Gradual-moving ladle of water could make Parkinson’s proteins ‘stickier’

Water — which makes up most of all cells in the body — plays a key role in how proteins, including those associated with Parkinson’s disease, fold, fold or clump together, according to a new study.

When trying to discover possible treatments for diseases related to protein misfolding, researchers have focused primarily on the structure of the proteins themselves. However, researchers led by the University of Cambridge have shown that a thin layer of water is essential in determining whether a protein starts to clump or clump together, forming the toxic clumps that eventually kill brain cells.

Using a technique known as Terahertz spectroscopy, the researchers showed that the movement of the water-based shell surrounding a protein can determine whether or not that protein aggregates. When the shell moves slowly, proteins are more likely to clump together, and when the shell moves quickly, proteins are less likely to clump together. The envelope’s rate of movement is altered in the presence of certain ions, such as salt molecules, which are commonly used in buffer solutions used to test new drug candidates.

The importance of the water envelope, known as the hydration or solvation envelope, in protein folding and function has been hotly contested in the past. This is the first time that the solvation envelope has been shown to play a key role in protein folding and aggregation, which could have profound implications for the search for treatments. The results are published in the journal International Applied Chemistry🇧🇷

In developing potential treatments for diseases related to protein misfolding, such as Parkinson’s disease and Alzheimer’s disease, researchers investigated compounds capable of preventing the aggregation of key proteins: alpha-synuclein for Parkinson’s disease or beta-amyloid for Alzheimer’s disease. So far, however, there is no effective treatment for any of the diseases, which affect millions of people around the world.

“Amino acids determine the final structure of a protein, but when it comes to aggregation, the role of the solvation shell, which is on the outside of a protein, has been neglected until now”, said Professor Gabriele Kaminski Schierle, from the Department Cambridge Institute of Chemical Engineering and Biotechnology, who led the research. “We wanted to know if this water shell plays a role in the protein’s behavior – it’s been a question in the field for some time, but no one has been able to prove it.”

The solvation shell slides over the surface of the protein, acting as a lubricant. “We wondered if, if the movement of water molecules was slower in the solvation layer of a protein, could this slow down the movement of the protein itself,” said Dr. Amberley Stephens, the paper’s first author.

To test the role of the solvation envelope in protein aggregation, the researchers used alpha-synuclein, the main protein implicated in Parkinson’s disease. Using Teraheartz spectroscopy, a powerful technique for studying the behavior of water molecules, they were able to observe the movement of water molecules surrounding the alpha-synuclein protein.

They then added two different salts in solution to the proteins: sodium chloride (NaCl), or common table salt, and cesium iodide (CsI). Sodium chloride ions – Na+ and Cl- – bond strongly with hydrogen and oxygen ions in water, while cesium iodide ions form much weaker bonds.

The researchers found that when sodium chloride was added, the strong hydrogen bonds slowed the movement of water molecules in the solvation layer. This resulted in slower movement of alpha-synuclein and increased rate of aggregation. On the other hand, when cesium iodide was added, water molecules accelerated and the aggregation rate decreased.

“Essentially, when the water shell decreases, the proteins have more time to interact with each other, so they are more likely to aggregate,” said Kaminski Schierle. “And conversely, when the solvation layer moves faster, the proteins become harder to capture, so they’re less likely to aggregate.”

“When researchers look for an aggregation inhibitor for Parkinson’s disease, they typically use a buffer composition, but very little thought has been given to how that buffer interacts with the protein itself,” Stephens said. “Our results show that you need to understand the composition of the solvent inside the cell to mimic the conditions you have in the brain and ultimately end up with a working inhibitor.”

“It’s very important to look at the big picture, and that didn’t happen,” said Kaminski Schierle. “To effectively test whether a drug candidate will work in a patient, you have to mimic cellular conditions, which means you have to take everything into account like salts and pH levels. Failure to look at the entire cellular environment has limited the field, which may explain why we still don’t have an effective treatment for Parkinson’s disease. 🇧🇷

The research was partially funded by Wellcome, Alzheimer’s Research UK, the Michael J Fox Foundation and the Medical Research Council (MRC), part of UK Research and Innovation (UKRI). Gabriele Kaminski Schierle is a Fellow of Robinson College, Cambridge.

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