Scientists have discovered the molecular mechanisms causing proteins to aggregate, a process especially detrimental in the brains of people with Alzheimer’s disease. According to a researcher, this discovery provides novel insight into the development of neurodegenerative diseases at the molecular level.
The aggregation of proteins to form amyloid fibrils in the brain is a feature of numerous neurodegenerative diseases, including Alzheimer’s and Parkinson’s. For many years, researchers and doctors have known that proteins can aggregate and form amyloid plaques in the brains of people with Alzheimer’s disease, disrupting brain function.
However, the precise mechanisms behind protein aggregation and the factors influencing this process remain less well understood.
In a groundbreaking study, researchers used advanced techniques to uncover key factors that facilitate protein aggregation. They demonstrated that their innovative method can greatly enhance understanding of neurodegenerative diseases and potentially pave the way for a cure.
“We hope that these findings will deepen understanding of the mechanisms by which proteins aggregate in the brains of people with neurodegenerative diseases, ultimately enabling more effective treatments to be developed to prevent this,” explains a researcher behind the study, Alexander Buell, Professor, Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby.
The research has been published in Nature Chemistry.
Crucial amino acids revealed
To delve deeper into protein aggregation, the researchers used Φ-value (pronounced phi-value) analysis, which was originally developed to investigate the critical amino acids involved in protein folding and provided valuable insight into the complex mechanism of folding.
When proteins are formed, they resemble long spaghetti-like strings of amino acids lacking both shape and function. Most proteins only begin to function when they fold up on themselves.
Φ-value analysis systematically replaces individual amino acids in a protein, one at a time, to study how rapidly the protein folds – as indicated by changes in the kinetic energy barrier – and to assess its stability.
If the protein only becomes less stable, the specific amino acid probably does not affect the folding mechanism. However, both declining stability and changes in the kinetic energy barrier suggest that the amino acid affects the folding process.
The researchers then tested how swapping amino acids from one end of the protein to the other affected protein folding.
“Φ-value analysis has greatly advanced understanding of protein folding. In this study, we aimed to determine whether it could obtain insight into protein aggregation,” says Alexander Buell.
Experiments and computer simulation
The researchers explored how replacing individual amino acids affected how amyloid fibrils form. These fibrils are long chains of aggregated amyloid proteins, commonly present in the brains of people with various neurodegenerative diseases.
The researchers initially found which amino acids affect protein aggregation into amyloid fibrils and then fed the new data into a computer to simulate the aggregation process.
Simulating protein aggregation on a computer enables researchers to closely examine the process and capture detailed snapshots of the moment proteins begin to aggregate, providing novel insight into the mechanism of protein aggregation.
“This is not feasible experimentally and can only be achieved through computer simulation. Integrating experimental and computational methods provides much deeper understanding of the conditions required for proteins to aggregate. This study marks the first time Φ-value analysis has been validated for studying protein aggregation through both experimental and computational approaches,” notes Alexander Buell.
Identifying potential drug targets
One key insight from the research is that proteins seldom form amyloid fibrils. Only specific regions of the proteins facilitate aggregation, but once these regions interact, the proteins rapidly aggregate.
Alexander Buell notes that this insight can enhance understanding of the processes in the brain when proteins aggregate and cause problems.
“Various proteins aggregate and form fibrils through many mechanisms. We demonstrated how specific amyloids act, although other proteins may act differently. The key is that Φ-value analysis reveals critical factors for protein aggregation, and we believe that the method is generally applicable. This method holds potential for identifying new treatment targets for neurodegenerative diseases, although these targets will be found and applied in the future,” he concludes.
