Researchers have crafted a straightforward model system capable of dismantling fibrils, which are linked to various diseases, including Alzheimer’s and Parkinson’s, into their individual components or tiny liquid droplets.
Researchers at the universities in Mainz and Leiden have crafted a straightforward model system that can dismantle fibrils, responsible for several disorders including Alzheimer’s and Parkinson’s disease, into their individual components or small liquid droplets.
Many diseases, like Alzheimer’s or Parkinson’s, have their roots at the molecular level within our bodies, specifically in proteins. In a healthy state, these proteins perform multiple physiological roles. They may group together to execute specific functions and then disperse once those tasks are completed. However, when large clusters of proteins combine to form fibrils—long, filamentous bundles of proteins—their attraction becomes so intense that they cannot separate. The resulting plaques may cause a host of health issues. For example, if fibrils build up in the brain, they can raise intracranial pressure, potentially leading to neurodegenerative disorders.
Breakdown of fibrils achieved for the first time
The formation of fibrils is usually an irreversible process in both biological and synthetic scenarios. Professors Shikha Dhiman from Johannes Gutenberg University Mainz (JGU) in Germany and Lu Su from Leiden University in the Netherlands have successfully developed a model system that breaks down fibrils into their individual components or liquid droplets. This project also involved two Ph.D. students, Mohit Kumar in Mainz and Heleen Duijs in Leiden. “This is the first time we have reversed this process without any chemical reactions,” Dhiman said.
Within fibrils, non-covalent bonds—like hydrogen bonds—hold the individual units together. While these specific bonds are not very strong individually, their large numbers and organization contribute significantly to the stability of fibrils. The researchers applied an innovative approach: they introduced substances that integrate into fibrils, creating pocket-like structures that destabilize the fibril formation. “Essentially, we are adding competing binding partners. These new bonds with individual units make the existing interactions between those units insufficient, leading to the disintegration of the fibrils,” Dhiman explained.
Model system allows for systematic investigations
An intriguing aspect of the model system is its ability to analyze different parameters systematically. Previously, it was thought that single proteins combined to form fibrils. This idea has recently been challenged. Instead, it appears several proteins gather along with water and salts to create liquid droplets, where proteins align on the droplets’ surfaces. This represents a key intermediate step in the formation of fibrils. Unlike fibrils, these droplets can function normally in the body and can even disassemble to release proteins. “Our model system has mapped all three forms: single units, liquid droplets, and fibrils,” stated Shikha Dhiman, a professor at JGU’s Department of Chemistry and a senior researcher in the CoM2Life research network, which JGU is applying to fund as a Cluster of Excellence in Germany’s national strategy competition for excellence. CoM2Life stands for “Communicating Biomaterials: Convergence Center for Life-Like Soft Materials and Biological Systems.”
Fundamental basis for the development of innovative therapies
Ultimately, the model system will aid in creating medications for various disorders, especially neurodegenerative diseases like Alzheimer’s and Parkinson’s. Unlike complex systems such as living cells, all variables within this model can be easily studied to address different questions: What triggers the clumping of protein droplets into fibrils? How can this process be regulated? How can fibrils be broken down into shorter fibers? Once these fundamental queries are resolved, researchers can shift to cellular studies—utilizing large-scale screening of active substances. “The potential for therapeutic applications is vast,” highlighted Lu Su, an Assistant Professor at the Leiden Academic Centre for Drug Research. “We anticipate that drugs devised from this model will target and disintegrate pathological fibrils to ease symptoms and enhance patient outcomes.”
