are unable to separate. The resulting plaques can cause a wide range of diseases. If fibrils build in the brain, they can raise intracranial pressure and cause neurodegenerative diseases.

Disintegration of Fibrils Achieved for the First Time

In both synthetic and human systems, fibril production is typically an irreversible process. Recently, professors Lu Su of Leiden University in the Netherlands and Shikha Dhiman of Johannes Gutenberg University Mainz (JGU) in Germany were able to create a model system that allows fibrils to be broken down into their constituent liquid droplets. Two Ph.D. students, Heleen Duijs from Leiden and Mohit Kumar from Mainz were also involved in the project.

This is the first model system in which we have succeeded in reversing this process without any chemical reaction.”

Shikha Dhiman, Professor and Senior Researcher, Johannes Gutenberg University Mainz

Hydrogen bridges and other non-covalent connections bind the individual units of fibrils together. The increased stability of fibrils is due to the large number of bonds and their order, while these alone are not very resistant. The researchers therefore chose to employ a small trick: they introduced materials that become embedded in fibrils, forming pocket-like structures that cause instability in the fibril structure.

Dhiman added, “What we are in effect doing is introducing competing binding partners. These form bonds with single units, the interaction between units becomes redundant, and the fibrils begin to disintegrate.”

Model System Allows for Systematic Investigations

The model system's ability to carefully examine each variable one at a time is one of its most intriguing features. Prior to recently, scientists believed that separate proteins joined to form fibrils. However, this idea has recently been shown to be false. Instead, a number of proteins combine with salts and water to form liquid droplets, and the proteins then arrange themselves on the droplets’ surface.

In the actual process of fibril production, this is an important intermediate state. Unlike fibrils, these droplets can perform regular bodily tasks and even disintegrate to release the proteins again.

“Our model system has been able to map all three states, namely individual single units, liquid droplets, and fibrils,” Dhiman noted.

JGU is submitting an application for funding as a Cluster of Excellence in the German National Excellence Strategy competition through the CoM2Life research network.

The acronym CoM2Life stands for “Communicating Biomaterials: Convergence Center for Life-Like Soft Materials and Biological Systems.”

Fundamental Basis for the Development of Innovative Therapies

In the long run, the model system will help with the creation of drugs to treat a variety of diseases, including neurodegenerative diseases like Alzheimer's and Parkinson's. In contrast to complicated systems like cells, all parameters of the model system can be easily studied to answer numerous questions: What causes protein droplets to cluster and form fibrils? How can the procedure be regulated? How are fibrils broken down into short fibers? Once these fundamental challenges are answered, the researchers can examine them at the cellular level using large-scale screening of active compounds.

The potential in terms of therapeutic applications is enormous. We expect that drugs developed on the basis of this model will be used for the targeted disintegration of pathological fibrils to alleviate symptoms and improve outcomes for patients.”

Lu Su, Assistant Professor, Leiden Academic Centre for Drug Research