Slow-Moving Shell of Water Can Make Parkinson’s Proteins ‘Stickier’


Overview: Water plays a key role in how proteins associated with Parkinson’s disease fold, clump or misfold.

Source: University of Cambridge

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

In searching for potential treatments for diseases of 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 shell of water is key to whether a protein begins to clump together or aggregate, forming the toxic clusters that eventually kill brain cells.

Using a technique known as Terahertz spectroscopy, the researchers showed that the movement of the water-based shell around a protein can determine whether that protein aggregates or not.

When the shell moves slowly, proteins are more likely to aggregate, and when the shell moves quickly, proteins are less likely to aggregate. The speed of movement of the shell changes in the presence of certain ions, such as salt molecules, commonly used in the buffer solutions used to test new drug candidates.

The significance of the water shell, known as the hydration or solvation shell, to the folding and function of proteins has been much disputed in the past. This is the first time that the solvation shell has been shown to play a key role in protein misfolding and aggregation, which could have profound implications in the search for treatments.

The results are reported in the journal Angewandte Chemie International.

In developing potential treatments for diseases of protein misfolding, such as Parkinson’s disease and Alzheimer’s disease, researchers have been studying compounds that can prevent the aggregation of important proteins: alpha-synuclein for Parkinson’s disease or amyloid- beta for Alzheimer’s disease. However, to date there are no effective treatments for either condition, which affects millions of people worldwide.

“It is the amino acids that 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 overlooked until now,” says Professor Gabriele Kaminski Schierle of Cambridge’s Department of Chemical Engineering and Biotechnology, who led the research.

“We wanted to know if this water shell plays a role in protein behavior — it’s been a question in the field for a while, but no one has been able to prove it.”

The solvation shell slides around on the surface of the protein and acts as a lubricant. “We wondered if, if the movement of water molecules was slower in a protein’s solvation shell, it might slow down the movement of the protein itself,” said Dr Amberley Stephens, the paper’s first author.

To test the role of the solvation shell in protein aggregation, the researchers used alpha-synuclein, the main protein involved 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 the water molecules around 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). The ions in the sodium chloride – Na+ and Cl- – bind strongly to the hydrogen and oxygen ions in water, while the ions in the cesium iodide form much weaker bonds.

The researchers found that when the sodium chloride was added, the strong hydrogen bonds caused the movement of the water molecules in the solvation shell to slow down. This resulted in a slower movement of the alpha-synuclein and the rate of aggregation increased. Conversely, when the cesium iodide was added, the water molecules accelerated and the aggregation rate decreased.

Using a technique known as Terahertz spectroscopy, the researchers showed that the movement of the water-based shell around a protein can determine whether that protein aggregates or not. The image is in the public domain

“Essentially, when the water scale slows down, the proteins have more time to interact with each other, so they’re more likely to aggregate,” said Kaminski Schierle.

“And on the flip side, when the solvation shell moves faster, the proteins become harder to trap, so they’re less likely to aggregate.”

“When researchers look for an aggregation inhibitor for Parkinson’s disease, they will typically use a buffer compound, but there’s been very little thought about how that buffer interacts with the protein itself,” Stephens said.

“Our results show that you need to understand the composition of the solvent in the cell to mimic conditions in the brain and ultimately end up with an inhibitor that works.”

“It’s so important to look at the whole picture, and that hasn’t happened,” says 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, such as salts and pH levels.

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“The failure to look at the entire cellular environment has limited the field, which may be why we don’t yet have an effective treatment for Parkinson’s disease.”

financing: The research was supported in part 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.

About this Parkinson’s disease research news

Author: Sara Collins
Source: University of Cambridge
Contact: Sarah Collins – University of Cambridge
Image: The image is in the public domain

Original research: Open access.
“Reduced water mobility contributes to increased α-synuclein aggregation” by Gabriele Kaminski Schierle et al. Angewandte Chemie


Decreased water mobility contributes to increased α-synuclein aggregation

The solvation shell is essential for protein folding and functioning, but how it contributes to protein misfolding and aggregation remains to be elucidated.

We show that the mobility of solvation shell H2O molecules influences the aggregation rate of the amyloid protein α-synuclein (αSyn), a protein associated with Parkinson’s disease. When the mobility of H2O within the solvation shell is reduced by the presence of NaCl, the αSyn aggregation rate increases.

Conversely, in the presence of CsI, solvation shell mobility is increased and αSyn aggregation is reduced. Changing the solvent from H2O to D2O leads to increased aggregation rates, indicating a solvent-driven effect.

We show that the increased aggregation rate is not directly due to a change in the structural conformations of αSyn, but is also influenced by a reduction in both H2O and αSyn mobility.

We propose that reduced mobility of αSyn contributes to increased aggregation by promoting intermolecular interactions.

The Valley Voice
The Valley Voice
Christopher Brito is a social media producer and trending writer for The Valley Voice, with a focus on sports and stories related to race and culture.


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