Slow-moving water coat may make Parkinson’s disease proteins ‘stickier’

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

Source: University of Cambridge

Water – which makes up the majority of every cell in the body – plays a key role in how proteins, including those linked to Parkinson’s disease, fold, misfold or fold, according to a new study.

When trying to discover potential treatments for protein misfolding diseases, researchers focused primarily on the structure of the proteins themselves.

However, researchers led by the University of Cambridge have shown that the thin water shell is key to whether the protein begins to clump or clump together, forming toxic clumps that eventually kill brain cells.

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

When the shell moves slowly, the proteins are more likely to aggregate, and when the shell moves fast, the proteins are less likely to aggregate. The rate at which the shell moves 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 hydration or solvate shell, in protein folding and function has been strongly contested 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 published in the journal Applied Chemistry International.

In developing potential treatments for protein misfolding diseases such as Parkinson’s and Alzheimer’s, researchers have looked at compounds that can prevent the aggregation of key proteins: alpha-synuclein for Parkinson’s or amyloid-beta for Alzheimer’s. To date, however, there are no effective treatments for both conditions, which affect millions worldwide.

“It is the amino acids that determine the final structure of the protein, but when it comes to aggregation, the role of the solvation shell, which is located on the outside of the protein, has so far been neglected,” said Professor Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology. , who led the research.

“We wanted to know if this water shell plays a role in the behavior of the protein – this has been posited 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 like a lubricant. “We wondered if, if the movement of water molecules is slower in the solvation shell of a protein, it might slow down the movement of the protein itself,” said Dr. Amberley Stephens, first author of the paper.

To examine the role of the solvation shell in protein aggregation, the researchers used alpha-synuclein, a key 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 water molecules surrounding the protein alpha-synuclein.

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

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

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

“And on the other hand, when the solvation shell moves faster, the proteins are harder to capture, so they’re less likely to aggregate.”

“When researchers are looking for an aggregation inhibitor for Parkinson’s disease, they will usually 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 have to understand the composition of the solvent inside the cell in order to mimic the conditions you have in the brain and end up with an inhibitor that works.”

“It’s so important to look at the whole picture, and that wasn’t happening,” Kaminski told Schierle.

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

“Not looking at the entire cellular environment limits the field, which may be why we still don’t 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 at Robinson College, Cambridge.

About this Parkinson’s research news

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

Original research: Open access.
“Reduced water mobility contributes to increased α-synuclein aggregationGabriele Kaminski Schierle et al. applied chemistry

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Abstract

Reduced water mobility contributes to increased α-synuclein aggregation

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

We show that the mobility of H2O solvation shell molecules affects the rate of aggregation 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 rate of αSyn aggregation increases.

In contrast, in the presence of CsI, the mobility of the solvate shell increases and the aggregation of αSyn decreases. Changing the solvent from H2O to D2O leads to increased aggregation rates, indicating a solvent-driven effect.

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

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