̽��ֱ�� of Cambridge - Amberley Stephens

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

sc604 — Tue, 15 Nov 2022 14:32:31 +0000

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 ̽��ֱ�� 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. ̽��ֱ��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.

̽��ֱ��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. ̽��ֱ��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.”

̽��ֱ��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.

To test the role of the solvation shell in the aggregation of proteins, the researchers used alpha-synuclein, the key protein implicated in Parkinson’s disease. Using Teraheartz spectroscopy, a powerful technique to study the behaviour of water molecules, they were able to observe the movement of the water molecules that surround the alpha-synuclein protein.

They then added two different salts in solution to the proteins: sodium chloride (NaCl), or regular table salt, and cesium iodide (CsI). ̽��ֱ��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 make much weaker bonds.

̽��ֱ��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 slower movement of the alpha-synuclein, and the aggregation rate increased. Conversely, when the cesium iodide was added, the water molecules sped up, and the aggregation rate decreased.

“In essence, when the water shell 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 more quickly, the proteins become harder to catch, so they’re less likely to aggregate.”

“When researchers are screening for an aggregation inhibitor for Parkinson’s disease, they will usually use a buffer composition, but there’s been very little thought on how that buffer is interacting with the protein itself,” said Stephens. “Our results show that you need to understand the composition of the solvent inside the cell in order to mimic the conditions you have 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 been happening,” said Kaminski 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 consideration, like salts and pH levels. ̽��ֱ��failure to look at the whole cellular environment has been limiting the field, which may be why we haven’t yet got an effective treatment for Parkinson’s disease.”

̽��ֱ��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.

Reference:
Amberley D Stephens et al. ‘Decreased Water Mobility Contributes to Increased α-Synuclein Aggregation.’ Angewandte Chemie International (2022). DOI: 10.1002/anie.202212063

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.

̽��ֱ��failure to look at the whole cellular environment has been limiting the field, which may be why we haven’t yet got an effective treatment for Parkinson’s disease

Gabriele Kaminski Schierle

Sherbrooke Connectivity Imaging Lab via Getty

Corpus callosum, left-right connections, in a Parkinson's brain

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Calcium may play a role in the development of Parkinson’s disease

sc604 — Mon, 19 Feb 2018 10:00:00 +0000

̽��ֱ��international team, led by the ̽��ֱ�� of Cambridge, found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alpha-synuclein, the protein associated with Parkinson’s disease. Excess levels of either calcium or alpha-synuclein may be what starts the chain reaction that leads to the death of brain cells.

̽��ֱ��findings, reported in the journal Nature Communications, represent another step towards understanding how and why people develop Parkinson’s. According to the charity Parkinson’s UK, one in every 350 adults in the UK – an estimated 145,000 in all – currently has the condition, but as yet it remains incurable.

Parkinson’s disease is one of a number of neurodegenerative diseases caused when naturally occurring proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated alpha-synuclein, also known as Lewy bodies, are the sign of Parkinson’s disease.

Curiously, it hasn’t been clear until now what alpha-synuclein actually does in the cell: why it’s there and what it’s meant to do. It is implicated in various processes, such as the smooth flow of chemical signals in the brain and the movement of molecules in and out of nerve endings, but exactly how it behaves is unclear.

“Alpha-synuclein is a very small protein with very little structure, and it needs to interact with other proteins or structures in order to become functional, which has made it difficult to study,” said senior author Dr Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology.

Thanks to super-resolution microscopy techniques, it is now possible to look inside cells to observe the behaviour of alpha-synuclein. To do so, Kaminski Schierle and her colleagues isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters which send signals from one nerve cell to another.

In neurons, calcium plays a role in the release of neurotransmitters. ̽��ֱ��researchers observed that when calcium levels in the nerve cell increase, such as upon neuronal signalling, the alpha-synuclein binds to synaptic vesicles at multiple points causing the vesicles to come together. This may indicate that the normal role of alpha-synuclein is to help the chemical transmission of information across nerve cells.

“This is the first time we’ve seen that calcium influences the way alpha-synuclein interacts with synaptic vesicles,” said Dr Janin Lautenschläger, the paper’s first author. “We think that alpha-synuclein is almost like a calcium sensor. In the presence of calcium, it changes its structure and how it interacts with its environment, which is likely very important for its normal function.”

“There is a fine balance of calcium and alpha-synuclein in the cell, and when there is too much of one or the other, the balance is tipped and aggregation begins, leading to Parkinson’s disease,” said co-first author Dr Amberley Stephens.

̽��ֱ��imbalance can be caused by a genetic doubling of the amount of alpha-synuclein (gene duplication), by an age-related slowing of the breakdown of excess protein, by an increased level of calcium in neurons that are sensitive to Parkinson’s, or an associated lack of calcium buffering capacity in these neurons.

Understanding the role of alpha-synuclein in physiological or pathological processes may aid in the development of new treatments for Parkinson’s disease. One possibility is that drug candidates developed to block calcium, for use in heart disease for instance, might also have potential against Parkinson’s disease.

̽��ֱ��research was funded in part by the Wellcome Trust, the Medical Research Council, Alzheimer’s Research UK, and the Engineering and Physical Sciences Research Council.

Reference
Janin Lautenschläger, Amberley D. Stephens et al. ‘C-terminal calcium binding of Alpha-synuclein modulates synaptic vesicle interaction.’ Nature Communications (2018). DOI: 10.1038/s41467-018-03111-4

Researchers have found that excess levels of calcium in brain cells may lead to the formation of toxic clusters that are the hallmark of Parkinson’s disease.

This is the first time we’ve seen that calcium influences the way alpha-synuclein behaves.

Janin Lautenschlӓger

Janin Lautenschläger

Tyrosine hydroxylase positive neuron stained with a synaptic marker

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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