Slow-moving shell of water can make Parkinson’s proteins ‘stickier’

Water — which makes up the majority 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.

When attempting to discover potential treatments for protein misfolding diseases, researchers have primarily focused 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 which eventually kill brain cells.

Using a technique known as Terahertz spectroscopy, the researchers have shown that the movement of the water-based shell surrounding 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 rate of movement of the shell is altered in the presence of certain ions, such as salt molecules, which are 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, in the folding and function of proteins has been strongly disputed in the past. This is the first time 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.

When developing potential treatments for protein misfolding diseases such as Parkinson’s and Alzheimer’s disease, researchers have been studying compounds which can prevent the aggregation of key proteins: alpha-synuclein for Parkinson’s disease or amyloid-beta for Alzheimer’s disease. To date however, there are no effective treatments for either condition, which affect millions worldwide.

“It’s the amino acids that determine the final structure of a protein, but when it comes to aggregation, the role of the solvation shell, which sits on the outside of a protein, has been overlooked until now,” said Professor Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology, who led the research. “We wanted to know whether this water shell plays a role in protein behaviour — 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, acting like a lubricant. “We wondered whether, if the movement of water molecules was slower in the solvation shell of a protein, it could slow the movement of the protein itself,” said Dr Amberley Stephens, the paper’s first author.

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