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

Source: University of Cambridge

Water — the most abundant component of all cells in the body — plays a key role in how proteins fold, fold or fold, including those associated with Parkinson’s disease, new research suggests.

Researchers have focused primarily on the structure of proteins themselves when trying to find potential treatments for protein misfolding diseases.

However, researchers led by the University of Cambridge have discovered that when a protein begins to clump together, or aggregate, forming toxic clusters, the thin membrane is key to eventually killing brain cells.

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

When the shell is moving slowly, the proteins are more likely to be synthesized, and when the shell is moving faster, the proteins are less likely to be synthesized. The mobility of the shell changes 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 shell, known as the solvation shell, in the folding and function of proteins has been strongly debated in the past. This is the first time that the solvation shell plays a key role in protein misfolding and aggregation, which could have a significant impact on the search for therapeutics.

The results are reported in the journal Applied Chemistry International.

In developing potential treatments for protein misfolding diseases such as Parkinson’s and Alzheimer’s disease, researchers have been studying compounds that prevent the aggregation of key proteins: alpha-synuclein for Parkinson’s disease or amyloid-beta for Alzheimer’s disease. However, there are currently no effective treatments for both diseases, which affect millions worldwide.

“Amino acids determine the final structure of a protein, but when it comes to synthesis, the role of the solvation shell outside the protein has so far been overlooked,” said Professor Gabriele Kaminski-Schier from Cambridge’s Department of Chemical Engineering and Biotechnology, who led the study.

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

The solution shell glides over the protein like a lubricant. Dr. Amberly Stephenson, first author of the paper, said: “We wondered if the movement of water molecules in the protein’s solution shell is slower, so it might slow down the movement of the protein itself.”

To test the role of the solvation shell in protein synthesis, the researchers used alpha-synuclein, a key protein found in Parkinson’s disease. Using terahertz spectroscopy to study the behavior of water molecules, they were able to monitor the movement of water molecules around the alpha-synclin protein.

They then added two different salts to the proteins: sodium chloride (NaCl), or regular table salt, and cesium iodide (CCl). The ions in sodium chloride – Na+ and Cl – – bond strongly to the hydrogen and oxygen ions in water, while the ions in cesium iodide form very weak bonds.

The researchers found that when sodium chloride was added, strong hydrogen bonding reduced the mobility of water molecules in the solvation shell. This slows down the activity of alpha-synuclein, and increases its aggregation rate. On the contrary, when cesium iodide is added, the water molecules move to the surface, and the concentration decreases.

This shows the brain
Using a technique known as terahertz spectroscopy, the researchers found that the movement of the water-based shell around a protein can determine whether or not the protein folds. The image is in the public domain.

“Essentially, when the water shell shrinks, proteins have more time to interact with each other, so they’re more likely to aggregate,” says Kaminsky-Schierl.

“And on the flip side, when the solution shell moves faster, the proteins are harder to capture and less likely to aggregate.”

“Researchers often use a buffer when testing aggregate recovery for Parkinson’s disease, but little thought has been given to how this buffer interacts with the protein itself,” Stephens said.

“Our results show that in order to mimic the conditions you have in the brain and ultimately end up with a functional defense, you need to understand the composition of the solvent in the cell.”

“It’s very important to look at the whole picture, and that hasn’t happened,” Kaminsky-Schierl said.

“To effectively test whether a drug candidate works in a patient, you have to mimic cellular conditions, which means you have to take into account everything like salt and pH levels.

watch out

This shows the brain

“Not looking at the whole cellular environment is limiting the field, which may be why we don’t yet have effective treatments for Parkinson’s disease.”

Financial support 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.

So Parkinson’s disease research news

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

Preliminary study: Open Access.
Decreased water mobility contributes to α-Synuclein synthesisBy Gabriele Kaminski Schierle et al. Applied Chemistry


Decreased water mobility contributes to α-Synuclein synthesis

The solvation shell is important for protein folding and function, but how it contributes to protein disorder and aggregation remains to be elucidated.

We show that the mobility of solute shell H2O molecules affects the aggregation rate of the amyloid protein α-synuclein (αSyn), which is associated with Parkinson’s disease. When the mobility of H2O in the solvation shell decreases in NaCl, the aggregation rate of αSyn increases.

Conversely, in the presence of CsI, the mobility of the solution shell increases and the aggregation of αSyn decreases. Changing the solvent from H2O to D2O leads to an increased rate of fusion, indicating a solvent-driven effect.

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

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

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